WORLD HEALTH ORGANIZATION

INTERNATIONAL AGENCY FOR RESEARCH ON CANCER

IARC Monographs on the Evaluation of Carcinogenic Risks to Humans

Overall Evaluations of Carcinogenicity:

An Updating of IARC Monographs

Volumes 1 to 42 

Supplement 7

Acetaldehyde

Acetamide

Acrylonitrile

ActinomycinD

Adriamycin

Aldrin

Aluminum Production

para-Aminoazobenzene

4-Aminobiphenyl

Amitrole

Anaesthetics, Volatile

Androgenic (anabolic) Steroids

Aniline

Arsenic and Arsenic Compounds

Asbestos

Auramine (technical-grade) and Manufacture of Auramine

Azathioprine

Benzene

Benzidine

Benzidine-based Dyes

Benzoyl Chloride

Betel Quid with and without Tobacco

Caprolactam

N,N-Bis(2-Chloroethyl)-2-Naphthylamine (Chlornaphazine)

Bis(Chloromethyl)Ether and Chloromethyl Methyl Ether (Technical-Grade)

Bitumens and Extracts of Steam-refined and Air-refined Bitumens

Boot and Shoe Manufacture and Repair

Bleomycins

Bracken Fern

1,4-Butanediol Dimethanesulphonate (Myleran)

Carbon Tetrachloride

Carpentry and Joinery

Chlorambucil

α-Chlorinated Toluenes

Chlorodifluoromethane

Chloroethyl Nitrosoureas (BCNU, CCNU & Methyl CCNU)

Chloroform

Chlorophenols

Chlorophenoxy Herbicides

Chloroprene

Cholesterol

Chrysoidine

Cisplatin
Clomiphene Citrate

Coal Gasification

Coal-Tar Pitches

Coal-Tars

Coke Production

Creosotes

Cyclamates

Cyclophosphamide

Dacarbazine

Dapsone

1,2-Dibromo-3-Chloropropane

ortho & para-Dichlorobenzene

3,3'-Dichlorobenzidine

Dichloromethane

1,3-Dichloropropene (Technical-Grade

Dieldrin

Diethylstilboestrol

3,3'-Dimethoxybenzidine (ortho-Dianisidine)

Dimethylcarbamoyl Chloride

Dimethyl Sulphate

1,4-Dioxane

Epichlorohydrin

Erionite

Ethylene Dibromide

Ethylene Thiourea

Fluorides (Inorganic, Used in Drinking-Water

5-Fluorouracil

Furniture and Cabinet-Making

Griseofulvin

Gyromitrin

Haematite and Ferric Oxide

Hexachlorobenzene

Hexachlorocyclohexanes

Hydralazine

Hydrazine

Iron & Steel Founding

Iron Dextran Complex

Isonicotinic Acid Hydrazide (Isoniazid)

Isopropyl Alcohol Manufacture (strong-acid process), Isopropyl Alcohol and Isopropyl Oils

Lead and Lead Compounds

Leather Goods Manufacture

Leather Tanning & Processing

Lumber and Sawmill Industries

Medroxyprogesterone Acetate

Melphalan

6-Mercaptopurine

Methotrexate

5-Methoxypsoralen

8-Methoxypsoralen (methoxsalen) plus Ultraviolet Radiation

Methyl Bromide

Methyl Chloride

4,4'-Methylene Bis(2-Methylaniline)

N-Methyl-N'-Nitro-N-Nitrosoguanidine (MNNG)

Methyl Parathion

Metronidazole

Mineral Oils

MOPP and Other Combined Chemotherapy Including Alkylating Agents

Mustard Gas (Sulphur Mustard)
1-Naphthylamine

2-Naphthylamine

1-Naphthylthiourea (ANTU)

Nitrogen Mustard

Oestrogens, Nonsteroidal

Oestrogen-Progestin Replacement Therapy

Oestrogen Replacement Therapy

Oestrogens, Steroidal

Oral Contraceptives, Combined

Oral Contraceptives, Sequential

Phenacetin and Analgesic Mixtures Containing Phenacetin

Phenazopyridine Hydrochloride

Phenelzine Sulphate

Phenobarbital

Phenylbutazone

N-Phenyl-2-Naphthylamine

Polybrominated Biphenyls

Polychlorinated Biphenyls

Prednisone

Procarbazine Hydrochloride

Progestins

Propylthiouracil

Pulp and Paper Manufacture

Reserpine

Rubber Industry

Saccharin

Shale Oils

Sodium-o-Phenylphenate

Soots

Spironolactone

Sulfafurazole (Sulphisoxazole)

Sulfamethoxazole

Talc

1,1,2,2-Tetrachloroethane

Tobacco Products, Smokeless

Tobacco Smoke

ortho-Toluidine

Treosulphan

4,5',8-Trimethylpsoralen

Triaziquone

Tris(2,3-dibromopropyl) phosphate

Uracil Mustard

Vinblastine Sulphate

Vincristine Sulphate

Vinyl Chloride

Vinylidine Chloride
ACETAMIDE

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 389) 

CAS No.: 60-35-5

Evidence for carcinogenicity to animals (sufficient) 

Acetamide produced benign and malignant liver tumours in rats following its oral administration 

[ref: 1-3]. In male mice, an increased incidence of malignant lymphomas was also observed [ref: 

3]. 

Overall evaluation

Acetamide is possibly carcinogenic to humans (Group 2B). 

For definition of the italicized terms, see Preamble Evaluation. 

Subsequent evaluation: Vol. 71 (1999)

Also see previous evaluation: Vol. 7 (1974)

References

1. IARC Monographs, 7, 197-202, 1974 

2. Flaks, B., Trevan, M.T. & Flaks, A. (1983) An electron microscope study of hepatocellular changes 

in the rat during chronic treatment with acetamide. Parenchyma, foci and neoplasms. 

Carcinogenesis, 4, 1117-1125 

3. Fleischman, R.W., Baker, J.R., Hagopian, M., Wade, G.G., Hayden, D.W., Smith, E.R., 

Weisburger, J.H. & Weisburger, E.K. (1980) Carcinogenesis bioassay of acetamide, hexanamide, 

adipamide, urea and p-tolylurea in mice and rats. J. environ. Pathol. Toxicol., 3, 149-170 

Synonyms

● Acetic acid amide 

● Ethanamide 

● Methane carboxamide 

Last updated: 13 April 1999 
ACTINOMYCIN D

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 80)

CAS No.: 50-76-0 

A. Evidence for carcinogenicity to humans (inadequate) 

A comparison was made in the USA between survivors of childhood cancer who developed second 

malignant neoplasms and controls, also survivors, matched on hospital, primary diagnosis, length of 

follow-up, site and dose of radiotherapy, and chronological period. Subjects who had received no 

radiotherapy, or who were believed to have some 'predisposing genetic syndrome', and whose 

second tumour had been diagnosed within six months of the first diagnosis, or with tumours that lay 

outside the field previously treated with radiation were excluded. Unexpectedly, cases had been 

treated much less often with actinomycin D than controls (relative risk, 0.13; upper 95% confidence 

limit, 0.47), and those who had been treated had received fewer courses of treatment (median, 2, 

compared to 6.5). For each type of primary childhood malignancy, except for bone tumours, the 

majority of cases had not been treated with actinomycin D. Second malignancies included soft-tissue 

sarcomas, haematological malignancies and various solid tumours. A relationship is plausible in view 

of the radiomimetic properties of actinomycin D, the simultaneous exposure of the treated patients 

to radiation, and the modal shape of radiation dose-effect curves in some laboratory systems [ref: 

1]. 

A single attempt to confirm this finding covered only eight second malignancies (meeting criteria 

comparable to those in the first study) occurring among 412 patients who had been treated with 

radiation for Wilms' tumour of whom 222 had also received actinomycin D. No similar reduction in 

risk was observed. This study differed from the original in the small sample size, the uniformity with 

respect to primary diagnosis and that the comparison was made with historical controls [ref: 2]. 

B. Evidence for carcinogenicity to animals (limited) 

Actinomycin D was tested for carcinogenicity in rats by intraperitoneal injection and by intragastric 

administration and in mice by repeated subcutaneous injections. It produced peritoneal sarcomas in 

rats following intraperitoneal injections [ref: 3,4] and a low incidence of subcutaneous sarcomas 

occurred in mice following repeated subcutaneous injections [ref: 3]. No tumour was observed in 

rats after intragastric administration of actinomycin D, but the duration of the experiment was short 

[ref: 5]. 

C. Other relevant data

Actinomycin D did not induce sister chromatid exchanges in peripheral blood lymphocytes of treated 

patients in one study [ref: 6]. 

Actinomycin D induced chromosomal aberrations and DNA strand breaks in human cells in vitro. It 

transformed mouse C3H 10T1/2 cells and induced chromosomal aberrations, sister chromatid 

exchanges, mutation, DNA strand breaks and unscheduled DNA synthesis, but not aneuploidy, in 

rodent cells in vitro. It induced sex-linked recessive lethal mutations in Drosophila. Actinomycin D 

did not cause chromosomal aberrations in plants. It was mutagenic to Neurospora crassa but not to 

Saccharomyces cerevisiae, and conflicting results were obtained for gene conversion and mitotic 

recombination. It did not induce DNA damage in Schizosaccharomyces pombe. It was not mutagenic 

to bacteria and did not induce prophage [ref: 6]. 

Overall evaluation
Actinomycin D is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 10 (1976)

References

1. D'Angio, G.J., Meadows, A., Miké, V., Harris, C., Evans, A., Jaffe, N., Newton, W., Schweisguth, 

O., Sutow, W. & Morris-Jones, P. (1976) Decreased risk of radiation-associated second malignant 

neoplasms in actinomycin-D-treated patients. Cancer, 37, 1177-1185 

2. Li, F.P., Yan, J.C., Sallan, S., Cassady, J.R., Jr, Danahy, J., Fine, W., Gelber, R.D. & Green, D.M. 

(1983) Second neoplasms after Wilms' tumor in childhood. J. natl Cancer Inst., 71, 1205-1209 

3. IARC Monographs, 10, 29-41, 1976 

4. Weisburger, J.H., Griswold, D.P., Prejean, J.D., Casey, A.E., Wood, H.B. & Weisburger, E.K. 

(1975) The carcinogenic properties of some of the principal drugs used in clinical cancer 

chemotherapy. Recent Results Cancer Res., 52, 1-17 

5. Philips, F.S. & Sternberg, S.S. (1975) Tests for tumor induction by antitumor agents. Recent 

Results Cancer Res., 52, 29-35 

6. IARC Monographs, Suppl. 6, 32-34, 1987 

Synonyms

● Actinomycin A IV 

● Actinomycin C1 

● Actinomycin D deriv. of 1H-pyrrolo(2,1-1)(1,4,7,10,13)oxatetra-azacyclohexadecine 

● Actinomycin D deriv. of 3H-phenoxaocardazine 

● Actinomycin I 

● Actinomycin IV 

● Actinomycin X1 

● Actinomycin-(threo-val-pro-sar-meval) 

● 10,10'-[(2-Amino-4,6-dimethyl-3-oxo-3H-phenoxazine-1,9-Diyl)bis(carbonylimino)]bis-

[dodecahydro-6,13-diisopropyl-2,5,9-trimethyl-1H-Pyrrolo-(2,1-1)(1,4,7,10,13)oxatetraazacyclohexadecine]-1,4,7,11,14-pentone 

● 1H-Pyrrolo(2,1-1)-(1,4,7,10,13)oxatetraazacyclohexadecine 

● 2-Amino-N,N'-bis-[hexadecahydro-2,5,9-trimethyl-6,13-bis(1-methylethyl)-1,4,7,11,14-

pentaoxo-1H-pyrrolo(2,1-1)(1,4,7,10,13)oxatetraazacyclohexadecin-10-yl]-4,6-dimethyl-3-

oxo3H-phenoxazine-1,9-dicarboxamide

● 2-Amino-N,N'-bis[hexadecahydro-6,13-diisopropyl2,5,9-trimethyl-1,4,7,11,14-pentaoxo-1H-pyrrolo(2,1-

1)(1,4,10,13)oxatetraazacyclohexadecin-10-yl]-

4,6-dimethyl-3-oxo-3H-phenoxazine-1,9-dicarboxamide 

● Bis(XI-lactone)N,N'-[(2-amino-4,6-dimethyl-3-oxo-3H-phenoxazine-1,9-diyl)bis-

[carbonylimino(3-hydroxy-1-oxobutylidene)imino(3-methyl-1-oxobutylidene)(tetrahydro-1Hpyrrole-1,2-diyl)carbonyl(methylimino)-(1-oxo-1,2-ethanediyl)]bis(N-methyl)L-valine 

● Cosmegen 

● Dactinomycin 

● Dactinomycin D 

● Dilactone actinomycin D acid 

● Dilactone actinomycindioic D acid 

● HBF 386 meractinomycin 

● N,N'-[(2-Amino-4,6-dimethyl-3-oxo-3H-phenoxazine-1,9-diyl)bis(carbonylimino[3-hydroxy1-oxo-butylidene(tetrahydro-1H-pyrrole-1,2-diyl)carbonyl(methylimino)(1-oxo-1,2-
ethanediyl)-])

bis(N-methyl-L-valine)bis-(ζ-lactone)](stereoisomer) 

● Oncostatin K 

Last updated: 9 March 1998 
ADRIAMYCIN

(Group 2A)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 81) 

CAS No.: 23214-92-8

Chem. Abstr. Name: (85-cis)-10-[(3-Amino-2,3,6-trideoxy-α-L-lyxohexapyranosyl)oxy]-

7,8,9,10-tetrahydro- 6,8,11-trihydroxy-8-(hydroxyacetyl)-l-methoxy-5,12-naphthacenedione

A. Evidence for carcinogenicity to humans (inadequate)

No epidemiological study of adriamycin as a single agent was available to the Working Group. 

Occasional case reports, especially in the presence of concurrent therapy with other putative 

carcinogens, such as ionizing radiation, alkylating agents and other potent oncotherapeutic drugs, 

do not constitute evidence of carcinogenesis.

In a large systematic follow-up of patients with Hodgkin's disease treated with an intensive 

chemotherapeutic combination including adriamycin (plus vinblastine, bleomycin and dacarbazine) 

but no alkylating agent, preliminary evidence suggested no excess of acute nonlymphocytic 

leukaemia in the first decade after therapy [ref: 1]. 

B. Evidence for carcinogenicity to animals (sufficient)

Adriamycin was tested for carcinogenicity in rats by a single intravenous injection, producing 

mammary tumours [ref: 2-5], and by single or repeated subcutaneous injections, producing local 

sarcomas and mammary tumours [ref: 6,7]. Intravesicular instillation of adriamycin in rats resulted 

in a low incidence of bladder papillomas and enhanced the incidence of bladder tumours induced by 

N-nitroso-N-(4-hydroxybutyl)-N-butylamine [ref: 8]. 

C. Other relevant data

Adriamycin induced chromosomal aberrations in treated patients in one of two studies and sister 

chromatid exchanges in both studies. In another study, cisplatin-adriamycin combination 

chemotherapy induced sister chromatid exchanges in peripheral blood lymphocytes of treated 

patients. DNA strand breaks were induced in the cells of treated patients in one study [ref: 9].

Adriamycin has been tested extensively for genetic effects in a wide variety of tests in vivo and in 

vitro, giving consistently positive results. It induced chromosomal aberrations, micronuclei, sister 

chromatid exchanges and DNA damage in rodents in vivo and chromosomal aberrations, 

micronuclei, sister chromatid exchanges and DNA damage in human cells in vitro. It transformed 

virus-infected Fischer rat embryo cells and induced chromosomal aberrations, sister chromatid 

exchanges, mutation and DNA damage in cultured rodent cells. Adriamycin induced sex-linked 

recessive lethal mutations in Drosophila, chromosomal aberrations in plants and mutation in fungi. 

It was mutagenic to bacteria and induced DNA damage [ref: 9]. 

Overall evaluation

Adriamycin is probably carcinogenic to humans (Group 2A).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 10 (1976)
References

1. Valagussa, P., Santoro, A., Kenda, R., Fossati Bellani, F., Franchi, F., Banfi, A., Rilke, F. & 

Bonadonna, G. (1980) Second malignancies in Hodgkin's disease: a complication of certain forms of 

treatment. Br. med. J., i, 216-219

2. IARC Monographs, 10, 43-49, 1976

3. Marquardt, H., Philips, F.S. & Sternberg, S.S. (1976) Tumorigenicity in vivo and induction of 

malignant transformation and mutagenesis in cell cultures by adriamycin and daunomycin. Cancer 

Res., 36, 2065-2069

4. Solcia, E., Ballerini, L., Bellini, O., Sala, L. & Bertazolli, C. (1978) Mammary tumors induced in 

rats by adriamycin and daunomycin. Cancer Res., 38, 1444-1446

5. Bucciarelli, E. (1981) Mammary tumor induction in male and female Sprague-Dawley rats by 

adriamycin and daunomycin. J. natl Cancer Inst., 66, 81-84

6. Maltoni, C. & Chieco, P. (1975) Adriamycin: a new potent carcinogen (Ital.). Osp. Vita, 2, 107-

109

7. Casazza, A.M., Bellini, O., Formelli, F., Giuliani, F., Lenaz, L. & Magrini, U. (1977) Tumors and 

dental abnormalities after treatment of infant rats with adriamycin. Tumori, 63, 331-338

8. Ohtani, M., Fukushima, S., Okamura, T., Sakata, T., Ito, N., Koiso, K. & Niijima, T. (1984) Effects 

of intravesical instillation of antitumor chemotherapeutic agents on bladder carcinogenesis in rats 

treated with N-butyl-N-(4-hydroxybutyl)nitrosamine. Cancer, 54, 1525-1529

9. IARC Monographs, Suppl. 6, 35-39, 1987 

Synonyms

● 10-[(3-Amino-kg,6-trideoxy-D-lyxohexopyranosyl)oxy]-8-glycolcyl-7,8,9,10-tetrahydro6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione 

● Doxorubicin 

● F.I. 106 

● 1,2,3,4,6,11-Hexahydro-4β,5,12-trihydroxy-4-(hydroxyacetyl)-10- methoxy-6,11-

dioxonaphthacen-1β-yl-3-amino-2,3,6-trideoxy-α-L-lyxohexopyranoside 

● 14-Hydroxydaunomycin 

● 14'-Hydroxydaunomycin 

● NSC 123127 

Last updated: 11 February 1998 
ALDRIN

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 88) 

CAS No.: 309-00-2 

A. Evidence for carcinogenicity to humans (inadequate) 

Specific mention of aldrin in analytical epidemiological studies is limited to reports of follow-up of 

two cohorts of men employed in its manufacture in plants where dieldrin and endrin (and, in one, 

telodrin) were also manufactured [ref: 1-4]. In the most recent report of the first of these cohorts 

[ref: 3], 232 of 233 exposed workers were successfully followed from four to 29 (mean, 24) years, 

with duration of exposure to pesticides varying between four and 27 (mean, 11) years. There were 

nine deaths from cancer with 12 expected (standardized mortality ratio [SMR], 75; 95% confidence 

interval, 25-125). In the second cohort [ref: 4], 90% of 1155 men were followed for 13 years or 

more. Mortality from all cancers was not increased (SMR, 82; 56-116), although there were 

apparent increases in mortality from cancers of the oesophagus, rectum and liver, based on very 

small numbers. 

B. Evidence for carcinogenicity to animals (limited) 

Aldrin was tested for carcinogenicity by the oral route in mice and rats. In mice, it produced 

malignant liver neoplasms [ref: 1,5]. In rats, the incidence of thyroid tumours was increased in 

exposed animals in one study ref: 5], but this could not be clearly associated with treatment; three 

other studies in rats gave negative results [ref: 1,6] and one was inadequate [ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of aldrin in humans. It did not induce 

dominant lethal mutations in mice. In single studies, it induced chromosomal aberrations in bonemarrow cells of rats and mice, but no micronuclei in bone-marrow cells of mice treated in vivo. It 

induced chromosomal aberrations in cultured human lymphocytes; studies of DNA damage in 

human and rodent cells in vitro were inconclusive. Aldrin inhibited intercellular communication in 

both human and rodent cell systems. It did not induce sex-linked recessive lethal mutations in 

Drosophila but was mutagenic to yeast. It was not mutagenic to bacteria and did not induce 

breakage of plasmid DNA [ref: 7]. 

Overall evaluation

Aldrin is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 5 (1974)

References

1. IARC Monographs, 5, 25-38, 1974 

2. Van Raalte, H.G.S. (1977) Human experience with dieldrin in perspective. Ecotoxicol. environ. 

Saf., 1, 203-210 
3. Ribbens, P.H. (1985) Mortality study of industrial workers exposed to aldrin, dieldrin and endrin. 

Int. Arch. occup. environ. Health, 56, 75-79 

4. Ditraglia, D., Brown, D.P., Namekata, T. & Iverson, N. (1981) Mortality study of workers 

employed at organochlorine pesticide manufacturing plants. Scand. J. Work Environ. Health, 7 

(Suppl. 4), 140-146 

5. National Cancer Institute (1978) Bioassays of Aldrin and Dieldrin for Possible Carcinogenicity 

(Tech. Rep. Ser. No. 21; DHEW Publ. No. (NIH) 78-821), Bethesda, MD, US Department of Health, 

Education and Welfare 

6. Deichmann, W.B., Macdonald, W.E. & Lu, F.C. (1979) Effects of chronic aldrin feeding in two 

strains of female rats and a discussion on the risks of carcinogens in man. In: Deichmann, W.B., 

ed., Toxicology and Occupational Medicine, New York, Elsevier/North-Holland, pp. 407-413 

7. IARC Monographs, Suppl. 6, 57-59, 1987 

Synonyms

● 1,2,3,4,10,10-Hexachloro-1,4,4a,5,8,8a-hexahydro-1,4-endo-exo-5,8-dimethanonaphthalene 

● 1,2,3,4,10,10-Hexachloro-1,4,4a,5,8,8a-hexahydro-endo-1,4,-exo-5,8-

dimethanonaphthalene 

● 1,2,3,4,10,10-Hexachloro-1,4,4a,5,8,8a-hexahydro-exo-1,4-endo-5,8,-

dimethanonaphthalene 

● 1,2,3,4,10,10-Hexachloro-1,4,4a,8,8a-hexahydro-endo,exo-1,4:5,8-dimethanonaphthalene 

● Compound 118 

● ENT 15,949 

● Hexachlorohexahydro-endo-exo-dimethanonaphthalene 

● HHDN 

Last updated: 9 March 1998 
ALUMINIUM PRODUCTION

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 89) 

A. Evidence for carcinogenicity to humans (sufficient)

The lung has been the most common site identified for which there is an excess cancer risk in 

populations of aluminium production workers. Overall, early studies showed a borderline excess in 

relative risk, with some studies showing a doubling of risk and some showing no excess. Smoking 

histories were not given in any of these studies. In one study in which populations in the industry 

were compared on the basis of their exposures to pitch volatiles, there was a relationship between 

incidence of lung cancer and length of exposure, and there was a significant excess of cancer among 

workers who had worked for 21 years or more [ref: 1]. 

In three studies in the same aluminium-producing area, an increased risk of bladder cancer was 

associated with work in aluminium production in plants where primarily the Söderberg process was 

used. In one study in which smoking was controlled for, while there was a borderline excess in risk 

for nonsmokers, the risk for smokers was markedly increased [ref: 1]. 

Excess mortality from lymphosarcoma/reticulosarcoma was noted in two cohort studies, which 

covered partially the same population [ref: 1]. 

Statistically significant excess risks for pancreatic cancer and for leukaemia were noted as isolated 

findings in two studies and in one study, respectively [ref: 1]. 

Some of these studies have been updated. In Canada, the mortality of a large group of men 

employed in aluminium production using the Söderberg process was examined between 1950 and 

1977, and compared with the pertinent rates for the Province of Quebec. Workers 'ever' exposed to 

condensed pitch volatiles ('tar') exhibited significantly increased mortality from all cancers (304 

observed, 246.6 expected), and from oesophageal and stomach cancer (50 observed, 32.8 

expected), lung cancer (101 observed, 70.7 expected) and other malignancies (60 observed, 45.3 

expected). Analysis of lung cancer mortality by increasing years of exposure, tar-years of exposure 

and years since first exposure to tar revealed a steady, statistically significant, increasing trend. No 

similar clear-cut pattern was noted for cancers of the oesophagus or stomach. Deaths from cancer 

of the urinary organs (20 observed, 13.7 expected) and bladder (12 observed, 7.5 expected) were 

more numerous than expected, but not significantly so. Nonetheless, when mortality from cancer at 

each of these sites was analysed according to tar-years of exposure, significantly increasing trends 

were noted. Among workers 'never' exposed to tar, mortality was not elevated above expectancy for 

any cancer site [ref: 2]. 

The risk for bladder cancer was further investigated in a case-control study based on 488 bladder 

cancer cases occurring in 1970-1979 in regions of the Province of Quebec where five aluminium 

plants were operating using the Söderberg production process. A statistically significant odds ratio 

of 2.7, based on 45 exposed cases, was found for employment in Söderberg reactor rooms. The risk 

increased steadily with time worked in this department, with odds ratios ranging from 1.9 for those 

who had worked for one to nine years, up to 4.5 for those who had worked in the department for 

over 30 years. This trend was statistically significant. The risk also increased steadily with increasing 

estimated exposure to 'tar' and polycyclic aromatic hydrocarbons and remained almost unchanged 

after adjusting for cigarette smoking, length of employment and age [ref: 3]. This set of data was 

later reanalysed in an attempt to quantify the noted exposure-response relationship. More refined 

quantitative estimates of historical workplace exposure and more complete information on smoking 

habits were used. Estimates of bladder cancer risk were highly statistically significantly related to 

three exposure indices: years spent in the Söderberg potroom; cumulative exposure to benzenesoluble material, an indicator of overall exposure to tar volatiles; and cumulative exposure to 

benzo[a]pyrene, an indicator of exposure to polycyclic aromatic hydrocarbons. It was estimated that 

an aluminium smelter worker exposed to 0.2 mg/m3 benzene-soluble material for 40 years has a 
likelihood of contracting bladder cancer approximately 2.5-fold that of a nonexposed person. 

Workers exposed to 5 μg/m3 benzo[a]pyrene for 40 years had a likelihood of contracting bladder 

cancer approximately five-fold that of an unexposed person. Smoking did not confound the 

relationship [ref: 4]. 

There is sufficient evidence that certain exposures occurring during aluminium production cause 

cancer. Pitch volatiles have fairly consistently been suggested in epidemiological studies as being 

possible causative agents. Dose-response relationships have been clarified, and confounding by 

smoking controlled for. 

B. Other relevant data

No effect on the incidence of sister chromatid exchanges in peripheral blood lymphocytes of workers 

in the aluminium industry was observed in one study. No increase in the incidence of structural 

chromosomal aberrations was observed in the lymphocytes of workers in an aluminium reduction 

plant exposed to coal-tar pitch volatiles (anode production area); analyses of the semen showed no 

effect on sperm morphology, sperm count or double-Y bodies, when compared to matched controls 

from the same area, but there was an excess of mutagenic urine samples among these workers as 

compared to controls. Urine samples from workers in an anode manufacturing plant were not 

mutagenic to Salmonella typhimurium in the presence of a metabolic system. Methanol extracts of 

sputum and bronchial expectorates, pooled separately for smoking and for nonsmoking workers in a 

Söderberg process potroom, were tested for mutagenicity to S. typhimurium in the presence of an 

exogenous metabolic system. Expectorates from smokers were mutagenic, while those from 

nonsmokers yielded inconclusive results; samples from pooled controls were inactive [ref: 5]. 

Overall evaluation

Aluminium production is carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 34 (1984)

References

1. IARC Monographs, 34, 37-64, 1984 

2. Gibbs, G.W. (1985) Mortality of aluminum reduction plant workers, 1950 through 1977. J. occup. 

Med., 27, 761-770 

3. Thériault, G., Tremblay, C., Cordier, S. & Gingras, S. (1984) Bladder cancer in the aluminium 

industry. Lancet, i, 947-950 

4. Armstrong, B.G., Tremblay, C.G., Cyr, D. & Thériault, G.P. (1986) Estimating the relationship 

between exposure to tar volatiles and the incidence of bladder cancer in aluminum smelter workers. 

Scand. J. Work Environ. Health, 12, 486-493 

5. IARC Monographs, Suppl. 6, 57-59, 1987 

Last updated: 6 February 1998 
para-AMINOAZOBENZENE

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 390) 

CAS No.: 60-09-3

Chem. Abstr. Name: 4-(Phenylazo)benzenamine

Evidence for carcinogenicity to animals (sufficient)

para-Aminoazobenzene produced liver tumours in rats following its oral administration and produced 

epidermal tumours in rats after application to the skin [ref: 1]. In mice, hepatomas were found in 

50-100% of males after one or four intraperitoneal injections of para-aminoazobenzene, compared 

to 3% in controls and in females. In two other strains of mice, 93% and 46% of males had 

hepatomas at 11 months of age after a single intraperitoneal injection of the compound [ref: 2]. 

When pregnant and newborn male and female mice were administered high doses of paraaminoazobenzene by subcutaneous injection, there was a borderline increase in the incidences of 

tumours of the liver and of the haematopoietic and lymphoid tissues in mice treated transplacentally 

and a statistically significant increase in the incidence of these tumours in neonates [ref: 3]. 

Overall evaluation

para-Aminoazobenzene is possibly carcinogenic to humans (Group 2B). 

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 8 (1975)

References

1. IARC Monographs, 8, 53-60, 1975 

2. Delclos, K.B., Tarpley, W.G., Miller, E.C. & Miller, J.A. (1984) 4-Aminoazobenzene and N,Ndimethyl-4-aminoazobenzene as equipotent hepatic carcinogens in male C57BL/6xC3H/HeF1 mice 

and characterization of N-(deoxyguanosin-8-yl)-4-aminoazobenzene as the major persistent hepatic 

DNA-bound dye in these mice. Cancer Res., 44, 2540-2550 

3. Fujii, K. (1983) Induction of tumors in transplacental or neonatal mice administered 3'-methyl-4-

dimethylaminoazobenzene or 4-aminoazobenzene. Cancer Lett., 17, 321-325 

Synonyms

● AAB 

● Aminoazobenzene 

● 4-Aminoazobenzene 

● 4-Amino-1,1'-azobenzene 

● Aminoazobenzene [indicator] 

● 4-Aminoazobenzol 

● para-Aminoazobenzol 

● para-Aminoazotoluene 

● para-Aminodiphenylimide 

● Aniline Yellow 

● 4-Benzeneazoaniline 
● Brasilazina oil Yellow G 

● Ceres Yellow R 

● Fast spirit Yellow 

● Fast spirit Yellow AAB 

● Fat Yellow AAB 

● Induline R 

● Oil-sol. aniline Yellow 

● Oil Yellow AAB 

● Oil Yellow AN 

● Oil Yellow B 

● Oil Yellow 2G 

● Oil Yellow R 

● Organol Yellow 

● Organol Yellow 2A 

● Paraphenolazo aniline 

● para-(Phenylazo)aniline 

● 4-(Phenylazo)benzenamine 

● para-Phenylazophenylamine 

● Solvent Yellow 1 

● Somalia Yellow 2G 

● Stearix brown 4R 

● Sudan Yellow R 

● Sudan Yellow RA 

Last updated: 27 February 1998 
4-AMINOBIPHENYL

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 91) 

CAS No.: 92-67-1 

Chem. Abstr. Name: 4-Biphenylamine 

A. Evidence for carcinogenicity to humans (sufficient)

The extent of bladder cancer risk associated with exposure to 4-aminobiphenyl was first 

documented by a descriptive study in the mid 1950s: of 171 men exposed to 4-aminobiphenyl 

between 1935 and 1955, 19 developed bladder tumours [ref: 1]. This observation appears to have 

been sufficient to prompt discontinuation of production and to prevent widespread use of the 

chemical. In 1955, a surveillance programme was initiated on workers reported to have been 

exposed to the chemical: during the following 14 years, 541 men were kept under surveillance by 

clinical and laboratory examinations; 86 had positive or suspicious cytology of the urinary sediment 

some time during the observation period, and 43 developed histologically confirmed carcinoma of 

the urinary bladder [ref: 2].

The hypothesis that another potential carcinogen, 4-nitrobiphenyl, was actually associated with the 

increased bladder cancer risk among these workers was raised but was dismissed by careful 

reconsideration of the processes involved and the possible exposures of the workers under 

surveillance [ref: 3].

In a survey of cancer mortality among workers at a chemical plant producing a variety of chemicals, 

a ten-fold increase in mortality from bladder cancer was reported. All of the nine cases on which the 

excess was based had started work in the plant before 1949, and 4-aminobiphenyl was known to 

have been used from 1941 until 1952 [ref: 4]. 

B. Evidence for carcinogenicity to animals (sufficient)

4-Aminobiphenyl was tested for carcinogenicity by oral administration in rabbits, dogs and mice and 

by subcutaneous administration in rats. Following its oral administration, it induced bladder 

papillomas and carcinomas in rabbits [ref: 1] and dogs [ref: 1,5], and neoplasms at various sites in 

mice, including dose-related increases in the incidences of angiosarcomas [ref: 6], hepatocellular 

tumours [ref: 1,6] and bladder carcinomas [ref: 1,6]. Following its subcutaneous administration to 

rats, it induced tumours of the mammary gland and intestine [ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of 4-aminobiphenyl in humans. It formed 

DNA adducts in the bladder epithelium of dogs and protein adducts in serum albumin of rats treated 

in vivo. It induced mutation in human fibroblasts and mutation, DNA strand breaks and unscheduled 

DNA synthesis in cultured rodent cells. 4-Aminobiphenyl was mutagenic to bacteria and induced 

prophage [ref: 7]. 

Overall evaluation

4-Aminobiphenyl is carcinogenic to humans (Group 1). 

For definition of the italicized terms, see Preamble Evaluation.
Also see previous evaluation: Vol. 1 (1972)

References

1. IARC Monographs, 1, 74-79, 1972 

2. Melamed, M.R. (1972) Diagnostic cytology of urinary tract carcinoma. A review of experience with 

spontaneous and carcinogen induced tumors in man. Eur. J. Cancer, 8, 287-292 

3. Melick, W.F. (1972) Bladder carcinoma and xenylamine. New Engl. J. Med., 287, 1103 

4. Zack, J.A. & Gaffey, W.R. (1983) A mortality study of workers employed at the Monsanto 

Company plant in Nitro, West Virginia. Environ. Sci. Res., 26, 575-591 

5. Block, N.L., Sigel, M.M., Lynne, C.M., Ng, A.B. & Grosberg, R.A. (1978) The initiation, progress, 

and diagnosis of dog bladder cancer induced by 4-aminobiphenyl. Invest. Urol., 16, 50-54 

6. Schieferstein, G.J., Littlefield, N.A., Gaylor, D.W., Sheldon, W.G. & Burger, G.T. (1985) 

Carcinogenesis of 4-aminobiphenyl in BALB/cStCr1fC3HfNctr mice. Eur. J. Cancer clin. Oncol., 21, 

865-873 

7. IARC Monographs, Suppl. 6, 60-63, 1987 

Synonyms

● para-Aminobiphenyl 

● para-Aminodiphenyl 

● 4-Aminodiphenyl 

● para-Biphenylamine 

● para-Phenylaniline 

● Xenylamine 

Last updated: 6 February 1998 
AMITROLE

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 92) 

CAS No.: 61-82-5

Chem. Abstr. Name: 1H-1,2,4-Triazol-3-amine 

A. Evidence for carcinogenicity to humans (inadequate)

In a small cohort study of 348 Swedish railroad workers exposed for 45 days or more to amitrole, 

2,4-D or 2,4,5-T and to other organic (e.g., monuron and diuron) and inorganic chemicals (e.g., 

potassium chlorate), there was an excess of deaths from malignant neoplasms (17 observed, 11.9 

expected). There was a statistically significant excess of all cancers among those exposed to 

amitrole and chlorophenoxy herbicides: six deaths from cancer with 2.9 expected, of which all six - 

with 1.8 expected (p < 0.005) - occurred in those first exposed ten years or more before death. No 

significant excess was seen among those exposed mainly to amitrole: five deaths from cancer with 

3.3 expected; three deaths with two expected occurring in those first exposed ten years or more 

before death [ref: 1]. The role of amitrole exposure is therefore not possible to evaluate. 

B. Evidence for carcinogenicity to animals (sufficient)

Amitrole was tested for carcinogenicity in mice by oral administration, skin application and 

transplacental exposure, in rats by oral and subcutaneous administration and in hamsters by oral 

administration. After oral administration, it produced thyroid tumours and benign and malignant liver 

tumours in mice of each sex, benign and malignant thyroid tumours in male and female rats and 

benign pituitary tumours in female rats [ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of amitrole in humans.

Amitrole did not induce micronuclei in bone-marrow cells of mice or unscheduled DNA synthesis in 

hepatocytes of rats treated in vivo. It induced transformation of Syrian hamster embryo cells and 

increased the incidence of sister chromatid exchanges in Chinese hamster ovary cells; both positive 

and negative results were reported for mutation in cultured rodent cells. Amitrole did not induce sexlinked recessive lethal mutations or aneuploidy in Drosophila; it induced chromosomal aberrations in 

plants. Both positive and negative results were obtained in assays for gene conversion and mutation 

in fungi, but amitrole induced aneuploidy. It was not mutagenic to bacteria and did not induce DNA 

damage [ref: 2]. 

Overall evaluation

Amitrole is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Subsequent evaluation: Vol. 79 (2001)

Also see previous evaluations: Vol. 7 (1974); Vol. 41 (1986)

References
1. IARC Monographs, 41, 293-317, 1986

2. IARC Monographs, Suppl. 6, 64-67, 1987 

Synonyms

● 3-Amino-s-triazole 

● 3-Amino-1,2,4-triazol 

● Aminotriazole 

● 2-Aminotriazole 

● 3-Aminotriazole 

● 3-Amino-1,2,4-triazole 

● 3-Amino-1H-1,2,4-triazole 

● 2-Amino-1,3,4-triazole 

● 5-Amino-1H-1,2,4-triazole 

● 5-Amino-1,2,4-triazole 

● Amitrol 

● Amitrol 90 

● Amizol 

● AT 

● 3,A-T 

● ATA 

● Azaplant 

● Cytrol 

● Cytrole 

● ENT 25445 

● Herbidal total 

● 1,2,4-Triazole-3-amine 

Last updated: 27 February 1998 
ANAESTHETICS, VOLATILE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 93) 

A. Evidence for carcinogenicity to humans (inadequate for volatile anaesthetics) 

Data from postal surveys of cancer incidence among working populations showed a higher rate of 

cancer among female operating-room personnel than among controls [ref: 1-4], partly reflecting an 

excess of leukaemia and lymphoma [ref: 2]. In one of the studies [ref: 4], a higher rate of cancer 

was reported among dental assistants with relatively heavy exposure to anaesthetics, reflecting a 

higher prevalence of cervical and uterine cancer in women with heavier exposure to anaesthetics 

than in those with a lighter exposure (significant only for cancer of the cervix). All of these postal 

surveys had major shortcomings [ref: 5], with response rates varying from 40-82%. Five mortality 

studies were carried out on anaesthetists [ref: 6-10]. A deficiency of deaths from cancer was seen in 

four [ref: 6,8-10]; however, in one study [ref: 6], there was an excess of deaths from lymphoma 

and myeloma (17 observed, 8.9 expected, with a ratio of 1.91 [95% confidence interval, 1.2-2.6) 

and, in another, a possible excess of cancer of the pancreas [ref: 7]. Cancer incidence was also 

studied in 28 235 registered nurses. Minor excesses of breast cancer, lymphoma and acute 

myelogenous leukaemia were balanced by deficits in cancers at other sites. No significant difference 

was found for active operation and anaesthetic nurses as compared to the female Norwegian 

population [ref: 11]. In a study of the incidence of cancer among offspring born to nurse 

anaesthetists, three neoplasms occurred in two of 434 children born to anaesthetists who had 

worked during pregnancy (a neuroblastoma and a carcinoma of the thyroid in one, and a carcinoma 

of the parotid in the other) and one leukaemia among the 261 children born to anaesthetists who 

had not worked during pregnancy [ref: 12]. 

It is not possible to consider exposure to different volatile anaesthetics separately, although the 

study of US anaesthesiologists working during 1930-1946 [ref: 10] concerned the period before 

fluorinated anaesthetic agents were introduced in the 1950s. 

B. Evidence for carcinogenicity to animals (inadequate for enflurane, halothane, isoflurane, 

methoxyflurane and nitrous oxide) 

Enflurane was tested for carcinogenicity by inhalation in one strain of mice at the maximum 

tolerated dose [ref: 13] and at several dose levels in a limited study in which treatment started in 

utero [ref: 14]. No treatment-related neoplasm was observed. 

Halothane was tested for carcinogenicity by inhalation in mice and rats. When mice were exposed in 

utero and then three times weekly for 78 weeks at the maximum tolerated dose [ref: 15] or 24 

times at several dose levels [ref: 14], no treatment-related neoplasm was observed. No carcinogenic 

effect was seen in rats exposed to a low level of halothane alone or in combination with nitrous 

oxide [ref: 16]. 

Isoflurane was tested for carcinogenicity by inhalation in one strain of mice. It induced liver tumours 

in one experiment [ref: 1] but no treatment-related neoplasm in another [ref: 14]. Both 

experiments had limitations. 

Methoxyflurane was tested for carcinogenicity in mice by inhalation in utero in one limited study. No 

treatment-related neoplasm was observed [ref: 14]. 

Nitrous oxide was tested for carcinogencity by inhalation in mice and rats. In one limited study in 

mice in which exposure started in utero, no treatment-related neoplasm was observed [ref: 14]. No 

carcinogenic effect was seen in rats exposed chronically to a low dose of nitrous oxide alone or in 

combination with halothane [ref: 16]. 
C. Other relevant data

Studies in hospital personnel exposed to inhalation anaesthetics showed an increased frequency of 

chromosomal aberrations but not of sister chromatid exchanges in peripheral blood lymphocytes 

[ref: 17,18]. 

Neither enflurance nor halothane induced dominant lethal mutations in rodents in vivo, and 

halothane did not induce chromosomal aberrations, micronuclei or sister chromatid exchanges in 

rodents treated in vivo [ref: 19]. 

Divinyl ether and fluroxene induced sister chromatid exchanges in cultured Chinese hamster ovary 

cells and mutation in bacteria. Negative results were obtained in these tests with halothane, 

enflurane, diethyl ether, isoflurane, methoxyflurane and nitrous oxide. Halothane caused gene 

conversion and mutation in yeast under conditions that enhanced endogenous levels of cytochrome 

P450. Diethyl ether was not mutagenic to fungi. Cyclopropane was not mutagenic to bacteria [ref: 

19]. 

Overall evaluation

Anaesthetics, volatile are not classifiable as to their carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see General considerations on volatile anaesthetics: Vol. 11 (1976) (p. 285) 

References

1. IARC Monographs, 11, 285-293, 1976 

2. American Society of Anesthesiologists Ad Hoc Committee on the Effect of Trace Anesthetics on the 

Health of Operating Room Personnel (1974) Occupational disease among operating room personnel: 

a national study. Anesthesiology, 41, 321-340 

3. Spence, A.A., Cohen, E.N., Brown, B.W., Jr, Knill-Jones, R.P. & Himmelberger, D.U. (1977) 

Occupational hazards for operating room-based physicians. Analysis of data from the United States 

and the United Kingdom. J. Am. med. Assoc., 238, 955-959 

4. Cohen, E.N., Brown, B.W., Wu, M.L., Whitcher, C.E., Brodsky, J.B., Gift, H.C., Greenfield, W., 

Jones, T.W. & Driscoll, E.J. (1980) Occupational disease in dentistry and chronic exposure to trace 

anesthetic gases. J. Am. dent. Assoc., 101, 21-31 

5. Vessey, M.P. (1978) Epidemiological studies of the occupational hazards of anaesthesia - a 

review. Anaesthesia, 33, 430-438 

6. Bruce, D.L., Eide, K.A., Linde, H.W. & Eckenhoff, J.E. (1968) Causes of death among 

anesthesiologists: a 20-year survey. Anesthesiology, 29, 565-569 

7. Doll, R. & Peto, R. (1977) Mortality among doctors in different occupations. Br. med. J., i, 1433-

1436 

8. Bruce, D.L., Eide, K.A., Smith, N.J., Seltzer, F. & Dykes, M.H.M. (1976) A prospective survey of 

anesthesiologist mortality, 1967-1971. Anesthesiology, 41, 71-74 

9. Lew, E.A. (1979) Mortality experience among anesthesiologists, 1954-1976. Anesthesiology, 51, 

195-199 
10. Linde, H.W., Mesnick, P.S. & Smith, N.J. (1981) Causes of death among anesthesiologists: 1930-

1946. Anesth. Analg., 60, 1-7 

11. Lund, E. (1985) Cancer among nurses especially in relation to exposure to anaesthetic gases 

(Norv.). Tidsskr. Laeg., 105, 572-575 

12. Corbett, T.H., Cornell, R.G., Endres, J.L. & Lieding, K. (1974) Birth defects among children of 

nurse-anesthetists. Anesthesiology, 41, 341-344 

13. Baden, J.M., Egbert, B. & Mazze, R.I. (1982) Carcinogen bioassay of enflurane in mice. 

Anaesthesiology, 56, 9-13 

14. Eger, E.I., White, A.E., Brown, C.L., Biava, C.G., Corbett, T.H. & Stevens, W.C. (1978) A test of 

the carcinogenicity of enflurane, isoflurane, halothane, methoxyflurane, and nitrous oxide in mice. 

Anesth. Analg., 57, 678-694 

15. Baden, J.M., Mazze, R.I., Wharton, R.S., Rice, S.A. & Kosek, J.C. (1979) Carcinogenicity of 

halothane in Swiss/ICR mice. Anesthesiology, 51, 20-26 

16. Coate, W.B., Ulland, B.M. & Lewis, T.R. (1979) Chronic exposure to low concentrations of 

halothane-nitrous oxide: lack of carcinogenic effect in the rat. Anesthesiology, 50, 306-309 

17. Bigatti, P., Lamberti, L., Ardito, G., Armellino, F. & Malanetto, C. (1985) Chromosome 

aberrations and sister chromatid exchanges in occupationally exposed workers. Med. Lav., 76, 334-

339 

18. Husum, B. & Wulf, H.C. (1980) Sister chromatid exchanges in peripheral lymphocytes in 

operating room personnel. Acta anaesth. scand., 24, 22-24 

19. IARC Monographs, Suppl. 6, 68, 206-207, 248-249, 282-285, 319-320, 325-327, 345-346, 375-

376, 425-426, 1987

Last updated: 9 March 1998 
ANDROGENIC (ANABOLIC) STEROIDS

(Group 2A)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 96) 

Oxymetholone

CAS No.: 437-07-1

Chem. Abstr. Name: 17-Hydroxy-2-(hydroxymethylene)-17-methyl-5α, 17 β-androstan-3-one 

Testosterone

CAS No.: 58-22-0

Chem. Abstr. Name: (17β)-17-Hydroxyandrost-4-en-3-one 

Testosterone oenanthate

CAS No.: 315-37-7

Chem. Abstr. Name: (17β)-17-[(1-Oxoheptyl)oxy]-androst-4-en-3-one

Testosterone propionate

CAS No.: 57-85-2

Chem. Abstr. Name: (17β)-17-(1-Oxopropoxy)-androst-4-en-3-one

A. Evidence for carcinogenicity to humans (limited)

Cases of benign hepatoma, peliosis hepatis, primary hepatocellular carcinoma and hepatic 

cholangiocarcinoma have all been linked to the use of androgenic steroids, mostly oxymetholone 

[ref: 1-13]. At least 25 cases of liver-cell tumour have been reported in patients with Fanconi's 

anaemia [ref: 1-6,11,12], aplastic anaemia [ref: 1,4,7,8], paroxysmal nocturnal haemoglobinuria 

[ref: 1,12,13], panmyelopathy [ref: 9] or megaloblastic anaemia [ref: 10] treated with 

oxymetholone alone or in combination with other androgenic steroid drugs. Usually, treatment was 

given for years, but cancer has occurred within as little as two months of therapy [ref: 6], and there 

have been well-documented instances of remission following the withdrawal of oxymetholone 

treatment [ref: 8,9,11]. Hepatocellular carcinomas were also reported after extended treatment 

with oxymetholone of one patient with nephrolithiasis [ref: 14] and of another with chronic renal 

failure [ref: 15]; and hepatocellular carcinomas [ref: 1,16], cholangiocarcinomas [ref: 15] and 

adenomas [ref: 16] were reported after extended treatment of patients with methyltestosterone, 

testosterone enanthate and nandrolone decanoate for hypogonadism [ref: 16], hypopituitarism [ref: 

13], chronic renal failure [ref: 15] and generalized weakness [ref: 15].

The fact that castration palliates prostatic cancers suggests that testosterone may be involved in the 

genesis of these tumours [ref: 17], and a number of epidemiological observations suggest that 

increased testosterone levels may increase the risk for prostatic cancer. In addition, patients with 

cirrhosis, who have depressed testosterone levels [ref: 18], have low rates of prostatic cancer [ref: 

19], and prostatic cancer is seemingly unknown among castrates [ref: 20]. There have also been a 

number of case reports [ref: 21-23] of prostatic cancer developing after androgen therapy; there 

was only one, unusual case, however, in which the cancer developed in a 'body-builder' at the age 

of 40 who had taken anabolic steroids for 18 years [ref: 23].

Blacks in the USA have the highest prostatic cancer rates in the world. Their two-fold increased risk, 

compared to US whites, is evident at the earliest age at which prostatic cancer occurs. Ross et al.

[ref: 24] showed that young US blacks have a 15% higher mean testosterone serum level than 

young US whites, and argued that this difference could readily explain the two-fold difference in 

rates.

In one study [ref: 25], prostatic cancer cases were found to have higher mean levels of serum 

testosterone than healthy controls of the same age. Prostatic cancer cases in this study had a clear 

excess of high testosterone values. Another study [ref: 26] showed significantly higher levels of 
serum testosterone in prostatic cancer cases than in age-matched controls among US blacks, but 

not among African blacks. A number of case-control studies, however, showed no significant 

difference between cases and controls [ref: 7-29]. At present, there are insufficient data to permit 

firm conclusions to be drawn.

The development of myeloid leukaemia as a complication of Fanconi's anaemia has been reported in 

association with the use of oxymetholone [ref: 11,30,31], and there has been one case report of 

paroxysmal nocturnal haemoglobinuria in which a myeloproliferative disorder developed after 

oxymetholone therapy [ref: 32].

The evidence that anabolic steroids can cause both benign and malignant liver tumours is quite 

strong. However, because no analytical epidemiological study has been done, the Working Group 

felt constrained to classify the evidence for carcinogenicity to humans as no more than 'limited'. 

B. Evidence for carcinogenicity to animals (sufficient for testosterone)

Testosterone propionate was tested for carcinogenicity in mice and rats by subcutaneous 

implantation, producing cervical-uterine tumours in female mice and prostatic adenocarcinomas in 

male rats. Neonatal treatment of female mice by subcutaneous injection of testosterone induced 

hyperplastic epithelial lesions of the genital tract and increased the incidence of mammary tumours. 

5β-Dihydrotestosterone, which is considered hormonally inactive in adults, also increased the 

incidence of mammary tumours in mice when given neonatally by subcutaneous injection [ref: 33]. 

Depots of testosterone propionate implanted in rats resulted in an increased incidence of prostatic 

adenocarcinomas [ref: 34]. Subcutaneous administration of testosterone propionate following 

intravenous treatment with N-methyl-N-nitrosourea produced a high incidence of prostatic 

adenocarcinoma not seen with the individual compounds alone [ref: 35].

No data were available to the Working Group on oxymetholone. 

C. Other relevant data

No data were available on the genetic and related effects of testosterone in humans.

Testosterone did not induce sperm abnormalities or micronuclei in mice treated in vivo and was not 

mutagenic to bacteria [ref: 36]. 

Overall evaluation

Androgenic (anabolic) steroids are probably carcinogenic to humans (Group 2A).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 6 (1974); Vol. 13 (1977); Vol. 21 (1979)

References

1. IARC Monographs, 13, 131-139, 1977

2. Port, R.B., Petasnick, J.P. & Ranniger, K. (1971) Angiographic demonstration of hepatome in 

association with Fanconi's anemia. Am. J. Roentgenol., 113, 82-83

3. Kew, M.C., Van Coller, B., Prowse, C.M., Skikne, B., Wolfsdorf, J.I., Isdale, J., Krawitz, S., 

Altman, H., Levin, S.E. & Bothwell, T.H. (1976) Occurrence of primary hepatocellular cancer and 

peliosis hepatis after treatment with androgenic steroids. S.A. med. J., 50, 1233-1237
4. Sweeney, E.C. & Evans, D.J. (1976) Hepatic lesions in patients treated with synthetic anabolic 

steroids. J. clin. Pathol., 29, 626-633

5. Shapiro, P., Ikede, R.M., Ruebner, B.H., Connors, M.H., Halsted, C.C. & Abildgaard, C.F. (1977) 

Multiple hepatic tumors and peliosis hepatis in Fanconi's anemia treated with androgens. Am. J. Dis. 

Child., 131, 1104-1106

6. Mokrohisky, S.T., Ambruso, D.R. & Hathaway, W.E. (1977) Fulminant hepatic neoplasia after 

androgen therapy. New Engl. J. Med., 296, 1411-1412

7. Sale, G.E. & Lerner, K.G. (1977) Multiple tumors after androgen therapy. Arch. Pathol. Lab. Med., 

101, 600-603

8. Montgomery, R.R., Ducore, J.M., Githens, J.H., August, C.S. & Johnson, M.L. (1980) Regression 

of oxymetholone-induced hepatic tumors after bone marrow transplantation in aplastic anemia. 

Transplantation, 30, 90-96

9. Treuner, J., Niethammer, D., Flach, A., Fischbach, H. & Schenck, W. (1980) Hepatocellular 

carcinoma following oxymetholone treatment (Ger.). Med. Welt., 31, 952-955

10. Stromeyer, F.W., Smith, D.H. & Ishak, K.G. (1979) Anabolic steroid therapy and intrahepatic 

cholangiocarcinoma. Cancer, 43, 440-443

11. Obeid, D.A., Hill, F.G.H., Harnden, D., Mann, J.R. & Wood, B.S.B. (1980) Fanconi anemia. 

Oxymetholone hepatic tumors, and chromosome aberrations associated with leukemic transition. 

Cancer, 46, 1401-1404

12. Cap, J., Ondrus, B. & Danihel, L. (1983) Focal nodular hyperplasia of the liver and hepatocellular 

carcinoma in children with Fanconi's anaemia after long-term treatment with androgen (Czech.). 

Bratisl. lek. Listy., 79, 73-81

13. McCaughan, G.W., Bilous, M.J. & Gallagher, N.D. (1985) Long-term survival with tumor 

regression in androgen-induced liver tumors. Cancer, 56, 2622-2626

14. Zevin, D., Turani, H., Cohen, A. & Levi, J. (1981) Androgen-associated hepatoma in a 

hemodialysis patient. Nephron, 29, 274-276

15. Turani, H., Levi, J., Zevin, D. & Kessler, E. (1983) Hepatic lesions in patients on anabolic 

androgenic therapy. Isr. J. med. Sci., 19, 322-337

16. Westaby, D., Portmann, B. & Williams, R. (1983) Androgen related primary hepatic tumors in 

non-Fanconi patients. Cancer, 51, 1947-1952

17. Huggins, C. & Hodges, C.V. (1941) Studies on prostatic cancer. I. The effect of castration, of 

estrogen, and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 

Cancer Res., 1, 293-297

18. Gordon, G.G., Altman, K., Southren, A.L., Rubin, E. & Lieber, C.S. (1976) Effect of alcohol 

(ethanol) administration on sex-hormone metabolism in normal men. New Engl. J. Med., 295, 793-

797

19. Glantz, G.M. (1964) Cirrhosis and carcinoma of the prostate gland. J. Urol., 91, 291-293

20. Hovenanian, M.S. & Deming, C.L. (1948) The heterologous growth of cancer of the human 

prostate. Surg. Gynecol. Obstet., 86, 29-35
21. Sanderman, T.F. (1975) The possible dangers of androgens used for male climacteric. Med. J. 

Aust., i, 634-635

22. Guinan, P.D., Sadoughi, W., Alsheik, H., Ablin, R.J., Alrenga, D. & Bush, I.M. (1976) Impotence 

therapy and cancer of the prostate. Am. J. Surg., 131, 599-600

23. Roberts, J.T. & Essenhigh, D.M. (1986) Adenocarcinoma of prostate in a 40-year-old bodybuilder. Lancet, ii, 742

24. Ross, R., Bernstein, L., Judd, H., Hanisch, R., Pike, M. & Henderson, B. (1986) Serum 

testosterone levels in healthy young black and white men. J. natl Cancer Inst., 76, 45-48

25. Ghanadian, R., Puah, C.M. & O'Donoghue, E.P.N. (1979) Serum testosterone and 

dihydrotestosterone in carcinoma of the prostate. Br. J. Cancer, 39, 696-699

26. Ahluwalia, B., Jackson, M.A., Jones, G.W., Williams, A.O., Rao, M.S. & Rajguru, S. (1981) Blood 

hormone profiles in prostate cancer patients in high-risk and low-risk populations. Cancer, 48, 2267-

2273

27. Hammond, G.L., Kontturi, M., Vihko, P. & Vihko, R. (1978) Serum steroids in normal males and 

patients with prostatic diseases. Clin. Endocrinol., 9, 113-121

28. Bartsch, W., Steins, P. & Becker, H. (1977) Hormone blood levels in patients with prostatic 

carcinoma and their relationship to the type of carcinoma growth differentiation. Eur. Urol., 3, 47-52

29. Harper, M.E., Peeling, W.B., Cowley, T., Brownsey, B.G., Phillips, M.E.A., Groom, G., Fahmy, 

D.R. & Griffiths, K. (1976) Plasma steroid and protein hormone concentrations in patients with 

prostatic carcinoma, before and during oestrogen therapy. Acta endocrinol., 81, 409-426

30. Sarna, G., Tomasulo, P., Lotz, M.J., Bubinak, J.F. & Shulman, N.R. (1975) Multiple neoplasms in 

two siblings with a variant form of Fanconi's anemia. Cancer, 36, 1029-1033

31. Bourgeois, C.A. & Hill, F.G.H. (1977) Fanconi's anemia leading to acute myelomonocytic 

leukemia. Cytogenic studies. Cancer, 39, 1163-1167

32. Boyd, A.W., Parkin, J.D. & Castaldi, P.A. (1979) A case of paroxysmal nocturnal 

haemoglobinuria terminating in a myeloproliferative syndrome. Aust. N.Z. J. Med., 9, 181-183

33. IARC Monographs, 21, 519-547, 1979

34. Pollard, M. & Luckert, P.H. (1986) Promotional effects of testosterone and high fat diet on the 

development of autochthonous prostate cancer in rats. Cancer Lett., 32, 223-227

35. Pollard, M. & Luckert, P.H. (1986) Production of autochthonous prostate cancer in LobundWistar rats by treatment with N-nitroso-N-methylurea and testosterone. J. natl Cancer Inst., 77, 

583-587

36. IARC Monographs, Suppl. 6, 506-507, 1987

Synonyms for Oxymetholone:

● Adroidin 

● Adroyd 

● Anadrol 

● Anadroyd 
● Anapolon 

● Anasteron 

● Anasteronal 

● Anasterone 

● Becorel 

● CI-406 

● 4,5-Dihydro-2-hydroxymethylene-17α-methyltestosterone 

● Dynasten 

● HMD 

● 17β-Hydroxy-2-hydroxymethylene-17α-methyl-3-androstanone 

● 17β-Hydroxy-2-(hydroxymethylene)-17α-methyl-5α-androstan-3- one 

● 17β-Hydroxy-2-(hydroxymethylene)-17-methyl-5α-androstan-3-one 

● 2-Hydroxymethylene-17α-methyl-5α-androstan-17β-ol-3-one 

● 2-Hydroxymethylene-17α-methyldihydrotestosterone 

● 2-(Hydroxynethylene)-17-methyldihydrotestosterone 

● 2-(Hydroxymethylene)-17α-methyldihydrotestosterone 

● 2-Hydroxymethylene-17α-methyl-17β-hydroxy-3-androstanone 

● Nastenon 

● Methabol 

● 17α-Methyl-2-hydroxymethylene-17-hydroxy-5α-androstan-3-one 

● NSC-26 198 

● Oximetholonum 

● Oximetolona 

● Oxymethenolone 

● Oxitosona-50 

● Pavisoid 

● Plenastril 

● Protanabol 

● Roboral 

● Synasteron 

● Zenalosyn 

Synonyms for Testosterone

● δ4-Androsten-17β-ol-3-one; [Ablacton] 

● Andrestraq 

● Android-T 

● Androlan 

● Androlin 

● Andronaq 

● Andrusol 

● Cormone 

● Cristerona T 

● Depotest 

● Di-Met 

● Dura-Testrone 

● Geno-cristaux Gremy 

● Histerone 

● Homogene S 

● Homosteron 

● Homosterone 

● Hydrotest 

● Malestrone 

● Mal-O-Fem 

● Malogen 

● Mertestate 

● Nendron 

● Neo-Hombreol 

● Neo-Hombreol-F 

● Neotestis 

● Oreton 

● Oreton-F 

● Orquisteron 

● Perandren 
● Percutacrine Androgenique 

● Primotest 

● Primoteston 

● Rektandron 

● Sterotate 

● Sustanon 

● Sustanone 

● Synandrol F 

● Tesamone 

● Teslen 

● Tesone 

● Test 100 

● Testa denos 

● Testagen 

● Testalong 

● Testandrone 

● Testaqua 

● Test-Estrin 

● Testiculosterone 

● Testobase 

● Testodrin 

● Testoject-50 

● Testolent 

● Testolin 

● Testopropon 

● Testoral 

● Testosteroid 

● Testosteron 

● Testoviron 

● Testoviron Schering 

● Testoviron T 

● Testro-Med 

● Testrone 

● Testryl 

● Virormone 

● Virosterone 

Synonyms for Testosterone oenanthate

● Androtardyl 

● Delatestryl 

● Orquisteron-E 

● Reposo-TMD 

● Testoenant 

● Testosterone enanthate 

● Testosterone heptanoate 

● Testosterone heptylate 

Synonyms for Testosterone proprionate

● Agovirin 

● Androlon 

● Androsan 

● ∆4-Androstene-17β-propionate-3-one 

● Androtest P 

● Androteston 

● Anertan 

● Aguaviron 

● Bio-Testiculina 

● Enarmon 

● Enarmon-oil 

● Homandren 

● Hormoteston 
● Malogen 

● Masenate 

● Nasdol 

● Neo-Hombreol 

● NSC 9166 

● Okasa-Mascul 

● Orchiol 

● Orchisteron P 

● Orchisterone P 

● Orchistin 

● Oreton 

● Oreton Propionate 

● Pantestin 

● Paretest 

● Perandren 

● Propiokan 

● Recthormone Testosterone 

● Solvotest 

● Sterandryl 

● Synerone 

● Telipex 

● Testaform 

● Testex 

● Testine 

● Testodet 

● Testodrin 

● Testogen 

● Testolets 

● Testonique 

● Testormol 

● Testosid 

● Testosterone-17β-propionate 

● Testosterone-17-propionate 

● Testosteron propionate 

● Testoviron 

● Testoxyl 

● Testrex 

● Tostrin 

● TP 

● Uniteston 

Last updated: 11 February 1998 
ANILINE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 99)

CAS No.: 62-53-3

Chem. Abstr. Name: Benzenamine 

A. Evidence for carcinogenicity to humans (inadequate) 

The excess of bladder cancer deaths observed in clusters of cases of workers in the aniline-dye 

industry has been attributed to exposure to chemicals other than aniline. Epidemiological studies of 

workers exposed to aniline but not to other known bladder carcinogens have shown little evidence of 

increased risk. These studies are generally methodologically inadequate due to incomplete follow-up 

of workers who left the industry and to absence of estimates of expected numbers of bladder 

cancers. In the most methodologically vigorous study, one death from bladder cancer was reported 

among 1223 men who had produced or used aniline, with 0.83 deaths expected from population 

rates [ref: 1]. A recent mortality study of 342 men employed in the manufacture of organic dyes, in 

which two of the three processes involved aniline as a raw material, showed no death from bladder 

cancer [ref: 2]. 

B. Evidence for carcinogenicity to animals (limited) 

Aniline hydrochloride was tested for carcinogenicity in single experiments in mice and rats by oral 

administration. No increase in tumour incidence was observed in mice. In rats, it produced 

fibrosarcomas, sarcomas and haemangiosarcomas of the spleen and peritoneal cavity [ref: 1]. In 

several limited studies, largely negative results were obtained following oral administration to rats 

[ref: 1], subcutaneous injection of mice [ref: 1] and hamsters [ref: 3], and after single 

intraperitoneal injection of mice [ref: 4]. 

C. Other relevant data

No data were available on the genetic and related effects of aniline in humans. 

Aniline induced sister chromatid exchanges, but not micronuclei in bone-marrow cells of mice treated 

in vivo, and DNA strand breakage was induced in liver and kidney of rats in vivo. Sister chromatid 

exchange assays in human cells in vitro gave negative results. Syrian hamster embryo cells and 

virus-infected Fischer rat embryo cells were not transformed by aniline, but BALB/c 3T3 cells were. It 

induced sister chromatid exchanges and chromosomal aberrations but not DNA strand breaks or 

unscheduled DNA synthesis in mammalian cells in vitro. Aniline did not induce sex-linked recessive 

lethal mutations in Drosophila and did not induce mutation or mitotic recombination in fungi. It was 

not mutagenic to bacteria and did not cause DNA damage. Urine from rats treated with aniline was 

reported to be mutagenic to bacteria [ref: 5]. 

Overall evaluation Aniline is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 4 (1974); Vol. 27 (1982)

References 

1. IARC Monographs, 27, 39-61, 1982 
2. Ott, M.G. & Langner, R.R. (1983) A mortality survey of men engaged in the manufacture of 

organic dyes. J. occup. med., 25, 763-768 

3. Hecht, S.S., El-Bayoumy, K., Rivenson, A. & Fiala, E.S. (1983) Bioassay for carcinogenicity of 3,2'-

dimethyl-4-nitrosobiphenyl, o-nitrosotoluene, nitrosobenzene and the corresponding amines in 

Syrian golden hamsters. Cancer Lett., 20, 349-354 

4. Delclos, K.B., Tarpley, W.G., Miller, E.C. & Miller, J.A. (1983) 4-Aminoazobenzene and N,Ndimethyl-4-aminoazobenzene as equipotent hepatic carcinogens in male C57BL x C3H/He F1 mice 

and characterization of N-(deoxyguanosin-8-yl)-4-aminoazobenzene as the major persistent hepatic 

DNA-bound dye in these mice. Cancer Res., 44, 2540-2550 

5. IARC Monographs, Suppl. 6, 68-70, 1987 

Synonyms

● Aminobenzene 

● Aminophen 

● Aniline oil 

● Anyvim 

● Blue Oil 

● Phenylamine 

Last updated: 9 March 1998 
ARSENIC AND ARSENIC COMPOUNDS

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 100) 

CAS No.: 7440-38-2 

Chem. Abstr. Name: Arsenic 

Arsanilic acid:

CAS No.: 98-50-0

Chem. Abstr. Name: Arsonic acid, (4-aminophenyl)- 

Arsenic pentoxide:

CAS No.: 1303-28-2

Chem. Abstr. Name: Arsenic oxide [As2O5] 

Arsenic sulfide:

CAS No.: 1303-33-9

Chem. Abstr. Name: Arsenic sulfide [As2S3] 

Arsenic trioxide:

CAS No.: 1327-53-3

Chem. Abstr. Name: Arsenic oxide [As2O3] 

Arsine:

CAS No.: 7784-42-1 

Calcium arsenate:

CAS No.: 7778-44-1

Chem. Abstr. Name: Arsenic acid [H3AsO4], calcium salt (2:3) 

Dimethylarsinic acid:

CAS No.: 75-60-5

Chem. Abstr. Name: Arsinic acid, dimethylLead arsenate:

CAS No.: 7784-40-9

Chem. Abstr. Name: Arsenic acid [H3AsO4], lead (2+) salt (1:1) 

Methanearsonic acid, disodium salt:

CAS No.: 144-21-8

Chem. Abstr. Name: Arsonic acid, methyl-, disodium salt 

Methanearsonic acid, monosodium salt:

CAS No.: 2163-80-6

Chem. Abstr. Name: Arsonic acid, methyl-, monosodium salt 

Potassium arsenate:

CAS No.: 7784-41-0

Chem. Abstr. Name: Arsenic acid [H3AsO4], monopotassium salt 

Potassium arsenite:

CAS No.: 13464-35-2
Chem. Abstr. Name: Arsenenous acid, potassium salt 

Sodium arsenate:

CAS No.: 7631-89-2

Chem. Abstr. Name: Arsenic acid, [H3AsO4], sodium salt 

Sodium arsenite:

CAS No.: 7784-46-5

Chem. Abstr. Name: Arsenenous acid, sodium salt 

Sodium cacodylate:

CAS No.: 124-65-2

Chem. Abstr. Name: Arsinic acid, dimethyl-, sodium salt 

A. Evidence for carcinogenicity to humans (sufficient)

Many cases of skin cancer have been reported among people exposed to arsenic through medical 

treatment with inorganic trivalent arsenic compounds, particularly Fowler's solution [ref: 1], and 

further reports have confirmed these findings [ref: 2-9]. In some instances, skin cancers have 

occurred in combination with other cancers, such as liver angiosarcoma (after six months' treatment 

with Fowler's solution giving a total intake of 0.24 g arsenic) [ref: 6], intestinal and bladder cancers 

[ref: 7] and meningioma [ref: 9]. Liver angiosarcomas have also been associated with medicinal 

exposure to arsenic [ref: 1,6,10]. 

Epidemiological studies of cancer following medical treatment with arsenic have shown an excess of 

skin cancers, but no clear association with other cancers has been obtained [ref: 1], as confirmed 

by a recent cohort study on individuals treated with Fowler's solution [ref: 11]. No relation was 

found between prostatic cancer and treatment of syphilis with arsenicals [ref: 12]. 

An association between environmental exposure to arsenic through drinking-water and skin cancer 

has been observed [ref: 1] and confirmed [ref: 13,14]; two cases of bladder cancer were also 

described, with latent periods of eight to 20 years [ref: 15]. The latent periods for two cases of skin 

cancer related to arsenic in drinking-water were 20 and 23 years, and the concentrations or uptake 

of arsenic were reported to be 1.2 and 1 mg per day, respectively, with an estimated total ingested 

dose of about 8 g in one study [ref: 14]. 

Epidemiological studies in areas with different frequencies of black-foot disease and where drinkingwater contained 0.35-1.14 mg/l arsenic revealed elevated risks for cancers of the bladder, kidney, 

skin, lung, liver and colon in both men and women [ref: 16,17]. 

A case of liver angiosarcoma was reported in the 20-month-old child of an exposed worker living in 

the vicinity of a copper mine and smelter [ref: 18]. Four rather inconsistent studies describing the 

effect of air pollutants containing arsenic [ref.: 1,19,20] were followed by further reports that 

indicated an effect on lung cancer incidence of arsenic in polluted air from smelters and pesticide 

production, with risk ratios of 2.0-2.5 near smelters [ref: 21,22]. Two further studies near smelters 

showed no clear effect [ref: 23,24]. 

Occupational exposure to inorganic arsenic, especially in mining and copper smelting, has quite 

consistently been associated with an increased risk of cancer [ref: 1]. A number of studies of 

smelter workers relate to populations that have been reported previously [ref: 1] and represent 

both partial [ref: 25-27] and total [ref: 28,29] updates. An almost ten-fold increase in the incidence 

of lung cancer was found in workers most heavily exposed to arsenic, and relatively clear doseresponse relationships have been obtained with regard to cumulative exposure [ref: 29] and 

especially with 30-day ceiling levels [ref: 27]. Sulphur dioxide in the smelter environment appeared 

to play a minor role, if any, in the development of lung cancer [ref: 27]. Other forms of cancer were 

considered, but their incidences were not found to be consistently increased [ref: 28]. Other US 

smelter worker populations have been shown to have consistent increases in lung cancer incidence, 

as well as increases of about 20% in the incidence of gastrointestinal cancer and of 30% for renal 

cancer and haematolymphatic malignancies [ref: 30,31]. The observation in an earlier study of an 
increase in lung cancer risk among a population of Swedish smelter workers [ref: 1] has been 

confirmed, with a risk of six to eight fold among roasters [ref: 32]. 

A decrease in lung cancer risk after cessation of exposure to arsenic has been observed in some 

studies [ref: 30,33], possibly indicating a late-stage effect of arsenic [ref: 34,35]. 

With regard to histological type of lung cancer, a significant, relative excess of adenocarcinomas and 

a slight excess of oat-cell cancers were seen among smelter workers [ref: 36]. 

A multiplicative effect of arsenic exposure and smoking was observed among Swedish smelter 

workers [ref: 37]. A slightly increased risk was also indicated for exposure to sulphur dioxide in this 

study. Other studies have shown a lesser influence of smoking [ref: 25,33]. 

Relatively high concentrations of arsenic, as well as of antimony, cadmium, lead and lanthanum, 

were found in lung tissue of lung cancer cases, whereas the concentrations of selenium were low 

[ref: 38,39]. 

An approximately two-fold risk for lung and stomach cancers has been observed among (fine) glass 

workers with some exposure to arsenic but who were also exposed to other potentially carcinogenic 

metals and to asbestos. Stomach cancer was especially frequent among glass blowers, suggesting 

an association with oral contact with contaminated pipes [ref: 40]. 

Some excess of lung cancer was seen among female hat makers exposed to arsenic, but also to 

mercury [ref: 41]. 

Additional reports have suggested an increased risk of skin and lung cancers in vineyard workers 

[ref: 42,43] and have also suggested that ingestion of arsenic in wine byproducts may have 

contributed to this increase [ref: 42]. One case of lung cancer was reported in an individual involved 

in the production of lead arsenate and calcium arsenate [ref: 44]; multiple skin keratoses and 

chronic lymphatic leukaemia were reported in one person involved in the production of copper 

acetoarsenate [ref: 45]. 

Three studies of two populations of workers in pesticide production showed an increased risk ratio 

for lung cancer - up to about 3 - and some excess of malignant neoplasms of the lymphatic and 

haematopoietic tissues [ref: 1,46]. In a study of liver angiosarcomas, two of 26 cases had been in 

contact with arsenical pesticides occupationally [ref: 1]. 

B. Evidence for carcinogenicity to animals (limited)

Various arsenic compounds have been tested for carcinogenicity by perinatal treatment of mice, by 

intratracheal instillation in hamsters and rats and by implantation into the stomach of rats. Arsenic 

trioxide produced lung adenomas in mice after perinatal treatment [ref: 47], and induced low 

incidences of carcinomas, adenomas, papillomas and adenomatoid lesions of the respiratory tract in 

hamsters after its intratracheal instillation [ref: 48,49]. It induced a low incidence of 

adenocarcinomas at the site of its implantation into the stomach of rats [ref: 50]. A high incidence 

of lung carcinomas was induced in rats following a single intratracheal instillation of a pesticide 

mixture containing calcium arsenate [ref: 1]. Intratracheal instillations of calcium arsenate into 

hamsters resulted in a borderline increase in the incidence of lung adenomas, while no such effect 

was observed with arsenic trisulphide [ref: 51]. Sodium arsenite enhanced the incidence of renal 

tumours induced in rats by intraperitoneal injection of N-nitrosodiethylamine [ref: 52].

No adequate data on the carcinogenicity of organic arsenicals were available to the Working Group. 

C. Other relevant data

In one study of people exposed to trivalent arsenic in drinking-water, no increase in the incidence of 

sister chromatid exchanges or chromosomal aberrations was observed. A number of other studies 

published on people occupationally exposed to arsenic or patients treated with arsenic have shown 
increased levels of chromosomal aberrations or sister chromatid exchanges. The interpretation of 

these results remains uncertain because of methodological problems [ref: 53]. 

Trivalent arsenic did not induce dominant lethal mutations in mice, but it produced a small increase 

in the incidence of chromosomal aberrations and micronuclei in bone-marrow cells of mice treated in 

vivo. It induced chromosomal aberrations and sister chromatid exchanges in human and rodent cells 

in vitro, and transformation of Syrian hamster embryo cells; it did not induce mutation in rodent 

cells in vitro. It induced gene conversion in yeast but did not cause mutation or induce prophage in 

bacteria [ref: 53]. 

Pentavalent arsenic induced chromosomal aberrations in human and rodent cells in vitro; equivocal 

results were obtained in assays for the induction of sister chromatid exchanges. It induced 

transformation in Syrian hamster embryo cells but did not induce mutation or DNA strand breaks in 

rodent cells in vitro. It induced gene conversion in yeast but did not induce mutation in bacteria 

[ref: 53].

Overall evaluation

Arsenic and arsenic compounds are carcinogenic to humans (Group 1).

N.B. - This evaluation applies to the group of chemicals as a whole and not necessarily to all 

individual chemicals within the group.

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 1 (1972); Vol. 2 (1973); Vol. 23 (1980)

References

1. IARC Monographs, 23, 39-141, 1980 

2. Heddle, R. & Bryant, G.D. (1983) Small cell lung carcinoma and Bowen's disease 40 years after 

arsenic ingestion. Chest, 84, 776-777 

3. Cowlishaw, J.L., Pollard, E.J., Cowen, A.E. & Powell, L.W. (1979) Liver disease associated with 

chronic arsenic ingestion. Aust. N.Z. J. Med., 9, 310-313 

4. Kastl, J. & Horácek, J. (1980) Arning's carcinoids in a psoriatic receiving long-term arsenic 

treatment (Czech.). Cs. Dermatol., 55, 89-93 

5. Kastl, J. & Horácek, J. (1985) Multiple basal cell carcinomas after long-term intake of arsenic 

(Ger.). Dermatol. Monatsschr., 171, 158-161 

6. Roat, J.W., Wald, A., Mendelow, H. & Pataki, K.I. (1982) Hepatic angiosarcoma associated with 

short-term arsenic ingestion. Am. J. Med., 73, 933-936 

7. von Roemeling, R., Hartwich, G. & König, H. (1979) Occurrence of tumours at different locations 

after arsenic therapy (Ger.). Med. Welt., 30, 1928-1929 

8. Southwick, G.J. & Schwartz, R.A. (1979) Arsenically associated cutaneous squamous cell 

carcinoma with hypercalcemia. J. surg. Oncol., 12, 115-118 

9. Weiss, J. & Jänner, M. (1980) Multiple basal cell carcinomas and meningioma after long-term 

arsenic therapy (Ger.). Hautarzt, 31, 654-656 
10. Falk, H., Caldwell, G.G., Ishak, K.G., Thomas, L.B. & Popper, H. (1981) Arsenic-related hepatic 

angiosarcoma. Am. J. ind. Med., 2, 43-50 

11. Cuzick, J., Evans, S., Gillman, M. & Price Evans, D.A. (1982) Medicinal arsenic and internal 

malignancies. Br. J. Cancer, 45, 904-911 

12. Lees, R.E.M., Steele, R. & Wardle, D. (1985) Arsenic, syphilis, and cancer of the prostate. J. 

Epidemiol. Commun. Health, 39, 227-230 

13. Armando, V.L. & Angel, A.O. (1979) Chronical arsenicism (Span.). Bol. med. Hosp. Infant., 36, 

849-861 

14. Zaldivar, R., Prunés, L. & Ghai, G.L. (1981) Arsenic dose in patients with cutaneous carcinomata 

and hepatic haemangio-endothelioma after environmental and occupational exposure. Arch. 

Toxicol., 47, 145-154 

15. Nagy, G., Németh, A., Bodor, F. & Ficsór, E. (1980) Urinary bladder cancer induced by chronic 

arsenic poisoning (Hung.). Orv. Hetil., 121, 1009-1011 

16. Chen, C.-J., Chuang, Y.-C., Lin, T.-M. & Wu, H.-Y. (1985) Malignant neoplasmas among 

residents of a blackfoot disease-endemic area in Taiwan: high-arsenic artesian well water and 

cancers. Cancer Res., 45, 5895-5899 

17. Chen, C.-J., Chuang, Y.-C., You, S.-L., Lin, T.-M. & Wu, H.-Y. (1986) A retrospective study on 

malignant neoplasms of bladder, lung and liver in blackfoot disease endemic area in Taiwan. Br. J. 

Cancer, 53, 399-405 

18. Falk, H., Herbert, J.T., Edmonds, L., Heath, C.W., Jr, Thomas, L.B. & Popper, H. (1981) Review 

of four cases of childhood hepatic angiosarcoma - elevated environmental arsenic exposure in one 

case. Cancer, 47, 382-391 

19. Brown, L.M., Pottern, L.M. & Blot, W.J. (1984) Lung cancer in relation to environmental 

pollutants emitted from industrial sources. Environ. Res., 34, 250-261 

20. Pershagen, G. (1985) Lung cancer mortality among men living near an arsenic-emitting smelter. 

Am. J. Epidemiol., 122, 684-694 

21. Matanoski, G.M., Landau, E., Tonascia, J., Lazar, C., Elliott, E.A., McEnroe, W. & King, K. (1981) 

Cancer mortality in an industrial area of Baltimore. Environ. Res., 25, 8-28 

22. Matanoski, G.M., Landau, E., Tonascia, J. & Elliott, E.A. (1983) Epidemiologic approach to 

arsenic pollution. J. Univ. occup. environ. Health, 5 (Suppl.), 117-124 

23. Greaves, W.W., Rom, W.N., Lyon, J.L., Varley, G., Wright, D.D. & Chiu, G. (1981) Relationship 

between lung cancer and distance of residence from nonferrous smelter stack effluent. Am. J. ind. 

Med., 2, 15-23 

24. Rom, W.N., Varley, G., Lyon, J.L. & Shopkow, S. (1982) Lung cancer mortality among residents 

living near the El Paso smelter. Br. J. ind. Med., 39, 269-272 

25. Higgins, I., Welch, K., Oh, M., Bond, G. & Hurwitz, P. (1981) Influence of arsenic exposure and 

smoking on lung cancer among smelter workers: a pilot study. Am. J. ind. Med., 2, 33-41 

26. Lubin, J.H., Pottern, L.M., Blot, W.J., Tokudome, S., Stone, B.J. & Fraumeni, J.R., Jr (1981) 

Respiratory cancer among copper smelter workers: recent mortality statistics. J. occup. Med., 23, 
779-784 

27. Welch, K., Higgins, I., Oh, M. & Burchfiel, C. (1982) Arsenic exposure, smoking, and respiratory 

cancer in copper smelter workers. Arch. environ. Health, 37, 325-335 

28. Lee-Feldstein, A. (1983) Arsenic and respiratory cancer in humans: follow-up of copper smelter 

employees in Montana. J. natl Cancer Inst., 70, 601-609 

29. Lee-Feldstein, A. (1986) Cumulative exposure to arsenic and its relationship to respiratory 

cancer among copper smelter employees. J. occup. Med., 28, 296-302 

30. Enterline, P.E. & Marsh, G.M. (1980) Mortality studies of smelter workers. Am. J. ind. Med., 1, 

251-259 

31. Enterline, P.E. & Marsh, G.M. (1982) Cancer among workers exposed to arsenic and other 

substances in a copper smelter. Am. J. Epidemiol., 116, 895-911 

32. Wall, S. (1980) Survival and mortality pattern among Swedish smelter workers. Int. J. 

Epidemiol., 9, 73-87 

33. Pinto, S.S., Henderson, V. & Enterline, P.E. (1978) Mortality experience of arsenic-exposed 

workers. Arch. environ. Health, 33, 325-331 

34. Brown, C.C. & Chu, K.C. (1983) Implications of the multistage theory of carcinogenesis applied 

to occupational arsenic exposure. J. natl Cancer Inst., 70, 455-463 

35. Brown, C.C. & Chu, K.C. (1983) A new method for the analysis of cohort studies: implications of 

the multistage theory of carcinogenesis applied to occupational arsenic exposure. Environ. Health 

Perspect., 50, 293-308 

36. Wicks, M.J., Archer, V.E., Auerbach, O. & Kuschner, M. (1981) Arsenic exposure in a copper 

smelter as related to histological type of lung cancer. Am. J. ind. Med., 2, 25-31 

37. Pershagen, G., Wall, S., Taube, A. & Linnman, L. (1981) On the interaction between 

occupational arsenic exposure and smoking and its relationship to lung cancer. Scand. J. Work 

Environ. Health, 7, 302-309 

38. Wester, P.O., Brune, D. & Nordberg, G. (1981) Arsenic and selenium in lung, liver, and kidney 

tissue from dead smelter workers. Br. J. ind. Med., 38, 179-184 

39. Gerhardsson, L., Brune, D., Nordberg, I.G.F. & Wester, P.O. (1985) Protective effect of selenium 

on lung cancer in smelter workers. Br. J. ind. Med., 42, 617-626 

40. Wingren, G. & Axelson, O. (1985) Mortality pattern in a glass producing area in SE Sweden. Br. 

J. ind. Med., 42, 411-414 

41. Buiatti, E., Kriebel, D., Geddes, M., Santucci, M. & Pucci, N. (1985) A case control study of lung 

cancer in Florence, Italy. I. Occupational risk factors. J. Epidemiol. Commun. Health, 39, 244-250 

42. Lüchtrath, H. (1983) The consequences of chronic arsenic poisoning among Moselle wine 

growers. Pathoanatomical investigations of post-mortem examinations between 1960 and 1977. J. 

Cancer Res. clin. Oncol., 105, 173-182 

43. Thiers, H., Colomb, D., Moulin, G. & Colin, L. (1967) Arsenical skin cancer in vineyards in the 

Beaujolais (Fr.). Ann. Dermatol., 94, 133-158 
44. Horiguchi, S. (1979) A case of lung cancer due to exposure to arsenical compounds in an 

insecticides factory. (Studies on lead arsenate poisoning. Part 4). Osaka City med. J., 25, 45-51 

45. Leyh, F. & Rothlaender, J.P. (1985) Multiple bowenoid keratoses due to arsenic (Ger.). 

Dermatosen, 33, 99-101 

46. Mabuchi, K., Lilienfeld, A.M. & Snell, L.M. (1980) Cancer and occupational exposure to arsenic: a 

study of pesticide workers. Prev. Med., 9, 51-77 

47. Rudnay, P. & Börzsönyi, M. (1981) The tumorigenic effect of treatment with arsenic trioxide 

(Hung.). Magyar Onkol., 25, 73-77 

48. Ishinishi, N., Yamamoto, A., Hisanaga, A. & Inamasu, T. (1983) Tumorigenicity of arsenic 

trioxide to the lung in Syrian golden hamsters by intermittent instillations. Cancer Lett., 21, 141-

147 

49. Pershagen, G., Nordberg, G. & Björklund, N.-E. (1984) Carcinomas of the respiratory tract in 

hamsters given arsenic trioxide and/or benzo[a]pyrene by the pulmonary route. Environ. Res., 34, 

227-241 

50. Katsnelson, B.A., Neizvestnova, Y.M. & Blokhin, V.A. (1986) Stomach carcinogenesis induction 

by chronic treatment with arsenic (Russ.). Vopr. Onkol., 32, 68-73 

51. Pershagen, G. & Björklund, N.-E. (1985) On the pulmonary tumorigenicity of arsenic trisulfide 

and calcium arsenate in hamsters. Cancer Lett., 27, 99-104 

52. Shirachi, D.Y., Johansen, M.G., McGowan, J.P. & Tu, S.-H. (1983) Tumorigenic effect of sodium 

arsenite in rat kidney. Proc. West. pharmacol. Soc., 26, 413-415 

53. IARC Monographs, Suppl. 6, 71-76, 1987 

Synonyms for Arsenic

● Arsen 

● Arsenic black 

● Grey arsenic 

● Metallic arsenic 

Synonyms for Arsanilic acid

● 4-Aminobenzenearsonic acid 

● para-Aminophenylarsenic acid 

● Aminophenylarsine acid 

● para-Aminophenylarsine acid 

● para-Aminophenylarsinic acid 

● 4-Aminophenylarsonic acid 

● para-Anilinearsonic acid 

● Arsanilic acid-100 

● para-Arsanilic acid 

● 4-Arsanilic acid 

● Atoxylic acid 

● Premix 

● Pro gen 

● Pro-gen 227 

● Progen 90 
Synonyms for Arsenic pentoxide

● Arsenic acid 

● Arsenic acid anhydride 

● Arsenic anhydride 

● Arsenic oxide 

● Arsenic [V] oxide 

● Diarsenic pentoxide 

Synonyms for Arsenic sulfide

● Arsenic sesquisulphide 

● Arsenic sulphide 

● Arsenic tersulphide 

● Arsenic trisulphide 

● Arsenic Yellow 

● Arsenious sulphide 

● Arsenous sulphide 

● Auripigment 

● Diarsenic trisulphide 

● Orpiment 

● Pigment Yellow 39 

Synonyms for Arsenic trioxide

● Arsenic [III] oxide 

● Arsenic sesquioxide 

● Arsenicum album 

● Arsenious acid 

● Arsenious oxide 

● Arsenious trioxide 

● Arsenite 

● Arsenolite 

● Arsenous acid 

● Arsenous acid anhydride 

● Arsenous anhydride 

● Arsenous oxide 

● Arsenous oxide anhydride 

● Arsodent 

● Claudelite 

● Crude arsenic 

● Diarsenic trioxide 

● White arsenic 

Synonyms for Arsine

● Arsenic hydrid [AsH3] 

● Arsenic hydride 

● Arsenic trihydride 

● Arseniuretted hydrogen 

● Arsenous hydride 

● Hydrogen arsenide 

Synonyms for Calcium arsenate

● Calcium ortho-arsenate 

● Spra-cal 

● Tricalcium arsenate 

● Chip-cal 

● Pencal 
Synonyms for Dimethylarsinic acid

● Agent Blue 

● Ansar 138 

● Arsan 

● Arsine oxide, hydroxydimethyl- 

● Cacodylic acid 

● Hydroxydimethylarsine oxide 

● Dilic 

● Phytar 138 

● Phytar 560 

● Rad-E-Cate 25 

● Silvisar 510 

Synonyms for Lead arsenate

● Acid lead arsenate 

● Acid lead ortho-arsenate 

● Arsenate of lead 

● Arsinette 

● Gypsine 

● Lead acid arsenate 

● Plumbous arsenate 

● Schultenite 

● Standard lead arsenate 

● Soprabel 

● Talbot 

Synonyms for Methanearsonic acid, disodium salt

● Arrhenal 

● Ansar 184 

● Ansar 8100 

● Ansar DSMA liquid 

● Arsinyl 

● Arsynal 

● Cacodyl new 

● Chipco crab kleen 

● Cralo-E-Rad 

● Dal-E-Rad 100 

● Diarsen 

● Disodium methanearsenate 

● Disodium methanearsonate 

● Disodium methylarsonate 

● Disomear 

● Di-Tac 

● DMA 

● DMA 100 

● DSMA 

● DSMA liquid 

● Methar 

● Metharsan 

● Metharsinat 

● Namate 

● Neo-asycodile 

● Sodar 

● Somar 

● Stenosine 

● Tonarsen 

● Tonarsin 

● Weed broom 
● Weed-E-Rad 

● Weed-E-Rad DMA powder 

● Weed-E-Rad 360 

● Weed-Hoe 

Synonyms for Methanearsonic acid, monosodium salt

● Ansar 170 H.C. 

● Ansar 170 L 

● Ansar 529 H.C. 

● Arsonate liquid 

● Bueno 6 

● Daconate 6 

● Dal-E-Rad 

● Herb-All 

● Merge 823 

● Mesamate 

● Mesamate H.C. 

● Mesamate concentrate 

● Mesamate 400 

● Mesamate 600 

● Monosodium acid methanearsonate 

● Monosodium acid metharsonate 

● Monosodium methanearsonate 

● Monosodium methylarsonate 

● Monosodium methyl arsonate 

● MSMA 

● Sodium acid methanearsonate 

● Phyban H.C. 

● Silvisar 550 

● Target MSMA 

● Trans-vert 

● Weed 108 

● Weed-E-Rad 

● Weed-hoe 

Synonyms for Potassium arsenate

● Arsenic acid, monopotassium salt 

● Macquer's salt 

● Monopotassium arsenate 

● Monopotassium dihydrogen arsenate 

● Potassium acid arsenate 

● Potassium arsenate, monobasic 

● Potassium dihydrogen arsenate 

● Potassium hydrogen arsenate 

Synonyms for Potassium arsenite

● Arsenious acid, potassium salt 

● Arsenious acid [H3AsO3], potassium salt 

● Arsonic acid, potassium salt 

● Fowler's solution 

● Potassium metaarsenite 

Synonyms for Sodium arsenate

● Arsenic acid, sodium salt 

● Sodium ortho-arsenate 
Synonyms for Sodium arsenite

● Arsenious acid, sodium salt 

● Atlas 'A' 

● Chem pels C 

● Chem-sen 56 

● Kill-all 

● Penite 

● Prodalumnol 

● Sodium meta-arsenite 

● Sodium metaarsenite 

Synonyms for Sodium cacodylate

● Alkarsodyl 

● Arsecodile 

● Arsicodile 

● Arsine oxide, hydroxydimethyl-, sodium salt 

● Arsycodile 

● Boll's eye 

● Cacodylic acid, sodium salt 

● [(Dimethylarsino)oxy]sodium-As-oxide 

● Hydroxydi-methylarsine oxide, sodium salt 

● Phytar 560 

● Rad-E-Cate 25 

● Silvisar 

● Sodium dimethylarsinate 

● Sodium dimethylarsonate 

Last updated: 6 February 1998 
ASBESTOS

(Actinolite, amosite, anthophyllite, chrysotile, crocidolite, tremolite)

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 106) 

Asbestos fibre

CAS No.: 1332-21-4

Actinolite

CAS No.: 13768-00-8

Amosite

CAS No.: 12172-73-5

Anthophyllite

CAS No.: 17068-78-9

Chrysotile

CAS No.: 12001-29-5

Crocidolite

CAS No.: 12001-28-4

Tremolite

CAS No.: 14567-73-8

A. Evidence for carcinogenicity to humans (sufficient)

Numerous reports from several countries have described cases or series of pleural and peritoneal 

mesotheliomas in relation to occupational exposure to various types and mixtures of asbestos 

(including talc containing asbestos), although occupational exposures have not been identified in all 

cases [ref: 1-21]. Mesotheliomas of the tunica vaginalis testis and of the pericardium have been 

reported in persons occupationally exposed to asbestos [ref: 22-24]. 

Environmental exposure either in the houses of asbestos workers or in the neighbourhood of 

asbestos mines or factories has been noted in some of the cases [ref: 1,2,4-6,9,11,25,26]. It has 

been estimated that a third of the mesotheliomas occurring in the USA may be due to 

nonoccupational exposure [ref: 27]. In a study from Israel, the incidence of mesothelioma was 

found to be higher among those born in the USA or in Europe relative to those born in Israel [ref: 

9]. 

In some of these case reports and in other studies, asbestos fibres have been identified in the lung 

[ref: 5,6,11,28-32]. Amphibole fibres have usually predominated, but in a few cases mainly or only 

chrysotile fibres were found [ref: 6,28]. 

The long latency required for mesothelioma to develop after asbestos exposure has been 

documented in a number of publications [ref: 11,13,26,28,33-37]. An increasing proportion of cases 

has been seen with increasing duration of exposure [ref: 36]. 

A number of epidemiological studies of respiratory cancer and mesothelioma have been reported in 

relation to exposure to unspecified or complex mixtures of asbestos in shipyard work [ref: 38-45]. 

The risk ratio for lung cancer has usually been moderately increased, both in these studies and in 
studies on various other occupational groups with similarly job-related but unspecified or complex 

asbestos exposures [ref: 35,46-54]. Risk ratios of about 2-5 have been reported in some studies, 

but the ratio was considerably higher in one rather small study [ref: 55] and did not exceed unity in 

another [ref: 42]. In one study, individuals suffering from asbestosis had a considerably greater risk 

for lung cancer, with a risk ratio of 9.0 [ref: 56]. In some of the studies referred to, a number of 

mesotheliomas were also observed [ref: 41,42,44,47,51,53,55]. Abdominal mesotheliomas have 

sometimes been mistaken for pancreatic cancer [ref: 57]. Mesothelioma cases have been observed 

to have a relatively lower fibre content in the lungs than lung cancer cases [ref: 32]. 

Laryngeal cancer has been considered in two case-control studies, resulting in risk ratios of 2.4 and 

2.3 that relate to shipyard work and unspecified exposure, respectively [ref: 40,58] A cohort study 

of insulation workers showed a relative risk of 1.9, based on nine cases [ref: 57]. A case series 

indicated a high frequency of exposure to asbestos, especially in low-grade smokers [ref: 59]. A risk 

ratio of 3.2 for laryngeal cancer was reported among chrysotile miners in an area with generally 

high incidence [ref: 60], but no increased risk was seen in a cohort of workers with exposure to 

crocidolite [ref: 61]. Two correlation studies have also indicated a relationship between laryngeal 

cancer and exposure to asbestos [ref: 39,62]. 

Mesotheliomas related to shipyard work and other exposures, including household contact with 

asbestos workers, have also been subject to epidemiological studies [ref: 36,63-67], resulting in 

risk ratios of about 3-15 in comparison with background rates not clearly referable to asbestos 

exposure. 

Some studies have specifically considered environmental exposures with reference to 

mesotheliomas [ref: 66,67]. Three correlation studies and one case-control study considering 

exposure to piped drinking-water [ref: 68-71] did not show consistently increased risks for any type 

of cancer, whereas another study [ref: 72] considering chrysotile contamination mainly from natural 

sources gave some indication of an increase in the incidence of peritoneal and stomach cancers in 

persons of each sex, although no other cancer site was consistent in this respect. 

Exposure to crocidolite has been studied with regard to risk of lung cancer [ref: 61,73-76], and risk 

ratios of about 2-3 have been reported. Three lung cancers and two mesotheliomas occurred in 20 

individuals after one year of high exposure to crocidolite; at least 17 of the cases had asbestosinduced lung changes on X-ray films [ref: 77]. 

One study [ref: 78] of histological types of lung cancers showed that among persons exposed to 

crocidolite 45.7% of cases were squamous-cell carcinomas, as compared to 35.2% among 

unexposed persons. In the context of unspecified and complex exposures, small-cell carcinoma was 

found to be relatively more prevalent than other forms [ref: 50]. 

Exposure to chrysotile was found in some studies to result in virtually no increase in risk ratio [ref: 

60,79-81], or a slightly elevated relative risk of lung cancer [ref: 82-86]. Somewhat higher risk 

ratios, up to 2.5, 3.5 and 2, respectively, were obtained in one study of chrysotile miners [ref: 87] 

and in two independent studies from one asbestos [chrysotile] textile plant [ref: 88,89], the latter 

being the more comprehensive. With regard to mesotheliomas, one study suggested a particularly 

high risk of combined exposure to chrysotile and amphiboles (risk ratio, 61), thus almost multiplying 

the risk ratios (6 and 12, respectively) of exposures to chrysotile and amphiboles alone [ref: 90]. 

Another study showed no mesothelioma among a large worker population with exposure to 

chrysotile only [ref: 91]. 

A slight excess of lung cancer and some mesotheliomas appeared in some groups with mixed 

exposures involving amosite, chrysotile and crocidolite [ref: 92-94]. Exposure predominantly to 

amosite, but also to chrysotile, was reported to be the probable cause of at least four of five 

mesotheliomas (one peritoneal) observed in a UK insulation-board factory [ref: 95]. One cohort with 

exposure to cummingtonite-grunerite, which is closely related to amosite, had no clear excess of 

lung cancer, although one case of mesothelioma was observed [ref: 96]. 

Exposure to tremolite and actinolite has been the subject of a few studies in investigations of 

vermiculite mining and milling [ref: 97,98] and environmental exposure [ref: 99]. The studies of 

miners indicated a risk ratio for lung cancer of up to approximately six fold. Deaths from 

mesothelioma were found in the occupational studies, whereas the study of environmental exposure 
showed no increased risk, although pleural plaques were reported. Publication of one case report of 

a mesothelioma after environmental exposure suggests that tremolite was of etiological importance 

[ref: 31]. 

Cancers other than of the lung or mesothelioma have been considered in many studies [ref : 1, 17, 

35, 39, 41-44, 48, 51, 55, 60-62, 68-70, 72-74, 76, 83, 87, 89, 92, 93, 96, 97, 99-108]. Some 

indicated an approximately two-fold risk with regard to gastrointestinal cancer in connection with 

shipyard work [ref: 41,43], and some increased risk was also seen in association with exposure to 

both chrysotile and crocidolite [ref: 103], to crocidolite [ref: 61,74] or to chrysotile [ref: 87]. Cancer 

of the colon and rectum was associated with asbestos exposure during chrysotile production, with 

an approximately two-fold risk [ref: 87]; a similar excess was found for unspecified asbestos 

exposure [ref: 104]. Some excess of ovary cancer has been reported in two studies [ref: 73,76] but 

not in another [ref: 92]; exposure to crocidolite was probably more predominant in the studies that 

showed excesses. Bile-duct cancer appeared in excess in one study based on record-linking [ref: 

105], and large-cell lymphomas of the gastrointestinal tract and oral cavity appeared to be strongly 

related to asbestos exposure in one small study covering 28 cases and 28 controls, giving a risk 

ratio of 8; however, ten cases and one control also had a history of malaria [ref: 106]. An excess of 

lymphopoietic and haematopoietic malignancies has been reported in plumbers, pipe-fitters, sheetmetal workers and others with asbestos exposure [ref: 17,54,107,108]. 

The relationship between asbestos exposure and smoking indicates a synergistic effect of smoking 

with regard to lung cancer [ref: 1]. Further evaluations indicate that this synergistic effect is close 

to a multiplicative model [ref: 52,109]. As noted previously [ref: 1], the risk of mesothelioma 

appears to be independent of smoking [ref: 47,66], and a significantly decreasing trend in risk was 

observed with the amount smoked in one study [ref: 65]. 

The studies of the carcinogenic effect of asbestos exposure, including evidence reviewed earlier [ref: 

1], show that occupational exposure to chrysotile, amosite and anthophyllite asbestos and to 

mixtures containing crocidolite results in an increased risk of lung cancer, as does exposure to 

minerals containing tremolite and actinolite and to tremolitic material mixed with anthophyllite and 

small amounts of chrysotile. Mesotheliomas have been observed after occupational exposure to 

crocidolite, amosite, tremolitic material and chrysotile asbestos. Gastrointestinal cancers occurred at 

an increased incidence in groups occupationally exposed to crocidolite, amosite, chrysotile or mixed 

fibres containing crocidolite, although not all studies are consistent in this respect. An excess of 

laryngeal cancer has also been observed in some groups of exposed workers. No clear excess of 

cancer has been associated with the presence of asbestos fibres in drinking-water. Mesotheliomas 

have occurred in individuals living in the neighbourhood of asbestos factories and mines and in 

people living with asbestos workers. 

B. Evidence for carcinogenicity to animals (sufficient)

Asbestos has been tested for carcinogenicity by inhalation in rats, by intrapleural administration in 

rats and hamsters, by intraperitoneal injection in mice, rats and hamsters and by oral 

administration in rats and hamsters. Chrysotile, crocidolite, amosite, anthophyllite and tremolite 

produced mesotheliomas and lung carcinomas in rats after inhalation exposure [ref: 1,110,111] and 

mesotheliomas following intrapleural administration [ref: 1,112]. Chrysotile, crocidolite, amosite and 

anthophyllite induced mesotheliomas in hamsters following intrapleural administration [ref: 1]. 

Intraperitoneal administration of chrysotile, crocidolite and amosite induced peritoneal tumours, 

including mesotheliomas, in mice [ref: 1,113] and rats [ref: 1,111,114]. Given by the same route, 

crocidolite produced abdominal tumours in hamsters [ref: 115], and tremolite and actinolite 

produced abdominal tumours in rats [ref: 110,116-118]. A statistically significant increase in the 

incidence of malignant tumours was observed in rats given filter material containing chrysotile orally 

[ref: 1]. In more recent studies, tumour incidence was not increased by oral administration of 

amosite or tremolite in rats [ref: 119], of amosite in hamsters [ref: 120,121] or of chrysotile in 

hamsters [ref: 121]. In two studies in rats, oral administration of chrysotile produced a low 

incidence of benign adenomatous polyps of the large intestine in males (9/250 versus 3/524 pooled 

controls) [ref: 122] and of mesenteric haemangiomas (4/22 versus 0/47 controls) [ref: 123]. 

Synergistic effects were observed following intratracheal administration of chrysotile and 

benzo[a]pyrene to rats and hamsters [ref: 1] and of intratracheal administration of chrysotile and 

subcutaneous or oral administration of N-nitrosodiethylamine to hamsters [ref: 124]. 

C. Other relevant data
Insulation workers exposed to asbestos 'displayed a marginal increase' in the incidence of sister 

chromatid exchanges in lymphocytes in one study [ref: 125]. 

Chrysotile did not induce micronuclei in bone-marrow cells of mice or chromosomal aberrations in 

bone-marrow cells of rhesus monkeys treated in vivo. In cultured human cells, conflicting results 

were reported for the induction of chromosomal aberrations and negative results for the induction of 

sister chromatid exchanges by chrysotile and crocidolite; amosite and crocidolite did not induce DNA 

strand breaks, and crocidolite was not mutagenic. Amosite, anthophyllite, chrysotile and crocidolite 

induced transformation of Syrian hamster embryo cells, chrysotile and crocidolite transformed 

BALB/c3T3 mouse cells, and chrysotile transformed rat mesothelial cells. Neither amosite nor 

crocidolite transformed CH3 10T1/2 cells. In cultured rodent cells, amosite, anthophyllite, chrysotile 

and crocidolite induced chromosomal aberrations, and amosite, chrysotile and crocidolite induced 

sister chromatid exchanges; chrysotile and crocidolite induced aneuploidy and micronuclei. 

Chrysotile did not induce unscheduled DNA synthesis in rat hepatocytes. Amosite, chrysotile and 

crocidolite were inactive or weakly active in inducing mutation in rodent cells in vitro; none were 

mutagenic to bacteria [ref: 125]. 

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 2 (1973); Vol. 14 (1977)

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37. Selikoff, I.J., Hammond, E.C. & Seidman, H. (1980) Latency of asbestos disease among 

insulation workers in the United States and Canada. Cancer, 46, 2736-2740 

38. Blot, W.J., Harrington, J.M., Toledo, A., Hoover, R., Heath, C.W., Jr & Fraumeni, J.F., Jr (1978) 

Lung cancer after employment in shipyards during World War II. New Engl. J. Med., 299, 620-624 

39. Blot, W.J., Stone, B.J., Fraumeni, J.F., Jr & Morris, L.E. (1979) Cancer mortality in US counties 

with shipyard industries during World War II. Environ. Res., 18, 281-290 

40. Blot, W.J., Morris, L.E., Stroube, R., Tagnon, I. & Fraumeni, J.F., Jr (1980) Lung and laryngeal 

cancers in relation to shipyard employment in coastal Virginia. J. natl Cancer Inst., 65, 571-575 

41. Kolonel, L.N., Yoshizawa, C.N., Hirohata, T. & Myers, B.C. (1985) Cancer occurrence in shipyard 

workers exposed to asbestos in Hawaii. Cancer Res., 45, 3924-3928 

42. Rossiter, C.E. & Coles, R.M. (1980) HM Dockyard, Devonport: 1947 mortality study. In: Wagner, 

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43. Sandén, A., Näslund, P.-E. & Järvholm, B. (1985) Mortality in lung and gastrointestinal cancer 

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44. Lumley, K.P.S. (1976) A proportional study of cancer registrations of dockyard workers. Br. J. 

ind. Med., 33, 108-114 

45. Nicholson, W.J., Lilis, R., Frank, A.L. & Selikoff, I.J. (1980) Lung cancer prevalence among 
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46. Alies-Patin, A.M. & Valleron, A.J. (1985) Mortality of workers in a French asbestos cement 

factory 1940-82. Br. J. ind. Med., 42, 219-225 

47. Berry, G., Newhouse, M.L. & Antonis, P. (1985) Combined effect of asbestos and smoking on 

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48. Hodgson, J.T. & Jones, R.D. (1986) Mortality of asbestos workers in England and Wales. Br. J. 

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49. Coggon, D., Pannett, B. & Acheson, E.D. (1984) Use of job-exposure matrix in an occupational 

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65 

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Health, 57, 161-171 

54. Zoloth, S. & Michaels, D. (1985) Asbestos disease in sheet metal workers: the results of a 

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55. Elmes, P.C. & Simpson, M.J.C. (1977) Insulation workers in Belfast. A further study of mortality 

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1265 

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Cancer, 47 (Suppl.), 1469-1473 

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61. Musk, A.W., de Klerk, N., Hobbs, M.S.T. & Armstrong, B.K. (1986) Mortality in crocidolite miners 

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62. Graham, S., Blanchet, M. & Rohrer, T. (1977) Cancer in asbestos-mining and other areas of 

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63. Chiappino, G., Riboldi, L., Todaro, A. & Schulz, L. (1985) Survey of mesotheliomas in Lombardy 

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64. Mowé, G., Gylseth, G., Hartveit, F. & Skaug, V. (1984) Occupational asbestos exposure, lungfiber concentration and latency time in malignant mesothelioma. Scand. J. Work Environ. Health, 

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67. Vianna, N.J. & Polan, A.K. (1978) Non-occupational exposure to asbestos and malignant 

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191 

69. Wigle, D.T. (1977) Cancer mortality in relation to asbestos in municipal water supplies. Arch. 

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70. Harrington, J.M., Craun, G.F., Meigs, J.W., Landrigan, P.J., Flannery, J.T. & Woodhull, R.S. 

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incidence of gastrointestinal cancer in Connecticut, 1935-1973. Am. J. Epidemiol., 107, 96-103 

71. Polissar, L., Severson, R.K. & Boatman, E.S. (1984) A case-control study of asbestos in drinking 

water and cancer risk. Am. J. Epidemiol., 119, 456-471 

72. Kanarek, M.S., Conforti, P.M., Jackson, L.A., Copper, R.C. & Murchio, J.C. (1980) Asbestos in 

drinking water and cancer incidence in the San Francisco Bay area. Am. J. Epidemiol., 112, 54-72 

73. Acheson, E.D., Gardner, M.J., Pippard, E.C. & Grime, L.P. (1982) Mortality of two groups of 

women who manufactured gas masks from chrysotile and crocidolite asbestos: a 40-year follow-up. 

Br. J. ind. Med., 39, 344-348 

74. Botha, J.L., Irwig, L.M. & Strebel, P.M. (1986) Excess mortality from stomach cancer, lung 

cancer, and asbestosis and/or mesothelioma in crocidolite mining districts in South Africa. Am. J. 

Epidemiol., 123, 30-40 

75. Hobbs, M.S.T., Woodward, S.D., Murphy, B., Musk, A.W. & Elder, J.E. (1980) The incidence of 

pneumoconiosis, mesothelioma and other respiratory cancer in men engaged in mining and milling 

crocidolite in Western Australia. In: Wagner, J.C., ed., Biological Effects of Mineral Fibres (IARC 

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76. Wignall, B.K. & Fos, A.J. (1982) Mortality of female gas mask assemblers. Br. J. ind. Med., 39, 

34-38 

77. Hilt, B., Rosenberg, J. & Langard, S. (1981) Occurrence of cancer in a small cohort of asbestos-
exposed workers. Scand. J. Work Environ. Health, 7, 185-189 

78. Baker, J.E., Reutens, D.C., Graham, D.F., Sterrett, G.F., Musk, A.W., Hobbs, M.S.T., Armstrong, 

B.K. & de Klerk, N.H. (1986) Morphology of bronchogenic carcinoma in workers formerly exposed to 

crocidolite at Wittenoom Gorge in Western Australia. Int. J. Cancer, 37, 547-550 

79. Berry, G. & Newhouse, M.L. (1983) Mortality of workers manufacturing friction materials using 

asbestos. Br. J. ind. Med., 40, 1-7 

80. Gardner, M.J., Winter, P.D., Pannett, B. & Powell, C.A. (1986) Follow up study of workers 

manufacturing chrysotile asbestos cement products. Br. J. ind. Med., 43, 726-732 

81. Weiss, W. (1977) Mortality of a cohort exposed to chrysotile asbestos. J. occup. Med., 19, 737-

740

82. Haider, M. & Neuberger, M. (1980) Comparison of lung cancer risks for dust workers, asbestoscement workers and control groups. In: Wagner, J.C., ed., Biological Effects of Mineral Fibres (IARC 

Scientific Publications No. 30), Lyon, International Agency for Research on Cancer, pp. 973-977

83. McDonald, A.D., Fry, J.S., Woolley, A.J. & McDonald, J.C. (1984) Dust exposure and mortality in 

an American chrysotile asbestos friction products plant. Br. J. ind. Med., 41, 151-157 

84. Peto, J. (1980) Lung cancer mortality in relation to measured dust levels in an asbestos textile 

factory. In: Wagner, J.C., ed., Biological Effects of Mineral Fibres (IARC Scientific Publications No. 

30), Lyon, International Agency for Research on Cancer, pp. 829-836 

85. Peto, J., Doll, R., Howard, S.V., Kinlen, L.J. & Lewinsohn, H.C. (1977) A mortality study among 

workers in an English asbestos factory. Br. J. ind. Med., 34, 169-173 

86. Peto, J., Doll, R., Hermon, C., Binns, W., Clayton, R. & Goffe, T. (1985) Relationship of mortality 

to measures of environmental asbestos pollution in an asbestos textile factory. Ann. occup. Hyg., 

29, 305-355 

87. Liddell, F.D.K., Thomas, D.C., Gibbs, G.W. & McDonald, J.C. (1984) Fibre exposure and 

mortality from pneumoconiosis, respiratory and abdominal malignancies in chrysotile production in 

Quebec, 1926-75. Ann. Acad. Med., 13, 340-344 

88. Dement, J.M., Harris, R.L., Jr, Symons, M.J. & Shy, C. (1982) Estimates of dose-response for 

respiratory cancer among chrysotile asbestos textile workers. Ann. occup. Hyg., 26, 869-887 

89. McDonald, A.D., Fry, J.S., Woolley, A.J. & McDonald, J. (1983) Dust exposure and mortality in 

an American chrysotile textile plant. Br. J. ind. Med., 40, 361-367 

90. Acheson, E.D. & Gardner, M.J. (1979) Mesothelioma and exposure to mixtures of chrysotile and 

amphibole asbestos. Arch. environ. Health, 34, 240-242 

91. Browne, K. & Smither, W.J. (1983) Asbestos-related mesothelioma: factors discriminating 

between pleural and peritoneal sites. Br. J. ind. Med., 40, 145-152 

92. Newhouse, M.L., Berry, G. & Skidmore, J.W. (1982) A mortality study of workers manufacturing 

friction materials with chrysotile asbestos. Ann. occup. Hyg., 26, 899-909 

93. Ohlson, C.-G., Klaesson, B. & Hogstedt, C. (1984) Mortality among asbestos-exposed workers in 

a railroad workshop. Scand. J. Work Environ. Health, 10, 283-291 
94. McDonald, A.D. & Fry, J.S. (1982) Mesothelioma and fiber type in three American asbestos 

factories - preliminary report. Scand. J. Work Environ. Health, 8 (Suppl. 1), 53-58 

95. Acheson, E.D., Gardner, M.J., Bennett, C. & Winter, P.D. (1981) Mesothelioma in a factory using 

amosite and chrysotile asbestos. Lancet, ii, 1403-1405 

96. McDonald, J.C., Gibbs, G.W., Liddell, F.D.K. & McDonald, A.D. (1978) Mortality after long 

exposure to cummingtonite-grunerite. Am. Rev. respir. Dis., 118, 271-277 

97. McDonald, J.C., McDonald, A.D., Armstrong, B. & Sébastien, P. (1986) Cohort study of mortality 

in vermiculite miners exposed to tremolite. Br. J. ind. Med., 43, 436-444 

98. Amandus, H.E. & Wheeler, R. (1987) The morbidity and mortality of vermiculite miners and 

millers exposed to tremolite-actinolite: Part II. Mortality. Am. J. ind. Med., 11, 15-26 

99. Neuberger, M., Kundi, M. & Friedl, H.P. (1984) Environmental asbestos exposure and cancer 

mortality. Arch. environ. Health, 39, 261-265 

100. Ohlson, C.-G. & Hogstedt, C. (1985) Lung cancer among asbestos cement workers. A Swedish 

cohort study and a review. Br. J. ind. Med., 42, 397-402 

101. Thomas, H.F., Benjamin, I.T., Elwood, P.C. & Sweetnam, P.M. (1982) Further follow-up study 

of workers from an asbestos cement factory. Br. J. ind. Med., 39, 273-276 

102. Weill, H., Hughes, J. & Waggenspack, C. (1979) Influence of dose and fiber type on respiratory 

malignancy risk in asbestos cement manufacturing. Am. Rev. respir. Dis., 120, 345-354 

103. Finkelstein, M.M. (1984) Mortality among employees of an Ontario asbestos-cement factory. 

Am. Rev. respir. Dis., 129, 754-761 

104. Hardell, L. (1981) Relation of soft-tissue sarcoma, malignant lymphoma and colon cancer to 

phenoxy acids, chlorophenols and other agents. Scand. J. Work Environ. Health, 7, 119-130 

105. Malker, H.S.R., McLaughlin, J.K., Malker, B.K., Stone, B.J., Weiner, J.A., Ericsson, J.L.E. & Blot, 

W.J. (1986) Biliary tract cancer and occupation in Sweden. Br. J. ind. Med., 43, 257-262 

106. Ross, R., Nichols, P., Wright, W., Lukes, R., Dworsky, R., Paganini-Hill, A., Koss, M. & 

Henderson, B. (1982) Asbestos exposure and lymphomas of the gastrointestinal tract and oral 

cavity. Lancet, ii, 1118-1120 

107. Waxweiler, R.J. & Robinson, C. (1983) Asbestos and non-Hodgkin's lymphoma. Lancet, i, 189-

190 

108. Spanedda, R., Barbieri, D. & La Corte, R. (1983) Asbestos and non-Hodgkin's lymphoma. 

Lancet, i, 190 

109. Saracci, R. (1977) Asbestos and lung cancer: an analysis of the epidemiological evidence on 

the asbestos-smoking interaction. Int. J. Cancer, 20, 323-331 

110. Davis, J.M.G., Addison, J., Bolton, R.E., Donaldson, K., Jones, A.D. & Miller, B.G. (1985) 

Inhalation studies on the effects of tremolite and brucite dust in rats. Carcinogenesis, 6, 667-674 

111. Davis, J.M.G., Addison, J., Bolton, R.E., Donaldson, K. & Jones, A.D. (1986) Inhalation and 

injection studies in rats using dust samples from chrysotile asbestos prepared by a wet dispersion 

process. Br. J. exp. Pathol., 67, 113-129 
112. Stanton, M.F., Layard, M., Tegeris, A., Miller, E., May, M., Morgan, E. & Smith, A. (1981) 

Relation of particle dimension to carcinogenicity in amphibole asbestoses and other fibrous minerals. 

J. natl Cancer Inst., 67, 965-975 

113. Suzuki, Y, & Kohyama, N. (1984) Malignant mesothelioma induced by asbestos and zeolite in 

the mouse peritoneal cavity. Environ. Res., 35, 277-292 

114. Bolton, R.E., Davis, J.M.G., Donaldson, K. & Wright, A. (1982) Variations in the carcinogenicity 

of mineral fibres. Ann. occup. Hyg., 26, 569-582 

115. Pott, F., Huth, F. & Spurny, K. (1980) Tumour induction after intraperitoneal injection of 

fibrous dusts. In: Wagner, J.C., ed., Biological Effects of Mineral Fibres (IARC Scientific Publications 

No. 30), Lyon, International Agency for Research on Cancer, pp. 337-342 

116. Spurny, K., Pott, F., Huth, F., Weiss, G. & Opiela, H. (1979) Identification and carcinogenic 

action of fibrous actinolite from a diabase rock (Ger.). Staub-Reinhalt. Luft, 39, 386-389 

117. Pott, F., Schlipköter, H.W., Ziem, U., Spurny, K. & Huth, F. (1982) New results from 

implantation experiments with mineral fibres. In: Biological Effects of Man-made Fibres, Vol. 2, 

Copenhagen, WHO Regional Office for Europe, pp. 286-302 

118. Pott, F., Matscheck, A., Ziem, U., Muhle, H. & Huth, F. (1987) Animal experiments with 

chemically treated fibres. Ann. occup. Hyg. (in press) 

119. McConnell, E.E., Rutter, H.A., Ulland, B.M. & Moore, J.A. (1983) Chronic effects of dietary 

exposure to amosite asbestos and tremolite in F344 rats. Environ. Health Perspect., 53, 27-44 

120. National Toxicology Program (1983) Lifetime Carcinogenesis Studies of Amosite Asbestos (CAS 

No. 121-72-73-5) in Syrian Golden Hamsters (Feed Studies) (NIH Publ. No. 84-2505; NTP TR 249), 

Research Triangle Park, NC 

121. McConnell, E.E., Shefner, A.M., Rust, J.H. & Moore, J.A. (1983) Chronic effects of dietary 

exposure to amosite and chrysotile asbestos in Syrian golden hamsters. Environ. Health Perspect., 

53, 11-25 

122. National Toxicology Program (1985) Toxicology and Carcinogenesis Studies of Chrysotile 

Asbestos (CAS No. 12001-29-5) in F344/N Rats (Feed Studies) (NIH Publ. No. 86-2551; NTP TR 

295), Research Triangle Park, NC 

123. Bolton, R.E., Davis, J.M.G. & Lamb, D. (1982) The pathological effects of prolonged asbestos 

ingestion in rats. Environ. Res., 29, 134-150 

124. Küng-Vösamäe, A. & Vinkmann, F. (1980) Combined carcinogenic action of chrysotile asbestos 

dust and N-nitrosodiethylamine on the respiratory tract of Syrian golden hamsters. In: Wagner, 

J.C., ed., Biological Effects of Mineral Fibres (IARC Scientific Publications No. 30), Lyon, 

International Agency for Research on Cancer, pp. 305-310

125. IARC Monographs, Suppl. 6, 77-80, 1987

Overall evaluation

Asbestos is carcinogenic to humans (Group 1).

Synonym for Asbestos fibre:
● Asbestos 

Synonyms for Anthophyllite: 

● Azbolen asbestos 

● Ferroanthophyllite 

Synonym for Amosite:

● Brown asbestos 

● Mysorite 

Synonyms for Chrysotile: 

● Avibest C 

● Cassiar AK 

● Calidria RG 144 

● Calidria RG 600 

● Serpentine 

● White asbestos 

Synonym for Crocidolite:

● Blue asbestos 

Synonyms for Tremolite:

● Magnesium salt (8:4) 

● Silicic acid, calcium 

Last updated: 6 February 1998 
AURAMINE (TECHNICAL-GRADE) (Group 2B) 

and MANUFACTURE OF AURAMINE (Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 118) 

CAS No.: 492-80-8

Chem. Abstr. Name: C.I. Solvent yellow 34 

A. Evidence for carcinogenicity to humans (inadequate for auramine, technical-grade; sufficient

for the manufacture of auramine)

The manufacture of auramine (which also involves exposure to other chemicals) was judged to be 

causally associated with an increased incidence of bladder cancer on the basis of one study dealing 

with experiences in the first half of the century in the UK [ref: 1]. Data reported later, in two studies 

dealing with one group of workers in the Federal Republic of Germany involved in the manufacture 

of auramine, were judged to show increased risks of both bladder cancer and prostatic cancer; 

however, these workers had also been exposed to other chemicals, including 2-naphthylamine (see 

p. 261) [ref: 2,3]. 

In a study of mortality and cancer incidence among hairdressers, the hypothesis was raised that the 

observed excess risk of bladder cancer was associated with exposure to colouring agents present in 

brilliantines used on men's hair. Auramine was reported to be one of the most commonly used dyes 

in brilliantines, at least in the 1930s; however, the occurrence of impurities, such as 2-

naphthylamine could not be ruled out [ref: 4]. Data on exposure to auramine alone were considered 

to be inadequate for evaluation. 

B. Evidence for carcinogenicity to animals (sufficient for auramine, technical-grade)

Auramine (technical-grade) was tested for carcinogenicity by oral administration in mice and rats 

and by subcutaneous injection in rats. Following its oral administration, it induced liver neoplasms in 

animals of each species [ref: 1,2]. After subcutaneous injection in one study in rats, it induced local 

sarcomas [ref: 1]. Studies in rabbits and dogs were inadequate for evaluation [ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of auramine in humans. Auramine did not 

induce micronuclei in bone-marrow cells of mice treated in vivo. It transformed Syrian hamster 

embryo cells and induced sister chromatid exchanges and DNA strand breaks in rodent cells in 

culture. It caused aneuploidy, mitotic recombination and DNA damage in yeast. Auramine was 

mutagenic to bacteria and induced prophage [ref: 5]. 

Overall evaluation

Manufacture of auramine is carcinogenic to humans (Group 1).

Auramine (technical-grade) is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 1 (1972)

References
1. IARC Monographs, 1, 69-73, 1972 

2. Kirsch, P., Fleig, I., Frentzel-Beyme, R., Gembardt, C., Steinborn, J., Thiess, A.M., Koch, W., 

Seibert, W., Wellenreuther, G. & Zeller, H. 1978) Auramine. Toxicology and occupational health 

(Ger.). Arbeitsmed. Sozialmed. Präventivmed., 13, 1-28 

3. Thiess, A.M., Link, R. & Wellenreuther, G. (1982) Mortality study of employees exposed to 

auramine. In: El-Attal, M., Abdel-Gelib, S., Massoud, A. & Noweir, M., eds, Proceedings of the 9th 

International Conference of Occupational Health in the Chemical Industry, Cairo, 1981, pp. 197-208 

4. Gubéran, E., Raymond, L. & Sweetnam, P.M. (1985) Increased risk for male bladder cancer 

among a cohort of male and female hairdressers from Geneva. Int. J. Epidemiol., 14, 549-554 

5. IARC Monographs, Suppl. 6, 83-85, 1987 

Synonyms for Auramine

● Aniline,4,4'-(imidocarbonyl)-bis(N,N'-dimethyl)- 

● Apyonine auramine base 

● Auramine N base 

● Auramine O base 

● Auramine SS 

● Auramine OO 

● Brilliant oil yellow 

● C.I. basic yellow 2 (free base) 

● 4,4'-Dimethylaminobenzophenonimide 

● bis(para-Dimethylaminophenyl)methyleneimine 

● Fat yellow A 

● Glauramine 

● Tetramethyl-p-diamino-imido-benzophenme 

● Tetramethyldiaminodiphenylacetimine 

● Yellow pyoctanine 

Last updated: 6 February 1998 
AZATHIOPRINE

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 119) 

CAS No.: 446-86-6

Chem. Abstr. Name: 1H-Purine, 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]- 

A. Evidence for carcinogenicity to humans (sufficient)

Two large prospective epidemiological studies have shown that renal transplant patients, who 

usually receive azathioprine as an immunosuppressant, become at high risk for non-Hodgkin's 

lymphoma, squamous-cell cancers of the skin, hepatobiliary carcinomas and mesenchymal tumours. 

While this is true for each of the various etiological entities resulting in the need for a transplant, 

these patients also have in common heavy exposure to foreign antigens [ref: 1]. Other patients who 

have received azathioprine as an immunosuppressant, including those with rheumatoid arthritis, 

systemic lupus and other 'collagen' disorders, inflammatory bowel disease and certain skin and renal 

diseases, have also been studied: the same array of malignancies was found to be in excess, 

although to a lesser extent [ref: 1,2]. For these patients, however, the picture is still not completely 

clear, because patients with rheumatoid arthritis constituted the largest category in the latter study 

[ref: 2], and some [ref: 3], but not all studies [ref: 4], have found that this disease conveys a risk 

for non-Hodgkin's lymphoma in the absence of treatment. 

B. Evidence for carcinogenicity to animals (limited)

Suggestive evidence was obtained that lymphomas were induced in mice after intraperitoneal, 

subcutaneous or intramuscular injection of azathioprine, and that thymic lymphomas and squamouscell carcinomas of the ear duct were induced in rats after oral administration, but there were 

limitations in the design and reporting of these studies [ref: 1,5]. 

C. Other relevant data

There are conflicting reports of effects on the incidence of chromosomal aberrations in lymphocytes 

and bone-marrow cells of patients treated with azathioprine. In one study, the incidence of sister 

chromatid exchanges in lymphocytes of treated patients was not increased [ref: 6]. 

In animals treated in vivo, azathioprine induced dominant lethal mutations in mice; chromosomal 

aberrations in rabbit lymphocytes and Chinese hamster bone-marrow cells, and micronuclei in mice, 

rats and hamsters; it did not induce sister chromatid exchanges in Chinese hamster bone-marrow 

cells. Azathioprine induced chromosomal aberrations but not sister chromatid exchanges in human 

lymphocytes in vitro. It induced chromosomal aberrations in Drosophila and was weakly mutagenic 

to fungi and was mutagenic to bacteria [ref: 6]. 

Overall evaluation

Azathioprine is carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 26 (1981)

References
1. IARC Monographs, 26, 47-78, 1981 

2. Kinlen, L.J. (1985) Incidence of cancer in rheumatoid arthritis and other disorders after 

immunosuppressive treatment. Am. J. Med., 78 (Suppl. 1A), 44-49 

3. Isomäki, H.A., Hakulinen, T. & Joutsenlahti, U. (1978) Excess risk of lymphomas, leukemia and 

myeloma in patients with rheumatoid arthritis. J. chron. Dis., 31, 691-696 

4. Fries, J.F., Bloch, D., Spitz, P. & Mitchell, D.M. (1985) Cancer in rheumatoid arthritis: a 

prospective long-term study of mortality. Am. J. Med., 78 (Suppl. 1A), 56-59 

5. Cohen, S.M., Erturk, E., Skibba, J.L. & Bryan, G.T. (1983) Azathioprine induction of lymphomas 

and squamous cell carcinomas in rats. Cancer Res., 43, 2768-2772 

6. IARC Monographs, Suppl. 6, 86-88, 1987 

Synonyms

● Amuran 

● Azamun 

● Azathioprin 

● Azatioprin 

● Azothiaprine 

● Azathioprene 

● BW 57322 

● Imuran 

● Imurel 

● Imurek 

● Methyl-nitroimidazolylmercaptopurine 

● 6-[(1-Methyl-4-nitroimidazol-5-yl)thio]purine 

● 6-(1-Methyl-4-nitro-imidazole-5-yl)thiopurine 

● 6-(1-Methyl-4-nitro-5-imidazolyl)mercaptopurin 

● Muran 

● NSC 39084 

Last updated: 6 February 1998 
BENZENE

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 120)

CAS No.: 71-43-2

Chem. Abstr. Name: Benzene 

A. Evidence for carcinogenicity to humans (sufficient)

Numerous case reports and series have suggested a relationship between exposure to benzene and 

the occurrence of various types of leukaemia [ref: 1]. Several case-control studies have also shown 

increased odds ratios for exposure to benzene, but mixed exposure patterns and poorly defined 

exposures render their interpretation difficult [ref: 1,2]. 

Three independent cohort studies have demonstrated an increased incidence of acute 

nonlymphocytic leukaemia in workers exposed to benzene [ref: 1,3]. An updating of a cohort study 

published earlier on benzene-exposed workers [ref: 1] confirmed the previous findings and added a 

further case of myelogenous leukaemia, giving a standardized mortality ratio (SMR) of 194 (95% 

confidence interval, 52-488), based on four cases; the difference was statistically significant when 

only myelogenous leukaemia was considered (4 observed, 0.9 expected; p = 0.011) [ref: 4]. A 

further cohort study found an excess of acute myeloid leukaemia (SMR, 394; 172-788) among 

refinery workers, based on eight cases; however, the patients had not worked in jobs identified as 

having the highest benzene exposure [ref: 5]. Another study of refinery workers showed no death 

from leukaemia (0.42 expected); however, the median exposure intensity for benzene was 0.14 

ppm (0.45 mg/m3), and only 16% of 1394 personal samples, taken between 1973 and 1982 

inclusive, contained more than 1 ppm (3.19 mg/m3). The median exposure intensity in 'benzenerelated units' was 0.53 ppm (1.7 mg/m3) [ref: 6]. 

In a Chinese retrospective cohort study, encompassing 28 460 workers exposed to benzene in 233 

factories, 30 cases of leukaemia (23 acute, seven chronic) were found, as compared to four cases in 

a reference cohort of 28 257 workers in 83 machine production, textile and cloth factories. The 

mortality rate from leukaemia was 14/100 000 person-years among the exposed and 2/100 000 

person-years among the unexposed (SMR, 574; p < 0.01). Mortality was especially high for workers 

engaged in organic synthesis, painting and rubber production. The mortality from leukaemia for 

cases that had previously had benzene poisoning was 701/100 000 person-years. 'Grab' samples of 

benzene in air were taken during the time of the survey in workplaces where cases of leukaemia 

were observed; the mean concentrations varied in a wide range from 10 to 1000 mg/m3, but the 

range 50-500 mg/m3 covered most of them [ref: 7]. 

B. Evidence for carcinogenicity to animals (sufficient)

Benzene was tested for carcinogenicity in mice and rats by several routes of administration. 

Following its oral administration at several dose levels, it induced neoplasms at multiple sites in 

males and females of both species [ref: 1,8-11]. After mice were exposed to benzene by inhalation, 

a tendency towards induction of lymphoid neoplasms was observed [ref: 1,12,13]. Exposure of rats 

by inhalation increased the incidence of neoplasms, mainly carcinomas, at various sites [ref: 

9,10,14-16]. Skin application or subcutaneous injection of benzene to mice did not produce 

evidence of carcinogenicity, but most of the experiments were inadequate for evaluation [ref: 1]. In 

a mouse-lung tumour bioassay by intraperitoneal injection, an increase in the incidence of lung 

adenomas was observed in males [ref: 17]. 

C. Other relevant data

Chromosomal aberrations in human peripheral lymphocytes were associated with occupational 

exposure to benzene, although many of the studies are very difficult to interpret [ref: 18]. 
Benzene induced chromosomal aberrations, micronuclei and sister chromatid exchanges in bonemarrow cells of mice, chromosomal aberrations in bone-marrow cells of rats and Chinese hamsters 

and sperm-head anomalies in mice treated in vivo. It induced chromosomal aberrations and 

mutation in human cells in vitro but did not induce sister chromatid exchanges in cultured human 

lymphocytes except in one study in which high concentrations of an exogenous metabolic system 

were used. In some test systems, benzene induced cell transformation. It did not induce sister 

chromatid exchanges in rodent cells in vitro, but did induce aneuploidy and, in some studies, 

chromosomal aberrations in cultured Chinese hamster ovary cells. Benzene induced mutation and 

DNA damage in some studies in rodent cells in vitro [ref: 18]. 

In Drosophila, benzene was reported to be weakly positive in assays for somatic mutation and for 

crossing-over in spermatogonia; in single studies, it did not induce sex-linked recessive lethal 

mutations or translocations. It induced aneuploidy, mutation and gene conversion in fungi. Benzene 

was not mutagenic to bacteria [ref: 18]. 

Overall evaluation

Benzene is carcinogenic to humans (Group 1)

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 7 (1974); Vol. 29 (1982)

References

1. IARC Monographs, 29, 93-148, 391-398, 1982 

2. Arp, E.W., Jr, Wolf, P.H. & Checkoway, H. (1983) Lymphocytic leukemia and exposures to 

benzene and other solvents in the rubber industry. J. occup. Med., 25, 598-602 

3. Decouflé, P., Blattner, W.A. & Blair, A. (1983) Mortality among chemical workers exposed to 

benzene and other agents. Environ. Res., 30, 16-25 

4. Bond, G.G., McLaren, E.A., Baldwin, C.L. & Cook, R.R. (1986) An update of mortality among 

chemical workers exposed to benzene. Br. J. ind. Med., 43, 685-691 

5. McCraw, D.S., Joyner, R.E. & Cole, P. (1985) Excess leukemia in a refinery population. J. occup. 

Med., 27, 220-222 

6. Tsai, S.P., Wen, C.P., Weiss, N.S., Wong, O., McClellan, W.A. & Gibson, R.L. (1983) Retrospective 

mortality and medical surveillance studies of workers in benzene areas of refineries. J. occup. Med., 

25, 685-692 

7. Yin, S.-N., Li, G.-L., Tain, F.-D., Fu, Z.-I., Jin, C., Chen, Y.-J., Luo, S.-J., Ye, P.-Z., Zhang, J.-Z., 

Wang, G.-C., Zhang, X.-C., Wu, H.-N. & Zhong, Q.-C. (1987) Leukaemia in benzene workers: a 

retrospective cohort study. Br. J. ind. Med., 44, 124-128 

8. Maltoni, C., Conti, B. & Scarnato, C. (1982) Squamous cell carcinomas of the oral cavity in 

Sprague Dawley rats, following exposure to benzene by ingestion. First experimental demonstration. 

Med. Lav., 4, 441-445 

9. Maltoni, C., Conti, B. & Cotti, G. (1983) Benzene: a multi-potential carcinogen. Results of longterm bioassays performed at the Bologna Institute of Oncology. Am. J. ind. Med., 4, 589-630 
10. Maltoni, C., Conti, B., Cotti, G. & Belpoggi, F. (1985) Experimental studies on benzene 

carcinogenicity at the Bologna Institute of Oncology: current results and ongoing research. Am. J. 

ind. Med., 7, 415-446 

11. National Toxicology Program (1986) Toxicology and Carcinogenesis Studies of Benzene (CAS 

No. 71-43-2) in F344/N rats and B6C3F1 Mice (Gavage Studies) (NTP Technical Report 289; NIH 

Publ. No. 86-2545), Research Triangle Park, NC 

12. Cronkite, E.P., Bullis, J.E., Inoue, T. & Drew, R.T. (1984) Benzene inhalation produces leukemia 

in mice. Toxicol. appl. Pharmacol., 75, 358-361 

13. Cronkite, E.P., Drew, R.T., Inoue, T. & Bullis, J.E. (1985) Benzene hematotoxicity and 

leukemogenesis. Am. J. ind Med., 7, 447-456 

14. Maltoni, C., Cotti, G., Valgimigli, L. & Mandrioli, A. (1982) Zymbal gland carcinomas in rats 

following exposure to benzene by inhalation. Am. J. ind. Med., 3, 11-16 

15. Maltoni, C., Cotti, G., Valgimigli, L. & Mandrioli, A. (1982) Hepatocarcinomas in Sprague-Dawley 

rats, following exposure to benzene by inhalation. First experimental demonstration. Med. Lav., 4, 

446-450 

16. Snyder, C.A., Goldstein, B.D., Sellakumar, A.R. & Albert, R.E. (1984) Evidence for 

hematotoxicity and tumorigenesis in rats exposed to 100 ppm benzene. Am. J. ind. Med., 5, 429-

434 

17. Stoner, G.D., Conran, P.B., Greisiger, E.A., Stober, J., Morgan, M. & Pereira, M.A. (1986) 

Comparison of two routes of chemical administration on the lung adenoma response in strain A/J 

mice. Toxicol. appl. Pharmacol., 82, 19-31 

18. IARC Monographs, Suppl. 6, 91-95, 1987 

Synonyms

● (6)-Annulene 

● Benzine 

● Benzol 

● Benzole 

● Benzolene 

● Bicarburet of hydrogen 

● Carbon oil 

● Coal naphtha 

● Cyclohexatriene 

● Mineral naphtha 

● Motor benzol 

● Phenyl hydride 

● Polystream 

● Pyrobenzol 

● Pyrobenzole 

Last updated: 6 February 1998 
BENZIDINE

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 123) 

Benzidine

CAS No.: 92-87-5

Chem. Abstr. Name: (1,1'-Biphenyl)-4,4'-diamine

Benzidine sulphate

CAS No.: 531-86-2

Chem. Abstr. Name: (1,1'-Biphenyl)-4,4'-diamine, sulfate (1:1)

Benzidine hydrochloride

CAS No.: 14414-63-7

Chem. Abstr. Name: (1,1'-Biphenyl)-4,4'-diamine, Hydrochloride

Benzidine dihydrochloride

CAS No.: 531-85-1

Chem. Abstr. Name: (1,1'-Biphenyl)-4,4'-diamine, Dihydrochloride

A. Evidence for carcinogenicity to humans (sufficient)

Case reports and follow-up studies of workers in many countries have demonstrated that 

occupational exposure to benzidine is causally associated with an increased risk of bladder cancer. 

In one extreme instance, all five of a group of workers continuously employed in the manufacture of 

benzidine for 15 years or more developed bladder cancer [ref: 1]. Earlier data suggesting that the 

incidence of this cancer in workers decreased after a reduction in industrial exposure [ref: 1] have 

been supported by a study of a cohort of workers at a US benzidine-manufacturing facility, in which 

major preventive measures were instituted in 1950 to minimize worker exposure. The study period 

covered 1945-1979, and, overall, there was a clearly significant excess of bladder cancer incidence, 

which, however, declined in those first employed after 1950 [ref: 2]. Although a longer follow-up is 

required to evaluate fully the effect of preventive measures on cancer risks, the causal association is 

strengthened by these two independent observations. Few other epidemiological studies have 

examined the cancer risk associated with exposure to benzidine alone. In a study at a dyestuffs 

factory in Italy, it was possible to distinguish a very high bladder cancer risk (5 deaths observed, 

0.06 expected) associated with benzidine production [ref: 3]. The study was extended and updated, 

but the role of exposure to benzidine alone in the dramatically increased bladder cancer risk could 

not be examined further [ref: 4]. Of 25 benzidine 'operators' at a plant in the USA, 13 developed 

bladder cancer; all cases had been exposed for six years or more [ref: 5]. A surveillance programme 

of 179 active and 65 retired workers in a dyestuffs manufacture plant in Japan revealed nine cases 

of bladder cancer that occurred between 1968 and 1981; all of the cases had been engaged in 

benzidine production [ref: 6]. 

Other investigations have shown high incidences of cancer of the bladder and urinary tract after 

concomitant exposure to benzidine and 2-naphthylamine [ref: 7,8]. Exposure to these two 

compounds was also associated with an increase in the occurrence of second primary cancers at 

sites other than the bladder, including the liver [ref: 9]. 

Among 1601 workers in the chemical-dye industry in China who were exposed to benzidine, 

methylnaphthylamine and dianisidine, 21 cases of bladder carcinoma were found. All had a history 

of exposure to benzidine, while no carcinoma was found among workers exposed to 

methylnaphthylamine or dianisidine. Suggestions of a dose-response relationship were provided by 

analysis according to length of exposure [ref: 10]. 

Bladder cancer was also found to be increased in ecological studies of areas where benzidine (as 
well as 2-naphthylamine and other compounds) was used, manufactured or stored [ref: 11,12]. 

B. Evidence for carcinogenicity to animals (sufficient)

Benzidine and its salts were tested for carcinogenicity by oral administration in mice, rats, hamsters 

and dogs and by subcutaneous and intraperitoneal injection and inhalation in rats. Following oral 

administration of benzidine and its hydrochloride, significant increases in the incidences of benign 

and malignant liver neoplasms were observed in mice and hamsters [ref: 1,13-17] and of mammary 

cancer in rats; benzidine induced bladder carcinomas in dogs. Following subcutaneous 

administration of benzidine and its sulphate to rats, a high incidence of Zymbal-gland tumours was 

observed. After intraperitoneal administration of benzidine to rats, a marked increase in the 

incidence of mammary gland and Zymbal-gland neoplasms was observed. The results of one study 

in rats by inhalation could not be evaluated [ref: 1]. 

Two metabolites of benzidine, N,N'-diacetylbenzidine and N-hydroxy-N,N'-diacetylbenzidine, 

produced mammary gland and Zymbal gland tumours in rats following their intraperitoneal injection 

[ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of benzidine in humans. 

Covalent binding products of benzidine with DNA have been described in the liver of mice and rats 

treated in vivo. Benzidine induced micronuclei, sister chromatid exchanges, DNA strand breaks and 

unscheduled DNA synthesis in cells of rodents treated in vivo. It induced unscheduled DNA synthesis 

in humans cells in vitro. It caused transformation of Syrian hamster embryo and BALB/c3T3 cells 

and induced chromosomal aberrations, sister chromatid exchanges, unscheduled DNA synthesis and 

DNA strand breaks in rodent cells in vitro; conflicting results were obtained for mutation. Benzidine 

induced aneuploidy, gene conversion and DNA damage in yeast, but not mutation. It was mutagenic 

to plants and bacteria [ref: 18]. 

Overall evaluation

Benzidine is carcinogenic to humans (Group 1). 

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 1 (1972); Vol. 29 (1982)

References

1. IARC Monographs, 29, 149-183, 391-398, 1982 

2. Meigs, J.W., Marrett, L.D., Ulrich, F.U. & Flannery, J.T. (1986) Bladder tumor incidence among 

workers exposed to benzidine: a thirty-year follow-up. J. natl Cancer Inst., 76, 1-8 

3. Rubino, G.F., Scansetti, G., Piolatto, G. & Pira, E. (1982) The carcinogenic effect of aromatic 

amines: an epidemiological study on the role of o-toluidine and 4,4'-methylene bis(2-methylaniline) 

in inducing bladder cancer in man. Environ. Res., 27, 241-254 

4. Decarli, A., Peto, J., Piolatto, G. & La Vecchia, C. (1985) Bladder cancer mortality of workers 

exposed to aromatic amines: analysis of models of carcinogenesis. Br. J. Cancer, 51, 707-712 

5. Horton, A.W. & Bingham, E.L. (1977) Risk of bladder tumors among benzidine workers and their 

serum properdin levels. J. natl Cancer Inst., 58, 1225-1228 
6. Yamaguchi, N., Tazaki, H., Okubu, T. & Toyama, T. (1982) Periodic urine cytology surveillance of 

bladder tumor incidence in dyestuff workers. Am. J. ind. Med., 3, 139-148 

7. Tsuchiya, K., Okubo, T. & Ishizu, S. (1975) An epidemiological study of occupational bladder 

tumours in the dye industry of Japan. Br. J. ind. Med., 32, 203-209 

8. Nakamura, J., Takamatsu, M., Doi, J., Ohkawa, T., Fujinaga, T., Ebisuno, S. & Sone, M. (1980) 

Clinical study on the occupational urinary tract tumor in Wakayama (Jpn.). Jpn. J. Urol., 71, 945-

951 

9. Morinaga, K., Oshima, A. & Hara, I. (1982) Multiple primary cancers following exposure to 

benzidine and beta-naphthylamine. Am. J. ind. Med., 3, 243-246 

10. Sun, L.D. & Deng, X.M. (1980) An epidemiologic survey of bladder carcinoma in chemical dye 

industry (Chin.). Chin. J. Surg., 18, 491-493 

11. Segnan, N. & Tanturri, G. (1976) Study on the geographical pathology of laryngeal, bladder and 

childhood cancer in the province of Torino (Ital.). Tumori, 62, 377-386 

12. Budnick, L.D., Sokal, D.C., Falk, H., Logue, J.N. & Fox, J.M. (1984) Cancer and birth defects 

near the Drake superfund site, Pennsylvania. Arch. environ. Health, 39, 409-413 

13. Littlefield, N.A., Nelson, C.J. & Frith, C.H. (1983) Benzidine dihydrochloride: toxicological 

assessment in mice during chronic exposures. J. Toxicol. environ. Health, 12, 671-685 

14. Littlefield, N.A., Nelson, C.J. & Gaylor, D.W. (1984) Benzidine dihydrochloride: risk assessment. 

Fundam. appl. Toxicol., 4, 69-80 

15. Littlefield, N.A., Wolff, G.L. & Nelson, C.J. (1985) Influence of genetic composition of test-animal 

populations on chronic toxicity studies used for risk estimation. J. Toxicol. environ. Health, 15, 357-

367 

16. Nelson, C.J., Baetcke, K.P., Frith, C.H., Kodell, R.L. & Schieferstein, G. (1982) The influence of 

sex, dose, time, and cross on neoplasia in mice given benzidine dihydrochloride. Toxicol. appl. 

Pharmacol., 64, 171-186 

17. Vesselinovitch, S.D. (1983) Perinatal hepatocarcinogenesis. Biol. Res. Pregn. Perinatol., 4, 22-

25 

18. IARC Monographs, Suppl. 6, 96-100, 1987 

Synonyms for benzidine

● Benzidine base 

● 4,4'-Bianiline 

● para,para'-Bianiline 

● 4,4'-Biphenyldiamine 

● 4,4'-Biphenylenediamine 

● C.I. azoic diazo component 112 

● 4,4'-Diaminobiphenyl 

● 4,4'-Diamino-1,1'-biphenyl 

● para,para'-Diaminobiphenyl 

● 4,4'-Diaminodiphenyl 

● para-Diaminodiphenyl 

● 4,4'-Diphenylenediamine 

● Fast Corinth base B 
Last updated: 6 February 1997 
BENZIDINE-BASED DYES

(Group 2A)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 125) 

A. Evidence for carcinogenicity to humans (inadequate for benzidine-based dyes)

The epidemiological data were inadequate to evaluate the carcinogenicity of three benzidine-based 

dyes, Direct Black 38, Direct Blue 6 and Direct Brown 95, to humans. However, a study of silk dyers 

and painters who had had multiple exposure to benzidine-based and other dyes indicated that those 

exposures were strongly associated with the occurrence of bladder cancer [ref: 1]. 

B. Evidence for carcinogenicity to animals (sufficient for technical-grade Direct Black 38, 

technical-grade Direct Blue 6 and technical-grade Direct Brown 95)

Direct Black 38 was tested for carcinogenicity in mice by administration in drinking-water, producing 

liver and mammary tumours. Commercial Direct Black 38 produced hepatocellular carcinomas within 

13 weeks after administration in the diet to rats and small numbers of carcinomas in the urinary 

bladder, liver and colon after administration to rats in drinking-water [ref: 1].

In a single study, commercial Direct Blue 6 produced hepatocellular carcinomas in rats within 13 

weeks after its oral administration.

Commercial Direct Brown 95 produced neoplastic nodules in the livers of 4/8 female rats and a 

hepatocellular carcinoma in one, after its oral administration in a single study terminated after 13 

weeks. The finding of preneoplastic lesions after such a short exposure prior indicates a carcinogenic 

effect similar to that of Direct Black 38 and Direct Blue 6 [ref: 1]. 

C. Other relevant data

Benzidine-based dyes are structurally related to benzidine, exposure to which is causally associated 

with cancer in humans, and commercial material may contain small amounts of benzidine. 

Commercial Direct Black 38 may contain small quantities of 4-aminobiphenyl and 2,4-

diaminobenzene (the hydrochloride of which is chrysoidine) [ref: 1].

Benzidine has been detected in the urine of workers exposed to benzidine-based azo dyes. No data 

were available on the genetic and related effects of Direct Black 38, Direct Blue 6 or Direct Brown 

95, in humans [ref: 1].

In experimental animals, Direct Black 38, Direct Blue 6 and Direct Brown 95 undergo reduction of 

the azo bonds with the appearance in the urine of benzidine and monoacetylbenzidine. The 

reductive cleavage of the azo bond has been attributed to the activities of intestinal microflora 

and/or liver azoreductases [ref: 2].

Direct Black 38 was mutagenic to bacteria. Urine from rodents treated with Direct Black 38 was 

mutagenic to bacteria in the presence of an exogenous metabolic system, and human intestinal 

microflora metabolized Direct Black 38 to highly mutagenic metabolites [ref: 2].

DNA adducts (including covalent binding products of benzidine) have been described in the livers of 

rats treated with Direct Blue 6 in vivo. Direct Blue 6 is mutagenic to bacteria only in the presence of 

an exogenous metabolic system and the cofactor flavine mononucleotide [ref: 2].

Direct Brown 95 induced unscheduled DNA synthesis in rat hepatocytes in an in-vivo/in-vitro assay 

but not in hepatocytes in vitro. It was mutagenic to bacteria in the presence of an exogenous 
metabolic system; this activity was enhanced by the cofactor flavine mononucleotide. The urine 

from rats treated with Direct Brown 95 was mutagenic to bacteria in the presence of an exogenous 

metabolic system [ref: 2]. 

Overall evaluation

Benzidine-based dyes are probably carcinogenic to humans (Group 2A).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Direct Black 38: Vol. 29 (1982); Direct Blue 6: Vol. 29 (1982); 

Direct Brown 95: Vol. 29 (1982)

References

1. IARC Monographs, 29, 295-310, 311-320, 321-330, 1982

2. IARC Monographs, Suppl. 6, 275-281, 1987 

Last updated: 11 February 1998 
BENZOYL CHLORIDE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 126) 

CAS No.: 98-88-4 

A. Evidence for carcinogenicity to humans (inadequate) 

Six cases of respiratory cancer were reported among workers in two small factories where benzoyl 

chloride and its chlorinated precursors were produced [ref: 1]. 

B. Evidence for carcinogenicity to animals (inadequate) 

Benzoyl chloride was tested in two sets of experiments by skin application to female mice. A few 

skin carcinomas were observed, but their incidence was not statistically significant [ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of benzoyl chloride in humans. It did not 

induce mutation or DNA damage in bacteria [ref: 2]. 

Overall evaluation

Benzoyl chloride is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Subsequent evaluation: Vol. 71 (1999)

Also see previous evaluation: Vol. 29 (1982)

References

1. IARC Monographs, 29, 83-91, 1982 

2. IARC Monographs, Suppl. 6, 103-104, 1987

Synonyms

● Benzene carbonyl chloride 

● Benzenecarbonyl chloride 

● Benzoic acid, chloride 

● α-Chlorobenzaldehyde 

Last updated: 9 March 1998 
BETEL QUID WITH TOBACCO (Group 1)

and BETEL QUID WITHOUT TOBACCO (Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 128) 

A. Evidence for carcinogenicity to humans (sufficient for betel quid with tobacco; inadequate for 

betel quid without tobacco)

Many descriptive studies and case reports have shown an association between the habit of chewing 

betel quid with tobacco and oral cancer. A significant increase in the risk of oral cancer has been 

observed in chewers of betel quid with tobacco in several case-control studies and in one large-scale 

cohort study. In chewers of betel quid with tobacco, a statistically significant increase in risk was 

also observed for cancers of the oropharynx, hypopharynx, larynx and oesophagus [ref: 1]. 

Several descriptive studies from Papua-New Guinea and a number of case-control studies have 

suggested an association between the habit of chewing betel quid without tobacco and oral cancer. 

In one of the case-control studies, in which smoking was not controlled for, a statistically significant 

increase in risk was also observed for cancers of the oropharynx, hypopharynx, larynx and 

oesophagus. In another case-control study of oral cancer, in which a clear effect of chewing betel 

with tobacco was found, no such effect was found for chewing betel without tobacco [ref: 1]. 

B. Evidence for carcinogenicity to animals (limited for betel quid with and without tobacco)

Aqueous extracts of betel quid containing tobacco were tested for carcinogenicity in mice by gastric 

intubation, skin painting and subcutaneous injection; some malignant tumours occurred at the site 

of skin or subcutaneous administration. In hamsters, forestomach carcinomas occurred after 

painting of the cheek-pouch mucosa with aqueous extracts or implantation of wax pellets containing 

powdered betel quid with tobacco in the cheek pouch; carcinomas occurred in the cheek pouch 

following implantation of wax pellets [ref: 1]. 

Aqueous extracts of betel quid without tobacco were tested in mice by gastric intubation and by 

subcutaneous administration; an increased incidence of local tumours was observed after 

subcutaneous injection. In hamsters, painting of the cheek-pouch mucosa or implantation of wax 

pellets into the cheek pouch resulted in the induction of forestomach carcinomas; carcinomas 

occurred in the cheek pouch following implantation of wax pellets [ref: 1]. 

Aqueous or dimethyl sulphoxide extracts of areca nut with tobacco were tested in mice by skin 

application; a low incidence of skin tumours was reported in a study lacking controls. In hamsters, 

applications of such extracts to cheek-pouch mucosa produced squamous-cell carcinomas of the 

cheek pouch and forestomach carcinomas [ref: 1]. 

Areca nut and aqueous extracts of areca nut were tested in mice by oral intubation, dietary 

administration, skin application and intraperitoneal and subcutaneous injection. Local tumours were 

produced following subcutaneous injection. In rats, areca nut was inadequately tested by oral 

administration; aqueous extracts tested by subcutaneous injection produced local mesenchymal 

tumours. In hamsters, administration of areca nut and application of aqueous or dimethyl sulphoxide 

extracts to the cheek-pouch mucosa resulted in squamous-cell carcinomas of the cheek pouch and 

carcinomas of the forestomach [ref: 1]. Oral administration of a diet containing 20% betel-nut 

powder enhanced the incidences of preneoplastic and neoplastic lesions of the tongue in rats 

pretreated with 4-nitroquinoline-1-oxide and of preneoplastic liver lesions in rats pretreated with 2-

acetylaminofluorene [ref: 2]. 

Aqueous extracts of betel leaf were tested in mice by oral intubation and by intraperitoneal injection, 

in hamsters by application to the cheek-pouch mucosa [ref: 1] and in rats by oral administration 

[ref: 3]. Betel leaf was tested in rats by dietary administration and in hamsters by implantation in 

beeswax pellets into the cheek pouch. All of these studies were inadequate for evaluation [ref: 1]. 
C. Other relevant data

Chewing of betel quid with or without tobacco increased the frequencies of micronucleated cells in 

the buccal mucosa of chewers; dose-dependence was observed in relation to the number of betel 

quids chewed per day. Chewing of betel quid with or without tobacco increased the frequency of 

sister chromatid exchanges in peripheral blood lymphocytes of chewers. Increased frequencies of 

sister chromatid exchanges were observed in peripheral blood lymphocytes of chewers of areca nut 

with slaked lime and tobacco, either alone or wrapped in betel leaf, particularly among chewers who 

had developed oral submucous fibrosis. Extracts of urine from chewers of betel quid with tobacco 

were mutagenic to Salmonella typhimurium in the presence of an exogenous metabolic system [ref: 

4]. 

An aqueous extract of betel quid (containing tobacco) induced micronuclei in bone-marrow cells of 

mice treated in vivo and was mutagenic to Chinese hamster V79 cells. No such effect was observed 

with extracts of betel quids not containing tobacco. Aqueous extracts of betel quids (both with and 

without tobacco) were mutagenic to S. typhimurium [ref: 4]. 

Overall evaluation

Betel quid with tobacco is carcinogenic to humans (Group 1).

Betel quid without tobacco is not classifiable as to its carcinogenicity to humans (Group 3). 

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 37 (1985)

Subsequent evaluation: Vol. 85 (2004)

References

1. IARC Monographs, 37, 141-200, 1985 

2. Tanaka, T., Kuniyasu, T., Shima, H., Sugie, S., Mori, H., Takahashi, M. & Hirono, J. (1986) 

Carcinogenicity of betel quid. III. Enhancement of 4-nitroquinoline-1-oxide and N-2-

fluorenylacetamide-induced carcinogenesis in rats by subsequent administration of betel nut. J. natl 

Cancer Inst., 77, 777-781 

3. Rao, A.R., Sinha, A. & Selvan, R.S. (1985) Inhibitory action of Piper betle on the initiation of 7,12-

dimethylbenz[a]anthracene-induced mammary carcinogenesis in rats. Cancer Lett., 26, 207-214 

4. IARC Monographs, Suppl. 6, 113, 1987 

Last updated: 6 February 1998 
N,N-BIS(2-CHLOROETHYL)-2-NAPHTHYLAMINE (CHLORNAPHAZINE)

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 130) 

CAS No.: 494-03-1

A. Evidence for carcinogenicity to humans (sufficient)

Among 61 patients with polycythaemia vera treated with chlornaphazine in 1954-1962 and followed 

until 1974, eight developed invasive carcinoma of the bladder, five developed papillary carcinomas 

of the bladder and eight had abnormal urinary cytology. The invasive carcinomas were seen in four 

of five patients treated with a cumulative dose of 200 g or moe, in two of 15 patients given 100-199 

g, in one of ten patients given 50-99 g and in one of 31 patients given less than 50 g. No noncausal 

explanation can be suggested [ref: 1]. 

B. Evidence for carcinogenicity to animals (limited)

Chlornaphazine produced lung tumours in mice following its intraperitoneal injection, and local 

sarcomas in rats after its subcutaneous administration [ref: 2]. 

C. Other relevant data

No data were available on the genetic and related effects of chlornaphazine in humans. 

Rats administered chlornaphazine excreted metabolites of 2-naphthylamine in the urine. 

Chlornaphazine induced chromosomal aberrations in Chinese hamster cells, mutation in mouse 

lymphoma cells and unscheduled DNA synthesis in rat hepatocytes in vitro. A single study of cell 

transformation in virus-infected Syrian hamster embryo cells was inconclusive. It induced sex-linked 

recessive lethal mutations and chromosomal aberrations in Drosophila and was mutagenic to 

bacteria [ref: 3]. 

Overall evaluation

N,N-Bis(2-chloroethyl)-2-naphthylamine (chlornaphazine) is carcinogenic to humans (Group 1). 

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 4 (1974)

References

1. Thiede, T. & Christensen, B.C. (1975) Tumours of the bladder induced by chlornaphazine (Norw.). 

Ugesk. Laeger, 137, 661-666 

2. IARC Monographs, 4, 119-124, 1974 

3. IARC Monographs, Suppl. 6, 113-115, 1987 

Synonyms
● CB 1048 

● Chlornaftina 

● Chlornaphazin 

● Chlornaphthin 

● Chloronaftina 

● Chloronaphthine 

● Dichloroethyl-β-naphthylamine 

● Di(2-chloroethyl)-β-naphthylamine 

● Erysan 

● Naphthylamine mustard 

● β-Naphthyl-bis(β-chloroethyl)amine 

● β-Naphthyldi-(2-chloroethyl)amine 

● R 48 

Last updated: 6 February 1998 
BIS(CHLOROMETHYL)ETHER AND 

CHLOROMETHYL METHYL ETHER (TECHNICAL-GRADE)

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p.59) 

CAS No.: 542-88-1

Chem. Abstr. Name: Bis(chloromethyl)ether

CAS No.: 107-30-2

Chem. Abstr. Name: Chloromethyl methyl ether (technical-grade) 

A. Evidence for carcinogenicity to humans (sufficient)

Numerous epidemiological studies [ref: 1-9] and case reports [ref: 10-13] from around the world 

have demonstrated that workers exposed to chloromethyl methyl ether and/or 

bis(chloromethyl)ether have an increased risk for lung cancer. Among heavily exposed workers, the 

relative risks are ten fold or more. Risks increase with duration and cumulative exposure. 

Histological evaluation indicates that exposure results primarily in lung cancer of the small-cell type 

[ref: 8]. Maximal relative risks appear to occur 15-20 years after first exposure [ref: 6], and latency 

is shortened among workers with heavier exposure [ref: 5,11]. 

B. Evidence for carcinogenicity to animals (sufficient)

Bis(chloromethyl)ether produced tumours at the site of its administration to mice after exposure by 

inhalation [ref: 1,14], skin application [ref: 1] or subcutaneous injection [ref: 1,15] and was an 

initiator of mouse skin tumours [ref: 15]; it also increased the incidence of lung tumours after its 

subcutaneous administration [ref: 1]. In rats, it produced tumours of the respiratory tract (lung 

tumours and nasal-cavity carcinoma) after exposure by inhalation [ref: 14,16-18]. 

Chloromethyl methyl ether produced local sarcomas in mice after its subcutaneous administration 

and was an initiator of mouse skin tumours [ref: 1]; in rats and hamsters, the technical grade 

produced a low incidence of tumours of the respiratory tract after exposure by inhalation [ref: 19]. 

C. Other relevant data

A slight increase in the incidence of chromosomal aberrations was observed in peripheral 

lymphocytes of workers exposed to bis(chloromethyl)ether or chloromethyl methyl ether in the 

preparation of ion-exchange resins [ref: 20]. 

Bis(chloromethyl)ether did not cause chromosomal aberrations in bone-marrow cells of rats treated 

in vivo. It induced unscheduled DNA synthesis in human fibroblasts in vitro and was mutagenic to 

bacteria [ref: 20]. 

Chloromethyl methyl ether enhanced virus-induced transformation of Syrian hamster embryo cells 

and was mutagenic to bacteria [ref: 20]. 

Overall evaluation

Bis(chloromethyl)ether and chloromethyl methyl ether (technical grade) are carcinogenic to humans 

(Group 1).

For definition of the italicized terms, see Preamble Evaluation.
Also see previous evaluation: Vol. 4 (1974)

References

1. IARC Monographs, 4, 231-238, 239-245, 1974 

2. Albert, R.E., Pasternack, B.S., Shore, R.E., Lippmann, M., Nelson, N. & Ferris, B. (1975) Mortality 

patterns among workers exposed to chloromethyl ethers - a prelimary report. Environ. Health 

Perspect., 11, 209-214 

3. DeFonso, L.R. & Kelton, S.C., Jr (1976) Lung cancer following exposure to chloromethyl methyl 

ether. An epidemiological study. Arch. environ. Health, 31, 125-130 

4. Pasternack, B.S., Shore, R.E. & Albert, R.E. (1977) Occupational exposure to chloromethyl 

ethers. A retrospective cohort mortality study (1948-1972). J. occup. Med., 19, 741-746 

5. Pasternack, B.S. & Shore, R.E. (1981) Lung cancer following exposure to chloromethyl ethers. In: 

Chwat, M. & Dror, K., eds, Proceedings of the International Conference on Critical Current Issues in 

Environmental Health Hazards, Tel-Aviv, Israel, pp. 76-85 

6. Weiss, W. (1982) Epidemic curve of respiratory cancer due to chloromethyl ethers. J. natl Cancer 

Inst., 69, 1265-1270 

7. McCallum, R.I., Woolley, V. & Petrie, A. (1983) Lung cancer associated with chloromethyl methyl 

ether manufacture: an investigation at two factories in the United Kingdom. Br. J. ind. Med., 40, 

384-389 

8. Weiss, W. & Boucot, K.R. (1975) The respiratory effects of chloromethyl methyl ether. J. Am. 

med. Assoc., 234, 1139-1142 

9. Weiss, W., Moser, R. & Auerbach, O. (1979) Lung cancer in chloromethyl ether workers. Am. Rev. 

respir. Dis., 120, 1031-1037 

10. Sakabe, H. (1973) Lung cancer due to exposure to bis(chloromethyl)ether. Ind. Health, 11, 145-

148 

11. Weiss, W. & Figueroa, W.G. (1976) The characteristics of lung cancer due to chloromethyl 

ethers. J. occup. Med., 18, 623-627 

12. Reznik, G., Wagner, H.H. & Atay, Z. (1977) Long cancer following exposure to 

bis(chloromethyl)ether: a case report. J. environ. Pathol. Toxicol., 1, 105-111 

13. Bettendorf, U. (1977) Occupational lung carcinoma after inhalation of alkylating agents. 

Dichlorodimethyl ether, monochlorodimethylether and dimethylsulphate (Ger.). Dtsch. med. 

Wochenschr., 102, 396-398 

14. Leong, B.K.J., Kociba, R.J. & Jersey, G.C. (1981) A lifetime study of rats and mice exposed to 

vapors of bis(chloromethyl)ether. Toxicol. appl. Pharmacol., 58, 269-281 

15. Zajdela, F., Croisy, A., Barbin, A., Malaveille, C., Tomatis, L. & Bartsch, H. (1980) 

Carcinogenicity of chloroethylene oxide, an ultimate reactive metabolite of vinyl chloride, and 

bis(chloromethyl)ether after subcutaneous administration and in intiation-promotion experiments in 

mice. Cancer Res., 40, 352-356 
16. Dulak, N.C. & Snyder, C.A. (1980) The relationship between the chemical reactivity and the 

inhalation carcinogenic potency of direct-acting chemical agents (Abstract No. 426). Proc. Am. 

Assoc. Cancer Res., 21, 106 

17. Kuschner, M., Laskin, S., Drew, R.T., Cappiello, V. & Nelson, N. (1975) Inhalation 

carcinogenicity of alpha halo ethers. III. Lifetime and limited period inhalation studies with 

bis(chloromethyl)ether at 0.1 ppm. Arch. environ. Health, 30, 73-77 

18. Leong, B.K.J., Kociba, R.J., Jersey, G.C. & Gehring, P.J. (1975) Effects of repeated inhalation of 

parts per billion of bis(chloromethyl)ether in rats (Abstract No. 131). Toxicol. appl. Pharmacol., 33, 

175 

19. Laskin, S., Drew, R.T., Cappiello, V., Kuschner, M. & Nelson, N. (1975) Inhalation 

carcinogenicity of alpha halo ethers. II. Chronic inhalation studies with chloromethyl methyl ether. 

Arch. environ. Health, 30, 70-72 

20. IARC Monographs, Suppl. 6, 119-120, 159-160, 1987 

Synonyms for Bis(chloromethyl)ether

● BCME 

● Chloro(chloromethoxy)methane 

● Dichloromethyl ether 

● Dimethyl-1,1'-dichloroether 

● Symmetrical-dichloro-dimethyl ether 

● Symmetrical-dichloromethyl ether 

Synonyms for Chloromethyl methyl ether

● CMME 

● Dimethylchloroether 

● Methyl chloromethyl ether 

Last updated: 6 February 1998 
BITUMENS 

(Group 3) and

EXTRACTS OF STEAM-REFINED AND AIR-REFINED BITUMENS 

(Group 2B) 

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 133) 

Bitumen

CAS No.: 8052-42-4

Chem. Abstr. Name: Asphalt 

Bitumens, oxidized

CAS No.: 64742-93-4

Chem. Abstr. Name: Asphalt, oxidized 

A. Evidence for carcinogenicity to humans (inadequate for bitumens)

No epidemiological study of workers exposed only to bitumens is available. A cohort study of US 

roofers indicates an increased risk for cancer of the lung and suggests increased risks for cancers of 

the oral cavity, larynx, oesophagus, stomach, skin and bladder and for leukaemia. Some evidence of 

excess risks for lung, oral cavity and laryngeal cancers is provided by other epidemiological studies 

of roofers. As roofers may be exposed not only to bitumens but also to coal-tar pitches and other 

materials, the excess cancer risk cannot be attributed specifically to bitumens [ref: 1]. Several case 

reports of skin cancer among workers exposed to bitumens are available; however, exposure to coaltars or products derived from them cannot be ruled out [ref: 1-3]. 

B. Evidence for carcinogenicity to animals (limited for undiluted steam-refined and crackingresidue bitumens; inadequate for undiluted air-refined bitumens; sufficient for extracts of steamrefined and air-refined bitumens)

In several studies, application to the skin of mice of various extracts of steam- and air-refined 

bitumens and mixtures of the two resulted in tumours at the sites of application [ref: 1,4]. Undiluted 

steam-refined bitumens and cracking-residue bitumens produced skin tumours when applied to the 

skin of mice. No skin tumour was found in mice after application of an undiluted air-refined bitumen. 

In limited studies, subcutaneous injection into mice and intramuscular injection into mice and rats of 

steam- and air-refined bitumens produced sarcomas at the injection sites [ref: 1]. 

C. Other relevant data

Antigenicity against benzo[a]pyrene diol epoxide-DNA adducts has been demonstrated in peripheral 

blood lymphocytes of roofers [ref: 5].

Both an extract of road-surfacing bitumen and its emissions were mutagenic to Salmonella 

typhimurium, whereas, in another study, 'asphalt tar' extracted from an asphalt concrete used for 

road surfacing was not. Bitumen-based paints for pipe coating were not mutagenic to S. 

typhimurium [ref: 5]. 

Overall evaluation

Bitumens are not classifiable as to their carcinogenicity to humans (Group 3).

Extracts of steam-refined and air-refined bitumens are possibly carcinogenic to humans (Group 2B). 
For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 35 (1985)

References

1. IARC Monographs, 35, 39-81, 1985

2. Jørgensen, N.K. (1984) Exposure to asphalt as the cause of development of skin cancer (Dan.). 

Ugeskr. Laeger, 146, 2832-2833

3. Tsyrkunov, L.P. (1985) Multiple basalioma in a worker laying asphalt (Russ.). Vestn. Dermatol. 

Venerol., 2, 48-51

4. Niemeier, R.W., Thayer, P.S., Menzies, K.T., vonThuna, P., Moss, C.E. & Burg, J. (1984) A 

comparison of the skin carcinogenicity of condensed roofing asphalt and coal tar pitch fumes. In: 

Cooke, M. & Dennis, A.J., eds, Proceedings of the 10th International Symposium on Polynuclear 

Aromatic Hydrocarbons, Chemistry Characterization and Carcinogenesis, Columbus, OH, Battelle, pp. 

609-647

5. IARC Monographs, Suppl. 6, 121, 1987 

Synonyms for Bitumen

● Asphaltic bitumen 

● Asphaltum 

● Petroleum asphalt 

Last updated 12/16/1997 
BOOT AND SHOE MANUFACTURE AND REPAIR

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 232) 

A. Evidence for carcinogenicity to humans (sufficient)

Nasal adenocarcinoma has been caused by employment in boot and shoe manufacture and repair. 

Relative risks well in excess of ten fold have been reported from studies in the boot and shoe 

manufacturing industry in England and in Italy. There is also evidence that an increased risk exists 

for other types of nasal cancer [ref: 1-3]. A far higher risk of nasal cancer was found for people who 

worked in the dustiest operations, and for those classified into the category of 'heavy' exposure to 

leather dust, strongly suggesting a role for exposure to leather dust [ref: 2,3]. Thus, in comparison 

with the 'nonexposed' category, the sex-adjusted standardized odds ratio for the 'uncertain or light 

exposure' category was 7.5, and for the 'heavy exposure' category, 121.0. A similar, highly 

significant pattern was noted when only adenocarcinomas were considered. Exposure to solvents or 

to tobacco smoking could not account for the noted increased risk [ref: 3]. A mortality study of over 

5000 men known to have been employed in the boot and shoe manufacturing industry in three 

towns in the UK in 1939 showed a large, significant excess of deaths from nasal cancer (10 

observed, 1.9 expected). An observed:expected ratio of 14 was found among workers in the 

finishing room [ref: 4]. The elevated nasal cancer risk was almost totally confined to employees in 

the preparation and finishing rooms, where most of the dusty operations occurred. It was estimated 

that the risk to those men was 4.5 relative to that in other operations, and 9.8 relative to that of 

men resident in the area who had never been employed in the footwear industry [ref: 2]. 

Case reports have also suggested an association between exposure to leather, including during shoe 

manufacture, and mucinous adenocarcinoma of the nose and ethmoidal cancer in Switzerland and 

France, respectively [ref: 5,6]. 

One mortality study conducted in London, UK, showed no association between nasal cancer deaths 

occurring between 1968 and 1978 and occupation in the boot and shoe industry, as recorded on 

death certificates [ref: 7]. A proportionate mortality analysis of 3754 deaths among US shoeworkers 

revealed no death from nasal cancer, whereas 2.2 were expected on the basis of data for the 

general population [ref: 8]. Similar results were obtained from a study of 2798 deaths between 1954 

and 1974 in a shoe and leather industry area in Massachusetts, USA; detailed occupational 

information was available, however, for only 289 of the deceased [ref: 9]. 

Early death certificate surveys showed an increased risk of bladder cancer among shoemakers and 

repairers. Later studies provided evidence of an increased risk associated with employment in the 

leather industry. Although boot and shoemakers were included in these studies, it was not possible 

to determine whether the risk was related to them in particular [ref: 1]. A nonsignificant increased 

risk for bladder cancer was reported in association with work in the boot and shoe industry in a casecontrol study based on deaths of male residents in certain London boroughs from 1968-1978. When 

data for these workers were combined with those for leather workers, the estimated risk became 

significant [ref: 7]. A significant association of leather work (leather or tanning industry, 

manufacture of leather goods, or shoemaking) with cancer of the lower urinary tract was found in a 

collaborative case-control study in the USA and the UK, but not in Japan [ref: 10]. A statistically 

significant increase was found among female shoe workers (7 deaths observed and 2.8 expected) in 

another, independent study in the USA. Male shoeworkers and leather workers showed no excess of 

bladder cancer in this study [ref: 9]. In Sweden, an increase in the incidence of bladder cancer (22 

cases observed, 14.5 expected) was reported among shoe factory workers [ref: 11]. An elevated 

risk that was not statistically significant was also found among boot and shoe repairers in a British 

county. Smoking did not appear to account for the increase [ref: 12]. In another study in the UK, in 

a cohort of 5108 boot and shoe workers, 32 deaths from bladder cancer were observed, with 39.2 

expected [ref: 13]. 

A possible increased risk for kidney cancer among shoe workers was suggested by a study in 

Sweden [ref: 11]. However, a large cohort study among boot and shoe workers in the UK did not 
support this hypothesis [ref: 13]. Three cases of mesothelioma were reported among 3806 deaths in 

shoe workers [ref: 14]; it has further been reported that a female shoemaker (whose husband was 

also a shoemaker) died of mesothelioma [ref: 15]. 

The occurrence of leukaemia among shoemakers exposed to benzene has been well documented 

[ref: 1,16], and this association has been supported further by a recent mortality study in one town 

in the UK [ref: 4]. 

Surveys conducted in the The Netherlands, the UK and the USA have suggested positive associations 

between boot and shoe manufacture/repair and cancers of the lung, oral cavity and pharynx and 

stomach [ref: 1]. These suggestions were later confirmed by a mortality survey in the USA, which 

also showed a significant increase in the proportion of deaths due to cancers of the rectum and of 

the liver and gall-bladder, in people of each sex [ref: 8]. Excess mortality from rectal cancer was 

also found among boot and shoemakers in two towns in the UK; the excess was significant for 

workers in the lasting and making room, who were probably exposed to solvents, glues and leather 

dust [ref: 4]. Exposure to solvents, dyes or metallic compounds in the footwear industry, among 

nonfactory shoemakers and repairers and among operatives making leather and leather products, 

was deemed to be associated with the increased risk of bowel cancer noted in a US study [ref: 17]. 

An increased proportion of cancer of the digestive tract among male shoeworkers was found in 

another US study; however, it was suggested that factors other than their occupation could have 

been responsible for the excess noted [ref: 9]. In a study of gall-bladder cancer occurring in Sweden 

between 1961 and 1969, in which information on occupation was drawn from 1960 census data, the 

incidences of cancers of the gall-bladder and the biliary tract were found to be significantly elevated 

among men employed in shoemaking and repair [ref: 18]. In view of the exploratory nature and 

design of these studies, the findings were considered to be inadequate for a definite evaluation. 

No indication of a link between Hodgkin's disease and work in 'textile, shoes, leather' industries 

emerged from investigations in Italy [ref: 19]. 

Overall evaluation

Boot and shoe manufacture and repair entails exposures that are carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 25 (1981)

References

1. IARC Monographs, 25, 249-277, 1981 

2. Acheson, E.D., Pippard, E.C. & Winter, P.D. (1982) Nasal cancer in the Northamptonshire boot 

and shoe industry: is it declining? Br. J. Cancer, 46, 940-946 

3. Merler, E., Baldasseroni, A., Laria, R., Faravelli, P., Agostini, R., Pisa, R. & Berrino, F. (1986) On 

the causal association between exposure to leather dust and nasal cancer: further evidence from a 

case-control study. Br. J. ind. Med., 43, 91-95 

4. Pippard, E.C. & Acheson, E.D. (1985) The mortality of boot and shoe makers, with special 

reference to cancer. Scand. J. Work Environ. Health, 11, 249-255 

5. Penneau, D., Pineau, B., Dubin, J., Géraut, C., Penneau, M. & Proteau, J. (1984) Pilot 

retrospective study of relative risk of ethmoidal cancer in leather work and shoe manufacture (Fr.). 

Arch. Mal. prof., 45, 633-638 

6. Rüttner, J.R. & Makek, M. (1985) Mucinous adenocarcinoma of the nose and paranasal sinuses, an 

occupational disease? (Ger.) Schweiz. med. Wochenschr., 115, 1838-1842 
7. Baxter, P.J. & McDowall, M.E. (1986) Occupation and cancer in London: an investigation into 

nasal and bladder cancer using the Cancer Atlas. Br. J. ind. Med., 43, 44-49 

8. Decouflé, P. & Walrath, J. (1983) Proportionate mortality among US shoeworkers, 1966-1977. 

Am. J. ind. Med., 4, 523-532 

9. Garabrant, D.H. & Wegman, D.H. (1984) Cancer mortality among shoe and leather workers in 

Massachusetts. Am. J. ind. Med., 5, 303-314 

10. Morrison, A.S., Ahlbom, A., Verhoek, W.G., Aoki, K., Leck, I., Ohno, Y. & Obata, K. (1985) 

Occupation and bladder cancer in Boston, USA, Manchester, UK, and Nagoya, Japan. J. Epidemiol. 

Commun. Health, 39, 294-300 

11. Malker, H.R., Malker, B.K., McLaughlin, J.K. & Blot, W.J. (1984) Kidney cancer among leather 

workers. Lancet, i, 56 

12. Cartwright, R.A. & Boyko, R.W. (1984) Kidney cancer among leather workers. Lancet, i, 850-851 

13. Acheson, E.D. & Pippard, E.C. (1984) Kidney cancer among leather workers. Lancet, i, 563 

14. Decouflé, P. (1980) Mesothelioma among shoeworkers. Lancet, i, 259 

15. Vianna, N.J. & Polan, A.K. (1978) Non-occupational exposure to asbestos and malignant 

mesothelioma in females. Lancet, i, 1061-1063 

16. IARC Monographs, 29, 93-148, 391-397, 1982 

17. Berg, J.W. & Howell, M.A. (1975) Occupation and bowel cancer. J. Toxicol. environ. Health, 1, 75-

89 

18. Malker, H.R.S., McLaughlin, J.K., Malker, B.K., Stone, B.J., Weiner, J.A., Ericsson, J.L.E. & Blot, 

W.J. (1986) Biliary tract cancer and occupation in Sweden. Br. J. ind. Med., 43, 257-262 

19. Fonte, R., Grigis, L., Grigis, P. & Franco, G. (1982) Chemicals and Hodgkin's disease. Lancet, ii, 

5 

Last updated: 9 February 1998 
BLEOMYCINS

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 134) 

CAS No.: 11056-06-7

Chem. Abstr. Name: Bleomycin

Bleomycin hydrochloride

CAS No.: 67763-87-5 

Bleomycin sulfate

CAS No.: 9041-93-4

Chem. Abstr. Name: Bleomycin, sulfate (salt) 

A. Evidence for carcinogenicity to humans (inadequate)

No epidemiological study of bleomycins alone was available to the Working Group. Occasional case 

reports of exposure to bleomycins, especially in the presence of concurrent therapy with other 

putative carcinogens such as ionizing radiation, alkylating agents and other potent oncotherapeutic 

drugs, do not constitute evidence of carcinogenesis [ref: 1].

In a large systematic follow-up of patients with Hodgkin's disease treated with an intensive 

chemotherapeutic combination including bleomycins (plus adriamycin, vinblastine and dacarbazine) 

but no alkylating agent, preliminary evidence suggested no excess of acute nonlymphocytic 

leukaemia in the first decade after therapy [ref: 2]. 

B. Evidence for carcinogenicity to animals (limited)

Bleomycin has been tested in mice by subcutaneous and intramuscular injection and in rats 

transplacentally. These studies could not be evaluated because of incomplete reporting [ref: 1]. A 

study in rats by repeated subcutaneous injections showed that bleomycin produced renal tumours 

(adenomas, adenocarcinomas, sarcomas) and fibrosarcomas at the site of application at significantly 

dose-related incidences [ref: 3]. 

C. Other relevant data

Bleomycins induced chromosomal aberrations in lymphocytes of treated patients in one study [ref: 

4].

In mice treated in vivo, bleomycins induced chromosomal aberrations (including heritable 

translocations) and sister chromatid exchanges but gave conflicting results in tests for micronuclei. 

It induced chromosomal aberrations and DNA strand breaks in human cells in vitro but gave 

conflicting results in tests for unscheduled DNA synthesis and sister chromatid exchange. It induced 

transformation of mouse C3H 10T1/2 cells, and induced aneuploidy, chromosomal aberrations, 

mutation and DNA damage in rodent cells in vitro; a weakly positive response was observed for the 

induction of sister chromatid exchanges. In Drosophila, bleomycin induced aneuploidy, chromosomal 

aberrations, sex-linked recessive lethal mutations, somatic mutations, genetic crossing-over and 

recombination, but not heritable translocations. It induced chromosomal aberrations but not sister 

chromatid exchanges in plants. Bleomycin was mutagenic to fungi and induced gene conversion, 

recombination and genetic crossing-over. It was mutagenic and caused DNA damage in bacteria 

[ref: 4]. 

Overall evaluation
Bleomycins are possibly carcinogenic to humans (Group 2B). 

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 26 (1981)

References

1. IARC Monographs, 26, 97-113, 1981

2. Santoro, A., Viviani, S., Villarreal, C.J.R., Bonfante, V., Delfino, A., Valagussa, P. & Bonadonna, G. 

(1986) Salvage chemotherapy in Hodgkin's disease irradiation failures: superiority of doxorubicincontaining regimens over MOPP. Cancer Treat. Rep., 70, 343-348

3. Habs, M. & Schmähl, D. (1984) Carcinogenicity of bleomycin sulfate and peplomycin sulfate after 

repeated subcutaneous application to rats. Oncology, 41, 114-119

4. IARC Monographs, Suppl. 6, 121-125, 1987 

Synonyms for Bleomycin

● Bleo 

● Bleomycins 

● NSC-125066 

Synonyms for Bleomycin sulfate

● BleMomycine 

● Blenoxane 

● Bleocin 

● Blexane 

Last updated: 27 February 1998 
BRACKEN FERN

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 135) 

A. Evidence for carcinogenicity to humans (inadequate)

In a case-control study of 98 oesophageal cancer patients and 476 controls in Japan, a relative risk 

of 2.7 was found for daily consumption of bracken fern. Interpretation of this study is hampered by 

the absence of detail about the survey and the method of selecting controls, and by failure to take 

account of consumption of alcohol, a risk factor for cancer of the oesophagus [ref: 1]. 

B. Evidence for carcinogenicity to animals (sufficient)

Bracken fern was tested for carcinogenicity in mice, rats, guinea-pigs, cows and toads by oral 

administration, producing leukaemia, intestinal tumours, lung adenomas and gastric tumours in 

mice, small-intestinal tumours, urinary bladder carcinomas and mammary adenocarcinomas in rats, 

urinary bladder tumours in guinea-pigs, alimentary-tract and bladder cancers in cows, and intestinal 

carcinomas and hepatomas in toads. Processed bracken fern produced intestinal tumours in rats; 

boiling-water extracts of bracken fern produced intestinal and bladder tumours in rats; and hotethanol extracts produced intestinal tumours in quails [ref: 1].

Shikimic acid isolated from bracken fern induced neoplasms of the glandular stomach in mice after a 

single intraperitoneal injection. Ptaquiloside derived from bracken fern induced mammary and smallintestinal carcinomas in female rats after administration by gavage [ref: 1].

Most of these studies involved small numbers of animals and were incompletely reported; however, 

they indicate that bracken fern is associated with cancers of the intestine and urinary bladder in 

many different species. 

C. Other relevant data

No data were available on the genetic and related effects of bracken fern in humans.

An acetone extract of bracken fern was mutagenic to Salmonella typhimurium in the presence of an 

exogenous metabolic system. Light-petroleum and methanol extracts of bracken fern activated by 

alkaline treatment were also mutagenic to S. typhimurium [ref: 2]. 

Overall evaluation

Bracken fern is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 40 (1986)

References

1. IARC Monographs, 40, 47-65, 1986

2. IARC Monographs, Suppl. 6, 126, 1987 
Synonym

● Pteridium aquilinum 

Last updated: 27 February 1998 
1,4-BUTANEDIOL DIMETHANESULPHONATE (MYLERAN)

(Group 1) 

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p.137) 

CAS No.: 55-98-1

A. Evidence for carcinogenicity to humans (sufficient)

Leukaemia patients who had been treated with Myleran developed many different cytological 

abnormalities, and some developed carcinomas [ref: 1-8]. A follow-up study of patients with 

bronchial carcinoma who were randomized to chemotherapy after pulmonary resection showed that 

of 69 who had been given Myleran and had survived five years, four developed acute 

nonlymphocytic leukaemia (three myelomonocytic leukaemias and one erythroleukaemia) and 15 

others developed pancytopenia in the succeeding four years; among 148 other survivors at five 

years who had not been given Myleran, one case of pancytopenia appeared. Risk was not doserelated, although the cases were confined to those who had received no radiation and no other 

cytotoxic agent [ref: 9]. 

B. Evidence for carcinogenicity to animals (limited)

Myleran was tested for carcinogenicity by intraperitoneal injection and by intravenous injection in 

mice and rats and by oral administration to rats. Intraperitoneal administration of Myleran to mice 

did not increase the incidence of tumours in two studies [ref: 1,10], but leukaemia [ref: 11] and 

hypoplastic marrow [ref: 11,12] were induced in further studies and T-cell lymphoma in another, in 

which the effect was markedly enhanced by combined administration ofchloramphenico [ref: 13]. 

Leukaemia/lymphosarcoma was also reported in one study [ref: 12], but the experiment could not 

be evaluated due to incomplete reporting. No mammary rumour was seen in rats after 

intraperitoneal injection, but near-lethal doses were used and the animals were followed for only 

five months [ref: 14]. Intravenous administration of Myleran to mice significantly increased the 

incidences of thymic and ovarian tumours [ref: 1]. Intravenous administration of 7% of the LD50

dose to rats for one year was reported to induce a variety of tumours in male rats, but the 

experiments could not be evaluated due to incomplete reporting [ref: 15]. Oral administration to 

rats of Myleran did not increase the incidence of tumours over that seen in untreated animals [ref: 

1]. 

C. Other relevant data

Myleran is a bifunctional alkylating agent. Patients treated with Myleran for chronic myeloid 

leukaemia were found to have increased frequencies of sister chromatid exchanges and 

chromosomal aberrations (in a single study) in their peripheral blood lymphocytes [ref: 16]. 

Treatment of rodents in vivo with Myleran induced dominant lethal mutations and increased the 

frequency of chromosomal aberrations and micronuclei in bone-marrow cells; in single studies, it 

induced DNA damage but not mutation. Evidence for covalent binding to DNA, RNA and protein was 

obtained in mice treated in vivo. Myleran induced chromosomal aberrations and sister chromatid 

exchanges in human and rodent cells in vitro, and mutation in rodent cells in vitro. It induced sexlinked recessive lethal mutations in Drosophila and was mutagenic to bacteria [ref: 16]. 

Overall evaluation

1,4-Butanediol dimethane sulphonate (Myleran) is carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.
Also see previous evaluation: Vol. 4 (1974)

References

1. IARC Monographs, 4, 247-252, 1974 

2. Waller, U. (1960) Giant nuclei after Myleran therapy and spleen irradiation for chronic myeloid 

leukaemia (Ger.). Pathol. Microbiol., 23, 283-290 

3. Güreli, N., Denham, S.W. & Root, S.W. (1963) Cytologic dysplasia related to busulfan (Myleran) 

therapy. Report of a case. Obstet. Gynecol., 21, 466-470 

4. Japp, H. (1974) Toxic effect of busulfan (Myleran) with irradiation for chronic myeloid leukaemia 

(Ger.). Schweiz. med. Wochenschr., 104, 1115-1119 

5. Diamond, I., Anderson, M.M. & McCreadie, S.R. (1960) Transplacental transmission of busulfan 

(MyleranR) in a mother with leukaemia. Production of fetal malformation and cytomegaly. Pediatrics, 

25, 85-90 

6. Feingold, M.L. & Koss, L.G. (1969) Effects of long-term administration of busulfan. Report of a 

patient with generalized nuclear abnormalities, carcinoma of vulva, and pulmonary fibrosis. Arch. 

intern. Med., 124, 66-71 

7. Pezzimenti, J.F., Kim, H.C. & Lindenbaum, J. (1976) Erythroleukemia-like syndrome due to 

busulfan toxicity in polycythemia vera. Cancer, 38, 2242-2246 

8. Dittmar, K. (1979) Acute myeloblastic leukemia with polycythemia vera treated with busulfan and 

phlebotomy. N.Y. State J. Med., 79, 758-760 

9. Stott, H., Fox, W., Girling, D.J., Stephens, R.J. & Galton, D.A.G. (1977) Acute leukaemia after 

busulfan. Br. med. J., ii, 1513-1517 

10. Stoner, G.D., Shimkin, M.B., Kniazeff, A.J., Weisburger, J.H., Weisburger, E.K. & Gori, G.B. 

(1973) Test for carcinogenicity of food additives and chemotherapeutic agents by the pulmonary 

tumor response in strain A mice. Cancer Res., 33, 3069-3085 

11. Chu, J., Cao, S., Ying, H. & Li, D. (1981) Experimental study of busulfan-induced leukemia in 

strain 615 mice (Chin.). Zhonghua Xueyexue Zazhi, 2, 10-13 

12. Morley, A. & Blake, J. (1974) An animal model of chronic aplastic marrow failure. I. Late marrow 

failure after busulfan. Blood, 44, 49-56 

13. Robin, E., Berman, M., Bhoopalam, N., Cohen, H. & Fried, W. (1981) Induction of lymphomas in 

mice by busulfan and chloramphenicol. Cancer Res., 41, 3478-3482 

14. Philips, F.S. & Sternberg, S.S. (1975) Tests for tumor induction by antitumor agents. Recent 

Results Cancer Res., 52, 29-35 

15. Schmähl, D. (1975) Experimental investigations with anti-cancer drugs for carcinogenicity with 

special reference to immunodepression. Recent Results Cancer Res., 52, 18-28 

16. IARC Monographs, Suppl. 6, 129-131, 1987 

Synonyms
● 1,4-Bis(methanesulphonoxy)butane 

● 1,4-Bis(methanesulphonyloxy) butane 

● Busulfan 

● Busulphan 

● C.B.2041 

● 1,4-Dimethanesulphonoxybutane 

● 1,4-Dimethanesulphonoxylbutane 

● 1,4-Di(methanesulphonyloxy)butane 

● 1,4-Dimethylsulphonoxybutane 

● 1,4-Dimethylsulphonyloxybutane 

● Mablin 

● Methanesulphonic acid, tetramethylene ester 

● Mielevcin 

● Misulban 

● Mitosan 

● Myeloleukon 

● Myelosan 

● Myleran 

● Sulphabutin 

● Tetramethylene bis(methanesulphonate) 

● Tetramethylene dimethanesulphonate 

Last updated: 6 February 1998 
CARPENTRY AND JOINERY

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 378) 

A. Evidence for carcinogenicity to humans (limited)

The epidemiological data available suggest that there may be a carcinogenic risk connected with 

employment as a carpenter or joiner, although some of the studies produced negative results [ref: 

1].

The connection between nasal cancer other than adenocarcinoma and exposure to wood dust among 

carpenters and joiners, found in some studies, if true, cannot be ascribed to any specific exposure. 

Carpenters and joiners usually work with impregnated wood, use a variety of types of wood and are 

exposed to many chemicals used in carpentry [ref: 1].

Several studies raise the possibility of an increased risk of Hodgkin's disease. A number of studies 

suggest an association between work as a joiner and nasal adenocarcinoma, but it is possible that 

the workers involved may have worked in the furniture industry [ref: 1].

There is also some evidence of an association between nasal carcinomas other than adenocarcinoma 

and work as a carpenter. In a case-control study based on an analysis of occupational data in the 

hospital records of 121 men seen for nasal cancer in British Columbia, Canada, between 1939 and 

1977, a relative risk of 2.5 (adjusted for smoking and ethnic origin) was associated with exposure to 

wood. There was an increased risk for most histological types of epithelial tumour, except for 

transitional tumours. Of the 28 wood workers with nasal cancer, 16 had worked in the forestry 

industry, seven had been carpenters, four had been construction workers and one had been a 

cabinet-maker [ref: 2].

A case-control study on nasal and sinonasal cancer in Denmark, Finland and Sweden found a 

connection with exposure to spruce, pine and birch dust and the cancers studied, especially 

epidermoid and anaplastic carcinomas. There were 13 cases with exposure only these types of wood 

versus four controls (relative risk, 3.2; 95% confidence interval, 1.1-9.4). Of the cases, five were in 

construction carpenters and one in a cabinet-maker with no exposure to hardwood; there were two 

construction carpenters among the controls [ref: 3].

In a Norwegian study of 70 cases of nasal carcinoma, three cases of squamous-cell carcinoma had 

had exposure to pine and spruce dust in joinery and carpentry versus 1.5 expected on the basis of 

the occupational distribution in Norway according to the 1946 census [ref: 4]. In France, carpenters 

were not found to have an increased risk of nasal cancer, but no quantitative data were given [ref: 

5]. A case-control study of nasal cancer from North Carolina and Virginia, USA, showed a 

nonsignificant relative risk of 1.6 for carpentry [ref: 6].

In a national study of nasal cancer in England and Wales in 1963-1967, the occupations of 925 men 

were studied, using postal questionnaires and data from hospital and death records. Among wood 

workers, the standard incidence ratios (SIRs) for cabinet- and chairmakers, machinists and 'other' 

wood workers were 966, 616 and 293, respectively. For carpenters and joiners, the SIR was 149 

[ref: 7]. Another case-control study [ref: 8] showed no significantly increased risk for 'woodworkers 

and carpenters' residing in certain areas of London, selected for the study because of high 

incidences of nasal and bladder cancer.

A Swedish register-linkage study gave a two-fold excess of adenocarcinoma, based on five cases, 

among carpenters and joiners but no overall excess of nasal cancer in this group [ref: 9].

A cohort study comparing the experience of 10 322 men employed in wood-working industries with 

that of 406 798 non-wood workers showed no excess for all cancers combined. In the subcohort of 
carpenters and joiners, 36 cases of stomach cancer were found, yielding a standardized mortality 

ratio (SMR) of 170 (p < 0.01). There were 101 deaths from lung cancer, resulting in a SMR of 120 

(p < 0.05). Nonsignificantly elevated SMRs were found for cancers of the liver, biliary ducts and gallbladder (11 cases; SMR, 121), nonmelanocytic skin cancer (4 cases; SMR, 333) and melanoma (5 

cases; SMR, 161). There were two cases of nasal cancer (SMR, 333; nonsignificant) [ref: 10].

A proportionate mortality study showed an elevated risk for death from all cancers (proportionate 

mortality ratio [PMR], 112; p < 0.01), stomach cancer (PMR, 128; p < 0.01) and non-Hodgkin's 

lymphoma (PMR, 139; p < 0.05) among woodworkers (including carpenters, cabinet-makers and 

furniture workers, lumber graders and scalers, sawyers in sawmills andwoodworkers not classified 

elsewhere). In this mixed category, there was no death from sinonasal cancer [ref: 11].

A Dutch case-control study [ref: 12] of 116 male patients with primary sinonasal malignancies of 

epithelial origin showed an increased risk of adenocarcinoma for those employed in joinery and 

carpentry work in factories (odds ratio, 16.3; 90% confidence interval, 2.8-85.3). This work included 

production of doors and window frames; hence exposure to oak dust was likely. 

Overall evaluation

Carpentry and joinery entail exposures that are possibly carcinogenic to humans (Group 2B). 

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 25 (1981)

References

1. IARC Monographs, 25, 139-156, 1981

2. Elwood, J.M. (1981) Wood exposure and smoking: association with cancer of the nasal cavity and 

paranasal sinuses in British Columbia. Can. med. Assoc. J., 124, 1573-1577

3. Hernberg, S., Westerholm, P., Schultz-Larsen, K., Degerth, R., Kuosma, E., Englund, A., Engzell, 

U., Sand Hansen, H. & Mutanen, P. (1983) Nasal and sinonasal cancer. Connection with occupational 

exposures in Denmark, Finland and Sweden. Scand. J. Work Environ. Health, 9, 315-326

4. Voss, R., Stenersen, T., Oppedal, B.R. & Boysen, M. (1985) Sinonasal cancer and exposure to 

softwood. Acta otolaryngol., 99, 172-178

5. Duclos, J.-C., Dubreuil, C., Contassot, J.C., Guinchard, R. & Arnould, G. (1979) Nasal ethmoid 

adenocarcinomas in woodworkers. Clinical and forensic aspects (Fr.). Arch. Mal. prof., 40, 909-917

6. Brinton, L.A., Blot, W.J., Becker, J.A., Winn, D.M., Browder, J.P., Farmer, J.C., Jr & Fraumeni, 

J.F., Jr (1984) A case-control study of cancers of the nasal cavity and paranasal sinuses. Am. J. 

Epidemiol., 119, 896-906

7. Acheson, E.D., Cowdell, R.H. & Rang, E.H. (1981) Nasal cancer in England and Wales: an 

occupational survey. Br. J. ind. Med., 38, 218-224

8. Baxter, P.J. & McDowall, M.E. (1986) Occupation and cancer in London: an investigation into 

nasal and bladder cancer using the Cancer Atlas. Br. J. ind. Med., 43, 44-49

9. Malker, H.S.R., McLaughlin, J.K., Blot, W.J., Weiner, J.A., Malker, B.K., Ericsson J.L.E. & Stone, 

B.J. (1986) Nasal cancer and occupation in Sweden, 1961-1979. Am. J. ind. Med., 9, 477-485
10. Stellman, S.D. & Garfinkel, L. (1984) Cancer mortality among woodworkers. Am. J. ind. Med., 5, 

343-357

11. Gallagher, R.P., Threlfall, W.J., Band, P.R. & Spinelli, J.J. (1987) Cancer mortality experience of 

woodworkers, loggers, fishermen, farmers, and miners in British Columbia. Natl Cancer Inst. 

Monogr., 69, 163-167

12. Hayes, R.B., Gerin, M., Raatgever, J.W. & de Bruyn, A. (1986) Wood-related occupations, wood 

dust exposure, and sinonasal cancer. Am. J. Epidemiol., 124, 569-577

Last updated: 27 February 1998 
CHLORAMBUCIL

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 144)

CAS No.: 305-03-3

Chem. Abstr. Name: Benzenebutanoic acid, 4-[bis(2-chloroethyl)amino]- 

A. Evidence for carcinogenicity to humans (sufficient)

Many case reports and a few small epidemiological studies of malignancy after therapy with 

chlorambucil have been reported among patients treated for breast cancer, juvenile arthritis, 

glomerulonephritis and ovarian cancer. Although in each study an excess of subsequent malignancy, 

especially acute nonlymphocytic leukaemia (ANLL), is inferred, these reports are difficult to interpret 

because the cases are few or because they had also received radiation or other putative carcinogens 

[ref: 1,2]. A randomized trial of therapy in 431 polycythemia vera patients [ref: 3] showed a 

significant, 13-fold increase in the incidence of ANLL in those receiving chlorambucil - 2.3 times 

higher than in patients receiving radioactive phosphorus. The excess was strongly related to dose 

and persisted throughout the first decade after treatment. 

B. Evidence for carcinogenicity to animals (sufficient)

Chlorambucil has been tested for carcinogenicity in mice and rats by intraperitoneal injection and in 

female rats by oral gavage. It produced tumours of the lung and probably tumours of the 

haematopoietic system and ovaries in mice [ref: 1], and produced haematopoietic tumours in male 

rats and haematopoietic and lymphatic tumours in female rats [ref: 1,4]. It had an initiating effect 

in a two-stage skin carcinogenesis experiment in mice [ref: 1]. 

C. Other relevant data

Chlorambucil is a bifunctional alkylating agent. It induced sister chromatid exchanges in the 

lymphocytes of treated patients; studies of induction of chromosomal aberrations were inconclusive 

[ref: 5]. 

Chlorambucil induced chromosomal aberrations in embryo cells of rats treated in vivo. Sister 

chromatid exchanges and chromosomal aberrations were induced in human lymphocytes and sister 

chromatid exchanges and mutation in Chinese hamster cells in vitro. Chlorambucil induced sexlinked recessive lethal mutations in Drosophila and mutation and gene conversion in yeast. It was 

mutagenic to bacteria [ref: 5]. 

Overall evaluation

Chlorambucil is carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 9 (1975); Vol. 26 (1981)

References

1. IARC Monographs, 26, 115-136, 1981 
2. Greene, M.H., Boice, J.D., Jr, Greer, B.E., Blessing, J.A. & Dembo, A.J. (1982) Acute 

nonlymphocytic leukemia after therapy with alkylating agents for ovarian cancer. A study of five 

randomized clinical trials. New Engl. J. Med., 307, 1416-1421 

3. Berk, P.D., Goldberg, J.D., Silverstein, M.N., Weinfeld, A., Donovan, P.B., Ellis, J.T., Landaw, 

S.A., Laszlo, J., Najean, Y., Pisciotta, A.V. & Wasserman, L.R. (1981) Increased incidence of acute 

leukemia in polycythemia vera associated with chlorambucil therapy. New Engl. J. Med., 304, 441-

447 

4. Berger, M.R., Habs, M. & Schmähl, D. (1985) Comparative carcinogenic activity of prednimustine, 

chlorambucil, prenisolone and chlorambucil plus prednisolone in Sprague-Dawley rats. Arch. 

Geschwulstforsch., 55, 429-442 

5. IARC Monographs, Suppl. 6, 139-141, 1987 

Synonyms

● Ambochlorin 

● Amboclorin 

● 4-[para-Bis(β-chloroethyl)aminophenyl]butyric acid 

● CB 1348 

● Chlorbutinum 

● Chloroambucil 

● Chloroaminophen 

● Chloraminophene 

● Chlorbutin 

● Chlorobutin 

● Chlorobutine 

● N,N-Di-2-chloroethyl-gamma-p-aminophenylbutyric acid 

● para-N,N-Di(β-chloroethyl)aminophenylbutyric acid 

● Ecloril 

● Elcoril 

● Leukeran 

● Leukersan 

● Leukoran 

● Linfolizin 

● Linfolysin 

● Lympholysin 

● NSC 3088 

● Phenylbutyric acid nitrogen mustard 

Last updated: 6 February 1998 
CHLORODIFLUOROMETHANE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 149) 

CAS No.: 75-45-6 

A. Evidence for carcinogenicity to humans (inadequate) 

A small study of 539 refrigeration workers exposed to a mixture of chlorofluorocarbons, including 

chlorodifluoromethane, for at least six months with up to 30 years' follow up was uninformative with 

regard to the carcinogenic hazard of this chemical (6 deaths due to cancer, 5.7 expected; 2 deaths 

from lung cancer, 1.0 expected) [ref: 1]. 

B. Evidence for carcinogenicity to animals (limited) 

Chlorodifluoromethane was tested for carcinogenicity in rats by oral administration and in mice and 

rats by inhalation. Oral administration to rats yielded no increase in tumour incidence in one study. 

A study by inhalation in mice gave inconclusive results for males and negative results for females. 

One study by inhalation in rats was inadequate, while in another, males exposed to the highest 

concentration had a marginal increase in the incidence of subcutaneous fibrosarcomas and Zymbalgland tumours and negative results were obtained for female rats [ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of chlorodifluoromethane in humans. 

Chlorodifluoromethane did not induce dominant lethal mutations in rats or chromosomal aberrations 

in bone-marrow cells of mice treated in vivo. It did not induce unscheduled DNA synthesis in human 

cells in vitro or mutation in cultured Chinese hamster V79 cells. It did not induce mutation or mitotic 

gene conversion in yeast, either after direct exposure or in a host-mediated assay. It was mutagenic 

to plants and bacteria [ref: 2]. 

Overall evaluation

Chlorodifluoromethane is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Subsequent evaluation: Vol. 71 (1999)

Also see previous evaluation: Vol. 41 (1986)

References

1. IARC Monographs, 41, 237-252, 1986 

2. IARC Monographs, Suppl. 6, 150-151, 1987 

Synonyms

● Algeon 22 
● Algofrene 22 

● Algofrene type 6 

● Arcton 22 

● Arcton 4 

● CFC 22 

● Daiflon 22 

● Difluorochloromethane 

● Difluoromonochloromethane 

● Dymel 22 

● Electro-CF 22 

● F 22 

● FC 22 

● Flugene 22 

● Forane 22 

● Freon 22 

● Frigen 22 

● Genetron 22 

● Haltron 22 

● Isceon 22 

● Isotron 22 

● Khaladon 22 

● Monochlorodifluoromethane 

● R 22 

● Ucon 22 

Last updated: 13 April 1999 
CHLOROETHYL NITROSOUREAS:

BISCHLOROETHYL NITROSOUREA (BCNU) 

(Group 2A)

1-(2-CHLOROETHYL)-3-CYCLOHEXYL-1-NITROSOUREA (CCNU) 

(Group 2A)

1-(2-CHLOROETHYL)-3-(4-METHYLCYCLOHEXYL)-1-NITROSOUREA (METHYLCCNU) 

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p.150) 

Bischloroethyl nitrosourea (BCNU)

CAS No.: 154-93-8

Chem. Abstr. Name: Urea, N,N'-bis(2-chloroethyl)-N-nitroso1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)

CAS No.: 13010-47-4

Chem. Abstr. Name: Urea, N-(2-chloroethyl)-N'-cyclohexyl-N-nitroso1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (Methyl-CCNU)

CAS No.: 13909-09-6

A. Evidence for carcinogenicity to humans (limited for BCNU; inadequate for CCNU; sufficient for 

methyl-CCNU)

In seven randomized trials of treatment for brain tumours, two cases of acute nonlymphocytic 

leukaemia (ANLL) occurred among 1628 patients treated with BCNU (0.08 expected) within the first 

two years of treatment, whereas no such case occurred among 1028 patients not treated with BCNU 

[ref: 1]. 

No epidemiological study of CCNU as a single agent was available to the Working Group [ref: 2]. 

Adjuvant treatment with methyl-CCNU has been evaluated in 3633 patients with gastrointestinal 

cancer treated in nine randomized trials. Among 2067 patients treated with methyl-CCNU, 14 cases 

of ANLL occurred (relative risk, 12.4; 95% confidence interval, 1.7-250), whereas one occurred 

among 1566 patients treated with other therapies. Cumulative (actuarial) risk was 4% at six years 

and was not affected by concomitant radiotherapy or immunotherapy [ref: 3]. A subsequent report 

described a strong dose-response relationship, adjusted for survival time, giving a relative risk of 

almost 40 fold among patients who had received the highest dose [ref: 4]. 

B. Evidence for carcinogenicity to animals (sufficient for BCNU and for CCNU; limited for methylCCNU)

BCNU produced malignant tumours of the lung and an increased risk for neurogenic tumours in rats 

after its repeated intraperitoneal or intravenous administration, and tumours in the peritoneal cavity 

after its intraperitoneal administration [ref: 2,5,6]. Tests in mice by intraperitoneal administration 

and in rats by oral administration could not be evaluated [ref: 2]. When tested in mice by skin 

application together with ultraviolet B irradiation, BCNU caused an earlier appearance of skin 

tumours [ref: 2]. Two studies by skin painting in mice were inadequate [ref: 2,7]. 
CCNU produced lung tumours in rats following its intraperitoneal or intravenous injection [ref: 2,5]. 

When tested in mice by intraperitoneal injection, it induced a slight increase in the incidence of 

lymphomas. Tests in rats by oral administration could not be evaluated [ref: 2]. In one study by skin 

application to mice, no skin tumour was observed, but the duration of the experiment was 

inadequate [ref: 7]. 

Data on methyl-CCNU were included in a report in which a large number of cancer chemotherapeutic 

agents were tested for carcinogenicity by intraperitoneal injection in Sprague-Dawley and Swiss 

mice. In male rats injected with methyl-CCNU thrice weekly for six months, total tumour incidence 

was reported to be increased 1.5-2 fold over that in controls at 18 months. A slight increase in 

tumour incidence was reported in mice [ref: 8]. Intravenous administration of methyl CCNU to rats 

induced lung tumours [ref: 5]. 

C. Other relevant data

BCNU, CCNU and Me-CCNU are directly-acting, bifunctional alkylating agents [ref: 9]. 

No data were available on the genetic and related effects of BCNU and Me-CCNU in humans. An 

increased frequency of sister chromatid exchanges was observed in a single study of peripheral 

blood lymphocytes of patients treated with CCNU. 

BCNU induced chromosomal aberrations, micronuclei and sister chromatid exchanges in cells of mice 

treated in vivo, DNA damage in human cells in vitro, and aneuploidy, chromosomal aberrations, 

sister chromatid exchanges, mutation and DNA damage in rodent cells in vitro. It induced sex-linked 

recessive lethal mutations in Drosophila and gene conversion in yeast. It was mutagenic and caused 

DNA damage in bacteria [ref: 9]. 

CCNU induced dominant lethal mutations in rats and DNA damage in cells of mice and rats treated in 

vivo. It induced DNA damage in human and rodent cells in vitro and sister chromatid exchanges and 

mutation in cultured Chinese hamster cells. It induced mutation and DNA damage in bacteria [ref: 

9]. 

Overall evaluation

Bischloroethyl nitrosourea (BCNU) is probably carcinogenic to humans (Group 2A).

1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) is probably carcinogenic to humans (Group 

2A).

1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (Methyl-CCNU) is carcinogenic to humans 

(Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: BCNU: Vol. 26 (1981) (p. 89); CCNU: Vol. 26 (1981) (p. 144)

References

1. Greene, M.H., Boice, J.D., Jr & Strike, T.A. (1985) Carmustine as a cause of acute nonlymphocytic 

leukemia. New Engl. J. Med., 313, 579 

2. IARC Monographs, 26, 79-95, 137-149, 1981 

3. Boice, J.D., Jr, Greene, M.H., Killen, J.Y., Jr, Ellenberg, S.S. & Fraumeni, J.F., Jr (1986) Leukemia 

after adjuvant chemotherapy with semustine (methyl-CCNU). Evidence of a dose-response effect. 

New Engl. J. Med., 314, 119-120 
4. Boice, J.D., Jr, Greene, M.H., Killen, J.Y., Jr, Ellenberg, S.S., Keehn, R.J., McFadden, E., Chen, 

T.T. & Fraumeni, J.F., Jr (1983) Leukemia and preleukemia after adjuvant treatment of 

gastrointestinal cancer with semustine (methyl-CCNU). New Engl. J. Med., 309, 1079-1084 

5. Habs, M. & Schmahl, D. (1984) Long-term toxic and carcinogenic effects of cytostatic drugs. Dev. 

Oncol., 15, 201-209 

6. Eisenbrand, G. (1984) Anticancer nitrosoureas: investigations on antineoplastic, toxic and 

neoplastic activities. In: O'Neill, I.K., von Borstel, R.C., Miller, C.T., Long J. & Bartsch, H., eds, NNitroso Compounds: Occurrence, Biological Effects and Relevance to Human Cancer (IARC Scientific 

Publications No. 57), Lyon, International Agency for Research on Cancer, pp. 695-708 

7. Zackheim, H.S. & Smuckler, E.A. (1980) Tumorigenic effect of topical mechlorethamine, BCNU 

and CCNU in mice. Experientia, 36, 1211-1212 

8. Weisburger, E.K. (1977) Bioassay program for carcinogenic hazards of cancer chemotherapeutic 

agents. Cancer, 40, 1935-1951 

9. IARC Monographs, Suppl. 6, 116-118, 152-154, 1987 

Synonyms for Bischloroethyl nitrosourea (BCNU)

● BiCNU 

● 1,3-Bis(2-chloroethyl)-1-nitrosourea 

● Bis(2-chloroethyl)nitrosourea 

● 1,3-Bis(2-chloroethyl)nitrosourea 

● 1,3-Bis(β-chloroethyl)-1-nitrosourea 

● Carmustin 

● Carmustine 

● 1,3-Di(2-chloroethyl)-1-nitrosourea 

● Nitrumon 

● NSC 409962 

Synonyms for 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)

● Belustine 

● Cee NU 

● Chloroethylcyclohexylnitrosourea 

● 1-(2-Chloroethyl)-3-cyclohexylnitrosourea 

● ICIG 1109 

● Lomustine 

● NSC 79037 

Last updated: 6 February 1998 
CHLOROFORM

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 152) 

CAS No.: 67-66-3

Chem. Abstr. Name: Trichloromethane 

A. Evidence for carcinogenicity to humans (inadequate)

Two studies of trihalomethane levels in drinking-water supplies and community-based rates of 

cancer mortality have been reported. Correlations were found between these levels and various sitespecific cancer mortality rates, especially those for bladder cancer, but also those for cancers of the 

rectum/large intestine, brain and kidney and lymphoma [ref: 1,2]. In one study in which 

trihalomethane levels in drinking-water at place of residence were compared directly for 395 

matched pairs of female teachers with regard to colorectal cancer, no association with 

trihalomethane exposure was observed [ref: 3]. A mortality study of anaesthesiologists who worked 

at the time chloroform was used provided no significant information [ref: 4].

Several investigations have attempted to assess the effects of trihalomethanes in drinking-water 

indirectly by comparing risks of cancers at various sites with extent of chlorination. Although 

excesses of some cancers have been found, it is not possible to evaluate any effect of chloroform 

from such studies [ref: 5-16]. 

B. Evidence for carcinogenicity to animals (sufficient)

Chloroform produced benign and malignant tumours of the liver and kidney in mice following oral 

gavage [ref: 17,18]. Administration in drinking-water to female mice did not increase the incidence 

of liver tumours [ref: 19]. Administration of chloroform to rats by gavage or in drinking-water 

increased the incidences of kidney [ref: 17,19] and thyroid tumours [ref: 17] and of neoplastic 

nodules of the liver [ref: 20]. Chloroform was tested inadequately by subcutaneous and 

intraperitoneal injection in mice [ref: 17]. A study by oral administration in dogs gave negative 

results [ref: 21]. Oral administration of chloroform did not enhance the incidences of liver and lung 

tumours induced in mice by intraperitoneal injection of N-ethyl-N-nitrosourea [ref: 22], but it 

enhanced the incidence of liver preneoplastic foci in rats treated with a single dose of Nnitrosodiethylamine [ref: 23]. 

C. Other relevant data

No adequate data were available on the genetic and related effects of chloroform in humans.

Chloroform did not induce micronuclei in bone-marrow cells of mice or DNA damage in liver or 

kidney cells of rats treated in vivo. It did not induce chromosomal aberrations, sister chromatid 

exchanges or unscheduled DNA synthesis in human lymphocytes in vitro. Chloroform enhanced 

virus-induced cell transformation of Syrian hamster embryo cells. It did not induce sister chromatid 

exchanges or mutation in Chinese hamster cells or DNA damage in rat hepatocytes in vitro. 

Chloroform did not induce sex-linked recessive lethal mutations in Drosophila or aneuploidy, 

mutation or somatic segregation in Aspergillus. Chloroform induced DNA damage but not mutation, 

aneuploidy, mitotic recombination or gene conversion in Saccharomyces cerevisiae, whereas 

mutation, mitotic recombination and gene conversion were induced in S. cerevisiae under conditions 

in which endogenous levels of cytochrome P450 were enhanced. Chloroform did not induce mutation 

or DNA damage in bacteria [ref: 24]. 

Overall evaluation
Chloroform is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Subsequent evaluation: Vol. 73 (1999)

Also see previous evaluations: Vol. 1 (1972); Vol. 20 (1979)

References

1. Hogan, M.D., Chi, P.-Y., Hoel, D.G. & Mitchell, T.J. (1979) Association between chloroform levels 

in finished drinking water supplies and various site-specific cancer mortality rates. J. environ. 

Pathol. Toxicol., 2, 873-887

2. Cantor, K.P., Hoover, R., Mason, T.J., McCabe, L.J. (1978) Association of cancer mortality with 

halomethanes in drinking water. J. natl Cancer Inst., 61, 979-985

3. Lawrence, C.E., Taylor, P.R., Trock, B.J. & Reilly, A.A. (1984) Trihalomethanes in drinking water 

and human colorectal cancer. J. natl Cancer Inst., 72, 563-568

4. Linde, H.W. & Mesnick, P.S. (1980) Causes of Death of Anesthesiologists from the Chloroform Era 

(PB 80-125172 (EPA/600/1-79-043)), Springfield VA, National Technical Information Service

5. Cantor, K.P. (1982) Epidemiological evidence of carcinogenicity of chlorinated organics in drinking 

water. Environ. Health Perspect., 46, 187-195

6. Carlo, G.L. & Mettlin, C.J. (1980) Cancer evidence and trihalomethane concentrations in a public 

drinking water system. Am. J. publ. Health, 70, 523-525

7. Craun, G.F. (1985) Epidemiologic studies of organic micropollutants in drinking water. Sci. total 

Environ., 47, 461-472

8. DeRouen, T.A. & Diem, J.E. (1977) Relationships between cancer mortality in Louisiana drinkingwater source and other possible causative agents. In: Hiatt, H.H., Watson, J.D. & Winsten, J.A., eds, 

Origins of Human Cancer, Book A, Incidence of Cancer in Humans, Cold Spring Harbor, NY, CSH 

Press, pp. 331-345

9. Gottlieb, M.S., Carr, J.K. & Morris, D.T. (1981) Cancer and drinking water in Louisiana: colon and 

rectum. Int. J. Epidemiol., 10, 117-125

10. Alavanja, M., Goldstein, I. & Susser, M. (1978) A case control study of gastrointestinal and 

urinary tract cancer mortality and drinking water chlorination. In: Jolley, R.L., Gorchev, H. & 

Hamilton, D.H., Jr, eds, Water Chlorination, Environmental Impact and Health Effects, Vol. 2, Ann 

Arbor, MI, Ann Arbor Science, pp. 395-409

11. Brenniman, G.R., Vasilomanolakis-Lagos, J., Amsel, J., Namekata, T. & Wolff, A.H. (1980) Casecontrol study of cancer deaths in Illinois communities served by chlorinated or nonchlorinated water. 

In: Jolly, R.J., Brungs, W.A., Cumming, R.B. & Jacobs, V.A., eds, Water Chlorination, Environmental 

Impact and Health Effects, Vol. 3, Ann Arbor, MI, Ann Arbor Science, pp. 1043-1057

12. Crump, K.S. & Guess, H.A. (1982) Drinking water and cancer: review of recent epidemiological 

findings and assessment of risks. Am. Rev. publ. Health, 3, 339-357

13. Gottlieb, M.S., Carr, J.K. & Clarkson, J.R. (1982) Drinking water and cancer in Louisiana. A 

retrospective mortality study. Am. J. Epidemiol., 116, 652-667
14. Young, T.B., Kanarek, M.S. & Tsiatis, A.A. (1981) Epidemiologic study of drinking water 

chlorination and Wisconsin female cancer mortality. J. natl Cancer Inst., 67, 1191-1198

15. Kanarek, M.S. & Young, T.B. (1982) Drinking water treatment and risk of cancer death in 

Wisconsin. Environ. Health Perspect., 46, 179-186

16. Wilkins, J.R., III & Comstock, G.W. (1981) Source of drinking water at home and site-specific 

cancer incidence in Washington county, Maryland. Am. J. Epidemiol., 114, 178-190

17. IARC Monographs, 20, 401-427, 1979

18. Roe, F.J.C., Palmer, A.K., Worden, A.N. & Van Abbé, N.J. (1979) Safety evaluation of toothpaste 

containing chloroform. I. Long-term studies in mice. J. environ. Pathol. Toxicol., 2, 799-819

19. Jorgenson, T.A., Meierhenry, E.F., Rushbrook, C.J., Bull, R.J. & Robinson, M. (1985) 

Carcinogenicity of chloroform in drinking water to male Osborne-Mendel rats and female B6C3F1

mice. Fundam. appl. Toxicol., 5, 760-769

20. Tumasonis, C.F., McMartin, D.N. & Bush, B. (1985) Lifetime toxicity of chloroform and 

bromodichloromethane when administered over a lifetime in rats. Ecotoxicol. environ. Saf., 9, 233-

240

21. Heywood, R., Sortwell, R.J., Noel, P.R.B., Street, A.E., Prentice, D.E., Roe, F.J.C., Wadsworth, 

P.F., Worden, A.N. & Van Abbe, N.J. (1979) Safety evaluation of toothpaste containing chloroform. 

III. Long-term study in beagle dogs. J. environ. Pathol. Toxicol., 2, 835-851

22. Pereira, M.A., Knutsen, G.L. & Herren-Freund, S.L. (1985) Effect of subsequent treatment of 

chloroform or phenobarbital on the incidence of liver and lung tumors initiated by ethylnitrosourea 

in 15 day old mice. Carcinogenesis, 6, 203-207

23. Deml, E. & Oesterle, D. (1985) Dose-dependent promoting activity of chloroform in rat liver foci 

bioassay. Cancer Lett., 29, 59-63

24. IARC Monographs, Suppl. 6, 155-158, 1987 

Synonyms

● Formyl trichloride 

● Freon 20 

● Methane trichloride 

● Methenyl chloride 

● Methenyl trichloride 

● Methyl trichloride 

● R 20 

● Trichloroform 

Last updated: 30 September 1999 
CHLOROPHENOXY HERBICIDES

(Group 2B)

For definition of Groups, see Preamble Evaluation.

Supplement 7: (1987) (p.156) 

2,4-D and esters

CAS No.: 94-75-7

Chem. Abstr. Name: (2,4-Dichlorophenoxy) acetic acid

2,4,5-T and esters

CAS No.: 93-76-5

Chem. Abstr. Name: (2,4,5-Trichlorophenoxy) acetic acid

MCPA

CAS No.: 94-74-6

Chem. Abstr. Name: (4-Chloro-2-methyl-phenoxy) acetic acid

2,4-DP

CAS No.: 120-36-5

Chem. Abstr. Name: 2-(2,4-Dichlorophenoxy) propanoic acid

Silvex

CAS No.: 93-72-1

Chem. Abstr. Name: 2-(2,4,5-Trichlorophenoxy) propanoicacid

MCPP

CAS No.: 93-65-2

Chem. Abstr. Name: 2-(4-Chloro-2-methylphenoxy) propanoicacid

A. Evidence for carcinogenicity to humans (limitedfor 

chlorophenoxy herbicides)

In a Danish cohort study of chemical workers exposed to 

chlorophenoxy herbicides [particularly (4-chloro-2-methylphenoxy) 

acetic acid (MCPA), 2-(4-chloro-2-methylphenoxy)propanoic acid 

(mecoprop), 2,4-dichlorophenoxyacetic acid (2,4-D) and 2-(2,4-
dichlorophenoxy)propanoic acid (dichlorprop)], as well as other 

chemicals, no overall increase in cancer incidence rate was observed, 

but there were significantly increased risks for soft-tissue sarcoma and 

lung cancer cancer in some subcohorts, which were not necessarily 

those with the highest exposures to chlorophenoxy herbicide 

preparations [ref: 1].

A recently reported cohort of 5784 male employees in a UK company 

that manufactured, formulated and sprayed MCPA and other pesticides 

but only small amounts of 2,4,5-trichlorophenoxy acetic acid (2,4,5-T) 

had no general excess mortality from cancer. Three potentially exposed 

workers died from nasal carcinoma, however. One death due to softtissue sarcoma approximately equalled the expected rate. No excess of 

lymphoma was seen [ref: 2].

A Finnish cohort study of brush control workers with short follow-up 

time showed no increased cancer risk. A small Swedish cohort study of 

railroad workers who sprayed herbicides showed an increased risk of 

cancers at all sites combined for those exposed to chlorophenoxy 

herbicide preparations and other herbicides. An excess incidence of all 

cancers was also reported from a very small cohort of Swedish forestry 

foremen exposed to chlorophenoxy herbicide preparations and other 

herbicides. A study of long-term pesticide applicators in the German 

Democratic Republic, heavily exposed to a number of chemicals, 

including 2,4-D and MCPA, demonstrated an increased risk of 

bronchial carcinoma [ref: 1].

Two population-based case-control studies conducted in northern and 

southern Sweden, respectively, showed a statistically significant 

association between exposure to chlorophenoxy herbicides, especially 

in forestry and agriculture, and the occurrence of soft-tissue sarcomas. 

An increased risk of soft-tissue sarcoma was described among highly 

exposed Italian rice weeders in a population-based case-control study. 

However, a case-control study from New Zealand did not demonstrate 

any increased risk of soft-tissue sarcoma in people exposed to 

chlorophenoxy herbicides [ref: 1]. Nor did a recently reported 

population-based case-control study of soft-tissue sarcoma and 
lymphoma in Kansas, USA, find any association between soft-tissue 

sarcoma and exposure to 2,4-D [ref: 3].

A statistically significant association between malignant lymphoma 

(Hodgkin's and non-Hodgkin's) and exposure to chlorophenoxy 

herbicides was found in a Swedish case-control study [ref: 1]. The 

population-based case-control study of soft-tissue sarcoma and 

Hodgkin's and non-Hodgkin's lymphoma in Kansas showed that use of 

2,4-D was associated with non-Hodgkin's lymphoma, especially 

among farmers who had been exposed for more than 20 days per year, 

among whom there was an approximately six-fold excess, and among 

those who had mixed or applied the herbicides themselves. Hodgkin's 

lymphoma was not, however, found to be associated with herbicide 

exposure [ref: 3]. No significant or consistent association was seen in a 

case-control study of these tumours from New Zealand, and in a 

Danish cohort of chemical workers exposed to chlorophenoxy 

herbicides there was also no significantly increased risk of malignant 

lymphoma [ref: 1,4]. Farmers and forestry workers in Washington 

State, USA, with exposure to phenoxy herbicides had a significantly 

increased risk of non-Hodgkin's lymphoma. People of Scandinavian 

descent in the area had an increased risk of soft-tissue sarcoma in 

connection with phenoxy herbicide exposure, but no increased risk of 

non-Hodgkin's lymphoma [ref: 5].

Three Swedish case-control studies of colon, liver and nasal and 

nasopharyngeal cancer, which used the same study design and methods 

as in the studies on soft-tissue sarcoma and malignant lymphoma, did 

not demonstrate significantly increased risks, although a risk ratio of 

2.1 was reached for nasal and nasopharyngeal cancer [ref: 1].

A record-linkage study using census data on occupation and cancer 

registry information in Sweden did not reveal any excess of soft-tissue 

sarcoma among agricultural and forestry workers [ref: 6,7]. However, 

on the basis of occupational titles, the elevated risks seen in Swedish 

case-control studies of soft-tissue sarcoma and lymphoma were 

reduced to 1.4 or less [ref: 8]. A UK study based on data from cancer 

registration showed a slightly but significantly increased risk of soft-
tissue sarcoma among farmers, farm managers and market gardeners, 

but not in other subgroups in forestry and farming [ref: 9]. No 

association with soft-tissue sarcoma has been found with military 

service in Viet Nam, despite potential exposure to phenoxy herbicides 

[ref: 1,10], although there is a case report in this respect [ref: 1].

B. Evidence for carcinogenicity to animals (inadequate for 2,4-D 

and 2,4,5-T)

2,4-D and several of its esters were tested in rats and mice by oral 

administration and in mice by subcutaneous administration. All of 

these studies had limitations, due either to inadequate reporting or to 

the small number of animals used. Therefore, although increased 

incidences of tumours were observed in one study in which rats 

received 2,4-D orally and in another in which mice received its 

isooctyl ester by subcutaneous injection, no evaluation of the 

carcinogenicity of this compound could be made [ref: 11].

2,4,5-T was tested in mice by oral and subcutaneous administration. 

All of the studies had limitations due to the small numbers of animals 

used. Therefore, although an increased incidence of tumours at various 

sites was observed in one study in which 2,4,5-T (containing less than 

0.05 mg/kg chlorinated dibenzodioxins) was given orally, no 

evaluation of the carcinogenicity of this compound could be made on 

the basis of the available data [ref: 12]. In rats fed diets containing 

three different concentrations of 2,4,5-T, the incidences of all tumour 

types were comparable to those in the control groups, with the 

exception that the incidence of interfollicular C-cell adenomas of the 

thyroid was increased significantly in female rats receiving the lowest 

dose. This increase was not considered to be related to treatment since 

it was not dose-related and the female control group had an unusually 

low incidence of thyroid adenomas [ref: 13].

A study of the incidence of small-intestinal adenocarcinoma in groups 

of sheep from different farms showed an association with use of 

phenoxy herbicides, as elicited by farmers' responses to a 

questionnaire. However, other herbicides were in use, and there was no 
documentation of exposures [ref: 14].

No adequate data were available on the carcinogenicity of MCPA [ref: 

15].

C. Other relevant data

In single studies, lymphocytes of persons occupationally exposed to 

chlorophenoxy herbicides, including 2,4-D, did not show increased 

frequencies of sister chromatid exchanges or chromosomal aberrations. 

Other studies could not be assessed since workers were also exposed to 

other formulations. A single study of herbicide and pesticide sprayers 

exposed to 2,4,5-T, in which a small increase in the incidence of sister 

chromatid exchanges was reported, could not be assessed since 

workers were also exposed to other formulations. Persons 

occupationally exposed to MCPA did not have increased frequencies 

of sister chromatid exchanges (one study) or chromosomal aberrations 

in their lymphocytes [ref: 16].

2,4-D did not induce dominant lethal mutations, micronuclei or sister 

chromatid exchanges in rodents treated in vivo. Pure 2,4-D did not 

induce chromosomal aberrations in human lymphocytes in vitro, 

whereas a commercial formulation did. 2,4-D induced sister chromatid 

exchanges and unscheduled DNA synthesis in human cells in vitro. It 

did not induce sister chromatid exchanges but did induce mutation and 

inhibited intercellular communication in Chinese hamster cells in vitro, 

2,4-D induced somatic mutation in Drosophila, but conflicting results 

were obtained for induction of sex-linked recessive lethal mutations; it 

did not induce aneuploidy. 2,4-D caused chromosomal aberrations and 

was mutagenic in plants. It induced mutation, gene conversion and 

mitotic recombination in yeast. It was not mutagenic to bacteria or 

bacteriophage. The n-butyl and iso-octyl esters of 2,4-D were also not 

mutagenic to bacteria [ref: 16].

2,4,5-T induced chromosomal aberrations in bone-marrow cells of 

Mongolian gerbils, but not in spermatogonia of Chinese hamsters, and 

aneuploidy in oocytes of rats treated in vivo. It did not induce 
micronuclei in mice or dominant lethal mutations in mice or rats in 

vivo. 2,4,5-T inhibited intercellular communication in Chinese hamster 

V79 cells in vitro. There was weak evidence for the induction of sexlinked recessive lethal mutations in Drosophila; it did not induce 

aneuploidy or somatic mutation. It induced chromosomal aberrations 

in plants. It was mutagenic to yeast, but neither 2,4,5-T nor the n-butyl-

, iso-butyl or iso-octyl ester of 2,4,5-T was mutagenic to bacteria [ref: 

16].

MCPA did not induce structural chromosomal aberrations or 

micronuclei in mice treated in vivo; weakly positive results were 

obtained for sister chromatid exchanges in cells of Chinese hamsters 

treated in vivo and in vitro. It was weakly active in inducing sex-linked 

recessive lethal mutations but did not induce aneuploidy in 

Drosophila. MCPA and its methyl ester were mutagenic to yeast but 

not to bacteria [ref: 16].

Overall evaluation

Chlorophenoxy herbicides are possibly carcinogenic to humans 

(Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 41 (1986)

References

1. IARC Monographs, 41, 357-406, 1986

2. Coggon, D., Pannett, B., Winter, P.D., Acheson, E.D. & Bonsall, J. 

(1986) Mortality of workers exposed to 2-methyl-4-

chlorophenoxyacetic acid. Scand. J. Work Environ. Health, 12, 448-

454

3. Hoar, S.K., Blair, A., Holmes, F.F., Boysen, C.D., Robel, R.J., 

Hoover, R. & Fraumeni, J.F., Jr (1986) Agricultural herbicide use and 
risk of lymphoma and soft-tissue sarcoma. J. Am. med. Assoc., 256, 

1141-1147

4. Pearce, N.E., Sheppard, R.A., Smith, A.H. & Teague, C.A. (1987) 

Non-Hodgkin's lymphoma and farming: an expanded case-control 

study. Int. J. Cancer, 39, 155-161

5. Woods, J.S., Polissar, L., Severson, R.K., Heuser, L.S. & Kulander, 

B.G. (1987) Soft tissue sarcoma and non-Hodgkin's lymphoma in 

relation to phenoxyherbicide and chlorinated phenol exposure in 

western Washington. J. natl Cancer Inst., 78, 899-910

6. Wirklund, K. & Holm, L.-E. (1986) Soft tissue sarcoma risk in 

Swedish agricultural and forestry workers. J. natl Cancer Inst., 76, 229-

234

7. Wirklung, K., Holm, L.-E. & Dich, J. (1987) Soft tissue sarcoma 

risk among agricultural and forestry workers in Sweden. Chemosphere 

(in press)

8. Hardell, L. & Axelson, O. (1986) Phenoxyherbicides and other 

pesticides in the etiology of cancer: some comments on Swedish 

experiences. In: Becker, C.E. & Coye, M.J., eds, Cancer Prevention. 

Strategies in the Workplace, Washington DC, Hemisphere, pp. 107-

119

9. Balarajan, R. & Acheson, E.D. (1984) Soft tissue sarcomas in 

agriculture and forestry workers. J. Epidemiol. Commun. Health, 38, 

113-116

10. Kang, H.K., Weatherbee, L., Breslin, P.P., Lee, Y. & Shepard, 

B.M. (1986) Soft tissue sarcomas and military service in Vietnam: a 

case comparison group analysis of hospital patients. J. occup. Med., 

28, 1215-1218

11. IARC Monographs, 15, 111-138, 1977

12. IARC Monographs, 15, 273-299, 1977
13. Kociba, R.J., Keyes, D.G., Lisowe, R.W., Kalnins, R.P., Dittenber, 

D.D., Wade, C.E., Gorzinski, S.J., Mahle, N.H. & Schwetz, B.A. 

(1979) Results of a two-year chronic toxicity and oncogenic study of 

rats ingesting diets containing 2,4,5-trichlorophenoxyacetic acid (2,4,5-

T). Food Cosmet. Toxicol., 17, 205-221

14. Newell, K.W., Ross, A.D. & Renner, R.M. (1984) Phenoxy and 

picolinic acid herbicides and small intestinal adenocarcinoma in sheep. 

Lancet, ii, 1301-1305

15. IARC Monographs, 30, 255-269, 1983

16. IARC Monographs, Suppl. 6, 161-163, 233-236, 538-540, 1987

Synonyms for 2,4-D and esters

● Abco W.K-67 2,4-D Weed Killer (butyl ester of 2,4-D)

● Abco W.K-DT 133 (isooctyl esters of 2,4-D and 2,4,5-T)

● Abco WKS-65 Brush Killer (isooctyl esters of 2,4-D, 2,4,5-Tand 

silvex [2-(2,4,5-trichloro-phenoxy)propionic acid])

● Acetic acid, (2,4-dichlorophenoxy)-

● Acide dichloro-2,4 phenoxyacetique

● Acido(2,4-dicloro-fenossi)-acetico

● Acme Poison Ivy Killer (dimethylamine salt of 2,4-D + 

triethylaminesalt of 2,4,5-T)

● Acme Vegetation Killer (2,4-D + prometone [2-methoxy-4,6-

bis(isopropylamino)-s-triazine])

● Acme Weed-No-More Spotter (dimethylamine salt of 2,4-D + 

triethylaminesalt of 2,4,5-T)

● Agent Orange (n-butyl esters of 2,4-D and 2,4,5-T)

● Agent Purple (n-butyl esters of 2,4-D and 2,4,5-T + isobutylester 

of 2,4,5-T)

● Agent White (triisopropanolamine salt of 2,4-D + 

triisopropanolamine)

● Agrotect (2,4-D, form unspecified)

● Agway 2,4-D and Silvex Lawn and Weed Killer (2-
ethylhexylester of 2,4-D + butoxyethanol ester of silvex [2-(2,4,5-

trichlorophenoxy)propionicacid])

● Agway Weed Killer "66" Improved (triethanolaminesalt of 2,4-

D)

● Allied Chemical Low Volatile 1-1/3-2/3 Brush Killer (2,4-D+ 

2,4,5-T + isooctyl esters of 2,4-D and 2,4,5-T

● Amchem 2,4-D 2,4,5-T Low Volatile Ester Brush Killer 

(isooctylesters of 2,4-D and 2,4,5-T)

● Amchem 6DT. Low Volatile Ester Brush Killer (isooctyl estersof 

2,4-D and 2,4,5-T)

● Amchem Amine 2,4-D Low Volatile Ester Weed Killer 

(isooctylester of 2,4-D)

● Amchem Emulsamine Brush Killer (alkyl C12 + C14 aminesalts 

of 2,4-D and 2,4,5-T)

● Amchem Emulsamine E-3 (dodecylamine salts of 2,4-D + 

tetradecylaminesalts of 2,4-D)

● Amchem Isooctyl-DT (isooctyl esters of 2,4-D and 2,4,5-T)

● Amchem Isooctyl-DT6 (isooctyl esters of 2,4-D and 2,4,5-T)

● Amchem Super D Weed one (diethanolamine salts of 2,4-D 

anddicamba [3,6-dichloro-2-methoxy-benzoic acid])

● Amchem Weed Killer 650 (isopropyl ester of 2,4-D)

● Amoco 2,4-D LV Ester (isooctyl ester of 2,4-D)

● Amoco 2,4-D Weed Killer No. 3-E-M (butyl and isopropyl 

estersof 2,4-D)

● Amoco 2,4-D Weed Killer No. 3E (butyl and isopropyl estersof 

2,4-D)

● Amoco 2,4-D Weed Killer No. 5 (butyl and isopropyl estersof 2,4-

D)

● Amoco 2,4-D Weed Killer No. 5-M (butyl ester of 2,4-D)

● Amoco 2,4-D Weed Killer No. 6B (butyl ester of 2,4-D)

● Amoco Brush Killer (isooctyl esters of 2,4-D and 2,4,5-T)

● Amoxone (triethanolamine salt of 2,4-D)

● Ansar 290D (triethanolamine salt of 2,4-D + 

triethanolaminemethanearsonate)

● Antrol 2,4-D and 2,4,5-T Weed and Brush Killer 

(alkanolaminesalts [of the ethanol and ispropanol series] of 2,4-D 
+ triethylaminesalts of 2,4,5-T)

● Antrol Jet Stream Weed Killer (alkanolamine salts [of theethanol 

and isopropanol series] of 2,4-D + 

butoxypolypropoxypropylesters of silvex [2-(2,4,5-

trichlorophenoxy)propionic acid])

● Antrol Squeeze'N Weed (alkanolamine salts [of the ethanoland 

isopropanol series] of 2,4-D + butoxypolypropoxypropyl estersof 

silvex [2-(2,4,5-trichlorophenoxy)propionic acid])

● Antrol Wide Stream Chickweed and Clover Killer 

(alkanolaminesalts [of the ethanol and isopropanol series] of 2,4-

D + butoxypolypropoxypropylesters of silvex [2-(2,4,5-

trichlorophenoxy)propionic acid])

● Aptrex (monuron trichloroacetate [3-(p-chlorophenyl)-1,1-

dimethylureatrichloracetate] + isooctyl ester of 2,4-D)

● Aqua-Kleen (butoxyethanol ester of 2,4-D)

● Asgrow Weed-Nix Lawn Food and Weed Killer with 2,4-D and 

silvex(dimethylamine 2,4-dichlorophenoxy-acetate + isooctyl 

ester ofsilvex [2-(2,4,5-trichlorophenoxy)propionic acid])

● Associated Sales 4-Pound 2,4-D Ester Weed Killer (butyl esterof 

2,4-D)

● Atlacide with 2,4-D (sodium chlorate + 2,4-D)

● Balcom's G-K-20 (2-ethylhexyl esters of 2,4-D and 2,4,5-T)

● Balcom's T-D Special Weed Killer (isooctyl esters of 2,4-Dand 

2,4,5-T)

● Barber's 2,4-D Ester Weed Killer (butyl ester of 2,4-D)

● Barber's Weed Killer (Amine Formulation) (dimethylamine saltof 

2,4-D)

● Barber's Weed Killer (Ester Formulation) (isopropyl esterof 2,4-

D)

● Barco Weed Killer (Ester Formulation) (butyl ester of 2,4-D)

● Best 4 Servis Brand Lawn Weed Killer (dimethylamine salt of2,4-

D)

● Blitz 64 (dimethylamine salts of 2,4-D)

● Bonide Crabgrass and Broadleaf Weed Killer 

(dodecylammoniumand octylammonium methanearsonate + 

octylammonium salt of 2,4-D)
● Bonide Dioweed 40% Liquid (triethanolamine salt of 2,4-D)

● Bonide Dioweed Dust (triethanolamine salt of 2,4-D)

● Bonide Dioweed Liquid (triethanolamine salt of 2,4-D + 2,4-D)

● Bonus Type B (2,4-D + 2-[2-methyl-4-

chlorophenoxy]propionicacid)

● Breck's Lawn Weed Killer (butoxyethoxypropanol esters of 2,4-

Dand 2,4,5-T)

● Bridgeport Spot Weed Killer (isopropyl ester of 2,4-D)

● Brulin's 2,4-D Liquid Weed Killer-20% (triethanolamine saltof 

2,4-D)

● Brulin's Brush Killer (butyl esters of 2,4-D and 2,4,5-T)

● Brush Killer 155 (dimethylamine salts of trichlorobenzoicacids + 

triethanolamine salts of 2,4-D and 2,4-

dichlorophenoxypropionicacid)

● Brush Killer 170 (butoxyethanol esters of 2,4-

dichlorophenoxypropionicacid and 2,4-D)

● Brush Killer 171 (butoxyethanol esters of 2,4-

dichlorophenoxypropionicacid and 2,4-D)

● Brush Killer 50-50 (butyl esters of 2,4-D and 2,4,5-T)

● Brush Killer X (isooctyl esters of 2,4-D and 2,4,5-T)

● Brush-O-Cide (isooctyl esters of 2,4-D + 2,4,5-T)

● Brush-Off No. 438 Conc. 2-2 LV Brush Killer (isooctyl estersof 

2,4-D and 2,4,5-T)

● Brush-Rhap A-2D-2T (dimethylamine salt of 2,4-D + 

triethylaminesalt of 2,4,5-T)

● Brush-Rhap Amine A-2D-2T (dimethylamine salt of 2,4-D + 

triethylaminesalt of 2,4,5-T)

● Brush-Rhap B-1.33D - 0.67T (butyl esters of 2,4-D and 2,4,5-T)

● Brush-Rhap B-2-2 (2,4-D + 2,4,5-T)

● Brush-Rhap B-2D-2T (butyl esters of 2,4-D and 2,4,5-T)

● Brush-Rhap Injection Fluid Low Volatile 2D-2T (2-

ethylhexylesters of 2,4-D and 2,4,5-T)

● Brush-Rhap Injection Fluid Low Volatile 3D-3T (2-

ethylhexylesters of 2,4-D and 2,4,5-T)

● Brush-Rhap Low Volatile 2D-2T (2-ethylhexyl esters of 2,4-

Dand 2,4,5-T)
● Brush-Rhap Low volatile 3D-2T (2-ethylhexyl esters of 2,4-Dand 

2,4,5-T)

● Brush-Rhap Low Volatile 3D-3T (2-ethylhexyl esters of 2,4-

Dand 2,4,5-T)

● Brush-Rhap LV 2D-2T (2-ethylhexyl esters of 2,4-D and 2,4,5-T)

● Brush-Rhap LV-2-2-0 (2,4-D + 2,4,5-T)

● Butoxyethanol ester of (2,4-dichlorophenoxy) acetic acid

● Butoxyethyl 2,4-dichlorophenoxyacetate

● Butyl (2,4-dichlorophenoxy)acetate

● Butyl 2,4-D

● Butyl 400 (butyl ester of 2,4-D)

● Butyl dichlorophenoxyacetate

● Butyl ester of dichlorophenoxyacetic acid

● Certified C-300 Selective Weed Killer (isooctyl esters of2,4-D 

and 2,4,5-T)

● Chem-Pels Plus (isooctyl esters of 2,4-D and 2,4,5-T)

● Chemform Butoxy Brush Killer (butoxyethoxypropanol estersof 

2,4-D and 2,4,5-T)

● Chemical Insecticide's Isopropyl Ester of 2,4-D Liquid 

Concentrate(isopropyl ester of 2,4-D)

● Chempar Low Volatile Brush Killer No. 2 (2,4,5-T + 2,4-D)

● Chipco Turf Herbicide "D" (2,4-D, form unspecified)

● Chipco Turf Herbicide "D" and "T" (dimethylaminesalt of 2,4-D 

+ triethylamine salt of 2,4,5-T)

● Chipco Turf Kleen (diethanolamine salts of 2-(2-methyl-4-

chlorophenoxy)propionicacid and 2,4-D)

● Chipman 2,4-D Amine 80 (2,4-D, form unspecified)

● Chipman 2,4-D Amine No. 4 (dimethylamine salt of 2,4-D)

● Chipman 2,4-D Butyl Ester 334E

● Chipman 2,4-D Butyl Ester 4E

● Chipman 2,4-D Butyl Ester 6 (n-butyl ester of 2,4-D)

● Chipman 2,4-D Butyl Ester 6E

● Chipman 2,4-D Ester 128 (2,4-D ester, form unspecified)

● Chipman 2,4-D Ester 5% Dust (2,4-D ester, form unspecified)

● Chipman 2,4-D Ester 64 (2,4-D ester, form unspecified)

● Chipman 2,4-D Ester 80 L.V. (2,4-D ester, form unspecified)
● Chipman 2,4-D Gran 20 (isooctyl ester of 2,4-D)

● Chipman 2,4-D Low Volatile Ester 4L (isooctyl ester of 2,4-D)

● Chipman 2,4-D Low Volatile Ester 6 (isooctyl ester of 2,4-D)

● Chipman 2,4-D Low Volatile Ester 6L (isooctyl ester of 2,4-D)

● Chipman Amine Brush Killer (triethylamine salts of 2,4-D 

and2,4,5-T)

● Chipman Brush Killer 128 (2,4-D + 2,4,5-T, forms unspecified)

● Chipman Brush Killer 128 L.V. (2,4-D + 2,4,5-T, forms 

unspecified)

● Chipman Brush Killer 128 Regular (2,4-D + 2,4,5-T, forms 

unspecified)

● Chipman Brush Killer 76 (isooctyl esters of 2,4-D and 2,4,5-T)

● Chipman Lawn Weed Killer (2,4-D [form unspecified] + disomerof mecoprop [2-(4-chloro-2-methylphenoxy)propionic 

acid])

● Chipman Low Volatile Brush Killer No. 2 (isooctyl esters of2,4-

D and 2,4,5-T)

● Chipman Low Volatile Brush Killer No. 3 (isooctyl esters of2,4-

D and 2,4,5-T)

● Chlorocrotyl ester of 2,4-D

● Chloroxone (2,4-D, form unspecified)

● Commercial Brush Killer (isooctyl esters of 2,4-D and 2,4,5-T)

● Crop Rider "45" (2-ethylhexyl ester of 2,4-D)

● Crop Rider 2.67D (butyl ester of 2,4-D)

● Crop Rider 20% Agua Granular (2-ethylhexyl ester of 2,4-D)

● Crop Rider 20% Terra Granular (2-ethylhexyl ester of 2,4-D)

● Crop Rider 3-34D-2 (isopropyl ester of 2,4-D)

● Crop Rider 3.34D (isopropyl ester of 2,4-D)

● Crop Rider 6D Weed Killer (butyl ester of 2,4-D)

● Crop Rider 6D-OS Weed Killer (butyl ester of 2,4-D)

● Crop Rider LV-6D (2-ethylhexyl ester of 2,4-D)

● Crop-Guard (isobutyl and n-butyl esters of 2,4-D)

● Cross Country Organic Lawn Food with Weed Killer (sodium 

saltof 2,4-D)

● Cross Country Poison Ivy Killer (butoxyethoxypropanol estersof 

2,4-D and 2,4,5-T)
● Cross Country Weed Killer Spray (alkanolamine salts of 2,4-D)

● Cross Country Weedeath (isopropyl and triethylamine saltsof 2,4-

D)

● Crotilin (chlorocrotyl ester of 2,4-D)

● Crotylin (chlorocrotyl ester of 2,4-D)

● (2,4-Dichloor-fenoxy)azijnzuur

● (2,4-Dichlor-phenoxy)essigsaure

● (2,4-Dichlorophenoxy)acetic acid, butyl ester

● (2,4-Dichlorophenoxy)acetic acid, crotyl ester

● (2,4-Dichlorophenoxy)acetic acid, dimethylamine salt

● (2,4-Dichlorophenoxy)acetic acid, isooctyl ester

● (2,4-Dichlorophenoxy)acetic acid, isopropyl ester

● (2,4-Dichlorophenoxy)acetic acid, sodium salt

● 006 Shrub-A-Dub (isooctyl ester of 2,4-D + bromacil [5-bromo-3-

sec-butyl-6-methyluracil]+ pentachlorophenol + other 

chlorophenols)

● 006 Weed Killer (isooctyl ester of 2,4-D + bromacil [5-bromo-3-

sec-butyl-6-methyluracil]+ pentachlorophenol + other 

chloropenols)

● 2,4-D + Bromacil [5-bromo-3-sec-butyl-6-methyluracil] + 

pentachlorophenol+ other phenols)

● 2,4-D acid

● 2,4-D amine (dimethylamine salt of 2,4-D)

● 2,4-D, alpha-chlorocrotyl ester

● 2,4-D, butyl ester

● 2,4-D, dimethylamine salt

● 2,4-D, isooctyl ester

● 2,4-D, isopropyl ester

● 2,4-Dichlorophenoxyacetic acid

● 2,4-Dichlorophenoxyacetic acid, 2-butenyl ester

● 2,4-Dichlorophenoxyacetic acid, 4-chlorocrotonyl alcohol ester

● 2,4-Dichlorophenoxyacetic acid, 4-chlorocrotonyl ester

● 2,4-Dichlorophenoxyacetic acid, butoxyethyl ester

● 2,4-Dichlorophenoxyacetic acid, butyl ester

● 2,4-Dichlorophenoxyacetic acid, isooctyl ester

● 2,4-Dichlorophenoxyacetic acid, isopropyl ester
● 2,4-Dichlorophenoxyacetic acid, sodium salt

● 2,4-Dichlorphenoxyacetic acid

● 2,4-Dow Weed Killer Formula 40 (alkanolamine salt of 2,4-D)

● 2,4-Dow Weed Killer Formula 40 (alkanolamine salts [of 

theethanol and isopropanol series] of 2,4-D)

● 2,4-Dwuchlorofenoksyoctowy Kwas

● D 50 (2,4-D, form unspecified)

● D-Weed-O (isooctyl ester of 2,4-D + Bromacil [5-bromo-3-secbutyl-6-methyluracil]+ pentachlorophenol + other chlorophenols)

● Dacamine (N-oleyl 1,3-propylenediamine salts of 2,4-D and2,4,5-

T)

● Dacamine 1D/1T (N-oleyl 1,3-propylenediamine salts of 2,4-

Dand 2,4,5-T)

● Dacamine 2D/2T (N-oleyl 1,3-propylenediamine salts of 2,4-

Dand 2,4,5-T)

● Dacamine 4D (N-oleyl 1,3-propylenediamine salt of 2,4-D)

● Dal-E-Rad + 2 Powder (disodium methanearsonate 

[hexahydrate]+ sodium 2,4-dichlorophenoxy acetate 

monohydrate)

● DB Granular (disodium tetraborate pentahydrate and 

decahydrate+ 2,4-D)

● De Witt S-77 Weed Killer (dimethylamine salts of 2,4-D 

and2,4,5-T)

● De-Pester Ded-Weed for Lawns (2,4-D + 2,4,5-T + Kerosene)

● De-Pester Ded-Weed LV-2 (2,4-D)

● De-Pester Ded-Weed ME-4 (butyl ester of 2,4-D)

● De-Pester Ded-Weed ME-5 (butyl ester of 2,4-D)

● De-Pester Ded-Weed ME-6 (butyl ester of 2,4-D)

● De-Pester Ded-Weed ME-9 (butyl ester of 2,4-D)

● Decamine (2,4-D, form unspecified)

● Ded-weed for Lawns, New Improved (isooctyl esters of 2,4-Dand 

2,4,5-T)

● Ded-weed LV-69 (2,4-D, form unspecified)

● Del SK 40 Heavy Duty Weed Killer (alkanolamine salts [of 

theethanol and isopropanol series] of 2,4-D)

● Del-Kill Weed Killer 400 Liquid (mixed aliphatic hydrocarbons+ 
isooctyl ester of

● Destruxol Weed Killer "D" (isooctyl esters of 2,4-Dand 2,4,5-T)

● Di-Met Chickweed and Weed Killer (isooctyl esters of 2,4-Dand 

silvex [2-(2,4,5-trichlorophenoxy) propionic acid])

● Di-Met Plus-2, Liquid for Crabgrass and Lawn Weeds 

(dodecylammonium methanearsonate + octyl ammonium 

methanearsonate + octylammonium salt of 2,4-D)

● Di-Met Plus-2, Liquid for Dallis Grass and Lawn Weeds 

(dodecylammonium methanearsonate + octyl ammonium 

methanearsonate + octylammonium salt of 2,4-D)

● Diamond Alkali Chemicals 2-2 2-Ethyl Hexyl Brush Killer (2-

ethylhexylesters of 2,4-D and 2,4,5-T)

● Diamond Alkali Chemicals 4 2-Ethyl Hexyl D Weed Killer (2-

ethylhexylester of 2,4-D)

● Diamond Alkali Chemicals 4-Mixed Amine-D Weed Killer 

(alkyland dialkanolamine salts of 2,4-D)

● Diamond Alkali Chemicals Crop Rider Amine 4-D (alkyl and 

dialkanolaminesalts of 2,4-D)

● Diamond Alkali Chemicals Crop Rider and Line Rider LV-4D (2-

ethylhexyester of 2,4-D)

● Diamond Alkali Chemicals Technical 2-Ethyl Hexyl-D (2-

ethylhexylester of 2,4-D)

● Diamond Alkali Chemicals The Line Rider (2-ethylhexyl estersof 

2,4-D and 2,4,5-T)

● Diamond Shamrock Amine 2D/2T (dimethylamine salts of 2,4-

Dand 2,4,5-T)

● Diamond Shamrock Amine 6D (dimethylamine salt of 2,4-D)

● Diamond Shamrock Butyl 4D (butyl ester of 2,4-D)

● Diamond Shamrock Butyl 6D Weed Killer (butyl ester of 2,4-D)

● Diamond Shamrock Dormant Cane LV 3D/3T-OS (isooctyl 

estersof 2,4-D and 2,4,5-T)

● Diamond Shamrock LO-VOL 2D/2T (isooctyl esters of 2,4-D 

and2,4,5-T)

● Diamond Shamrock LO-VOL 4D (isooctyl ester of 2,4-D)

● Diamond Shamrock LO-VOL 6D (isooctyl ester of 2,4-D)

● Dichlorophenoxyacetic acid
● Dichlorophenoxyacetic acid, butyl ester

● Dikonirt (sodium salt of 2,4-D)

● Dimethylamine, (2,4-dichlorophenoxy) acetate

● Dimethylammonium 2,4-dichlorophenoxy acetate

● Dinoxol (butoxyethanol esters of 2,4-D and 2,4,5-T)

● Dinoxol 64 (butoxyethanol esters of 2,4-D and 2,4,5-T)

● Dinoxol Super-6 (butoxyethanol esters of 2,4-D and 2,4,5-T)

● DMA-4 (dimethylamine salt of 2,4-D)

● Dolge E.W.T. Amine Type 2,4-D Weed Killer 

(diethanolaminesalt of 2,4-D)

● Dormone (2,4-D, form unspecified)

● Dow 2,4-ccDichlorophenoxyacetic Acid, Sodium Salt 

(monohydratesodium salt of 2,4-D)

● Dow Brush Killer 50-50 (butyl esters of 2,4-D and 2,4,5-T)

● Dow Brush Killer X (isooctyl esters of 2,4-D and 2,4,5-T)

● Dow Butyl 265 (butyl ester of 2,4-D)

● Dow Butyl 400 (butyl ester of 2,4-D)

● Dow DMA-4 (dimethylamine salt of 2,4-D)

● Dow Formula 40 (alkanolamine salt of 2,4-D)

● Dow Weed Killer X (butoxypropyl ester of 2,4-D)

● Dragon Lawn Weed Killer (2,4-D + dicamba [3,6-dichloro-2-

methoxybenzoicacid])

● DRO 2,4-D Concentrate (diethylamine salt of 2,4-D)

● Dro Weedtrol Concentrate (disodium monomethyl creonate 

pentahydrate+ sodium monohydrate of 2,4-D)

● Droweed Spot Treatment Kills Law Weeds (propylene glycol 

andbutyl ether esters of 2,4-D)

● Du Pont Lawn Weed Killer (dimethylamine salt of 2,4-D)

● Du Pont Turf Food with Weed Killer (dimethylamine salt of2,4-

D)

● Du Pont Weed Killer No. 2 (dimethylamine salt of 2,4-D)

● Dupont Lawn Weeder (propylene glycol and butyl ether estersof 

2,4-D)

● Emulsamine Brush Killer (dodecyl- and tetradecylamine saltsof 

2,4-D and 2,4,5-T)

● Emulsamine E-3 (dodecyl- and tetradecylamine salts of 2,4-D)
● Emulsavert 100 (2,4-D + 2,4,5-T + N,N-dimethyloleylamine 

saltsof 2,4-D and 2,4,5-T)

● Emulsavert 248 (2,4-D + 2,4,5-T + N,N-dimethyloleylamine 

saltsof 2,4-D and 2,4,5-T)

● Emulsavert-D (2,4-D, form unspecified)

● Envert-171 (2,4-D, form unspecified)

● Envert-DT (butoxyethanol esters of 2,4-D and 2,4,5-T)

● Esso Herbicide 10 (butyl ester of 2,4-D)

● Estasol (isopropyl ester of 2,4-D)

● Esteron 44 (isopropyl ester of 2,4-D)

● Esteron 44 Improved Weed Killer (butyl ester of 2,4-D)

● Esteron 44 Weed Killer (isopropyl and butyl esters of 2,4-D)

● Esteron 6E Herbicide (isooctyl ester of 2,4-D)

● Esteron 76 (isopropyl and butyl esters of 2,4-D)

● Esteron 76 BE (butyl ester of 2,4-D)

● Esteron 76 BE Herbicide (butyl ester of 2,4-D)

● Esteron 76-E Weed Killer (isopropyl and butyl esters of 2,4-D)

● Esteron 99 Concentrate (butoxyethanol ester of 2,4-D)

● Esteron 99 Weed Killer (propylene glycol butyl ether esterof 2,4-

D)

● Esteron 99 Weed Killer Concentrate (propylene glycol butylether 

esters of 2,4-D)

● Esteron Brush Killer (old formulation) (isopropyl esters of2,4-D 

and 2,4,5-T)

● Esteron Brush Killer (propylene glycol butyl ether estersof 2,4-D 

and 2,4,5-T)

● Esteron Brush Killer O.B. (propylene glycol butyl ether estersof 

2,4-D and 2,4,5-T)

● Esteron Ten-Ten (propylene glycol butyl ether esters of 2,4-D)

● Estone (ethyl ester of 2,4-D)

● Feed No Weed (triethylamine salts of 2,4-D and 2,4,5-T)

● Felco Butyl Ester 600 2,4-D Weed Killer (butyl ester of 2,4-D)

● Felco HV2 Weed Killer (butyl ester of 2,4-D)

● Felco HV4 Weed Killer (butyl ester of 2,4-D)

● Felco Low Volatile Ester 600 (isooctyl ester of 2,4-D)

● Felco LV 400 Weed Killer (isooctyl ester of 2,4-D)
● Felco Super Brush Killer (butyl esters of 2,4-D and 2,4,5-T)

● Fenac Plus (dimethylamine salts of 2,4-D and 2,3,6-

trichlorophenylaceticacid)

● Fence Painter Weed Out (monuron [3-(p-chlorophenyl)-1,1-

dimethylurea]+ sodium salt of 2,4-D + sodium tetraborate)

● Fence Rider "45" (isooctyl esters of 2,4-D and 2,4,5-T)

● Fence Rider 22 (butyl esters of 2,4-D and 2,4,5-T)

● Fence Rider LV-22 (2-ethylhexyl esters of 2,4-D and 2,4,5-T)

● Fence Rider LV-3D/3T (2-ethylhexyl esters of 2,4-D and 2,4,5-

T)

● Fernesta (2,4-D, form unspecified)

● Fernimine (ethanol and ispropyl esters of 2,4-D)

● Fernoxene (sodium salt of 2,4-D)

● Fernoxone (2,4-D, form unspecified)

● Ferxone (2,4-D, form unspecified)

● Field-Clean (isooctyl ester of 2,4-D)

● Floratox 4 LB.LV 2,4-D Weed Killer (isooctyl ester of 2,4-D)

● Floratox 428 4-Pound 2,4-D Ester Weed Killer (butyl esterof 2,4-

D)

● Floro Tox 2,4-D Amine Weed Killer (dimethylamine salt of 2,4-

D)

● Foredex 75 (2,4-D, form unspecified)

● Foremost All Season Weed Killer (mixed aliphatic 

hydrocarbons+ isooctyl ester of 2,4-D + pentachlorophenol + 

other chlorophenols+ bromacil[5-bromo-3-sec-butyl-6-

methyluracil])

● Formula 40 (ethanol and isopropyl esters of 2,4-D)

● FS Amine 400 Weed Killer (dimethylamine salt of 2,4-D)

● FS Ester 400 Weed Killer (butyl ester of 2,4-D)

● FS LV 400 Weed Killer (isooctyl ester of 2,4-D)

● G.L.F. Weed Killer 66 Sequestered (2,4-D, form unspecified)

● GCC-165 Weed Killer (isooctyl ester of 2,4-D + bromacil [5-

bromo-3-sec-butyl-6-methyluracil]+ pentachlorophenol + other 

chlorophenols)

● GCC-425 (isooctyl esters of 2,4-D, 2,4,5-T and 2-(2,4,5-

trichlorophenoxy)propionicacid)
● GCC-429 (isooctyl esters of 2,4-D, 2,4,5-T and 2-(2,4,5-

trichlorophenoxy)propionicacid)

● General Chemical 2,4-D 3.34 Butyl Ester Weed Killer

● General Chemical 2,4-D 4-Butyl Ester Weed Killer

● General Chemical 2,4-D 6.00 Butyl Ester Weed Killer

● General Chemical 2,4-D Butyl Ester Weed Killer

● Good-Life Weed Woe (diethanolamine salts of 2-(2-methyl-4-

chlorophenoxy)propionicacid, 2,4-D and dicamba [3,6-dichloro-2-

methoxy benzoic acid])

● Gormel's Brush Killer (propylene glycol butyl ether estersof 2,4-

D and 2,4,5-T)

● Gormel's Weed and Clover Killer (isooctyl esters of 2,4-Dand 

2,4,5-T)

● Gormel's Weed Kil (alkanolamine salts [of the ethanol 

andisopropanol series] of 2,4-D)

● Green Cross Commercial Weed Killer "96" (2,4-D +butyl ester of 

2,4-D)

● Green Cross Ester Weed Killer (2,4-D)

● Green Cross Roadside 2,4-D Low Volatile Weed Killer 

(isooctylester of 2,4-D)

● Green Cross Vegetation Killer (monuron [3-(p-chlorophenyl)-1,1-

dimethylurea]+ 2,4-D + 2,4,5-T)

● Green Cross Weed-No-More "80" (2,4-D)

● Green Cross Weed-No-More (butyl ester of 2,4-D)

● Green Light 2,4-D, 2,4,5-T Weed Killer (isooctyl esters of2,4-D 

and 2,4,5-T)

● Green Light Broadleaf Weed Killer (alkanolamine salts [ofthe 

ethanol and isopropanol series] of 2,4-D)

● Green Light Weed Killer (alkanolamine salts [of the ethanoland 

isopropanol series] of 2,4-D + triethylamine salt of 2,4,5-T)

● Greenfield Broadleaf Weed and Crab Grass Killer 

(trifluralin[alpha,alpha,alpha-trifluoro-2,6-dinitro-N,N-dipropyl-ptoluidine]+ disodium methylarsonate + sodium salts of 2,4-D and 

2,4,5-T)

● Greenfield Crab Grass and Broadleaf Weed Killer 

(trifluralin[alpha,alpha,alpha-trifluoro-2,6-dinitro-N,N-dipropyl-p-
toluidine]+ disodium methylarsonate hexahydrate + isooctyl 

esters of 2,4-Dand 2,4,5-T)

● Greenfield Crabgrass and Dandelion Killer (disodium 

methanearsonate+ trifluralin [alpha,alpha,alpha-trifluoro-2,6-

dinitro-N,N-dipropyl-p-toluidine]+ sodium salts of 2,4-D and 

2,4,5-T)

● Greenfield Dandelion and Broadleaf Weed Killer (isooctyl 

estersof 2,4-D and silvex [2-(2,4,5-trichlorophenoxy)propionic 

acid])

● Greenfield Dandelion and Chickweed Killer (isooctyl estersof 2,4-

D and silvex [2-(2,4,5-trichlorophenoxy)propionic acid])

● Greenfield Two-Way green Power (isooctyl esters of 2,4-D 

andsilvex [2-(2,4,5-trichlorophenoxy) propionic acid] + 

nitrogen+ phosphoric acid + soluble potash)

● Greenfield Weeds As It Feeds For Lawns (isooctyl esters of2,4-D 

and 2,4,5-T)

● Greever's 2,4-D Low Volatile Ester Weed Killer (isooctyl esterof 

2,4-D)

● Greever's Low Volatile Brush Killer (isooctyl esters of 2,4-Dand 

2,4,5-T)

● Halts Plus With Dandelion Control (S-(0,0-diisopropyl 

phosphorodithioate)ester of N-(2-mercaptoethyl) 

benzenesulphonamide + 2,4-D + 2(2-methyl-4-

chlorophenoxy)propionicacid)

● Hedonal (isooctyl ester of 2,4-D)

● Hedonal (The Herbicide) (2,4-D, form unspecified)

● Hedonol (2,4-D, form unspecified)

● Henry Field's Lawn Weed Killer (isooctyl ester of 2,4-D)

● Herbate Ester 128 (2,4-D, form unspecified)

● Herbate Ester 80 (isooctyl ester of 2,4-D)

● Home Use Weed Killer (alkanolamine salts [of the ethanol 

andisopropanol series] of 2,4-D)

● Hormit (sodium salt of 2,4-D)

● Hormoslyr 64 (2,4-D + 2,4,5-T)

● Hub States Selective Weed and Brush Killer Amine Formula 

400(diethylethanolamine salts of 2,4-D and 2,4,5-T)
● Instemul DA 120 Concentrate (oleyl amine salt of 2,4-D)

● Instemul DA 40 (oleyl amine salt of 2,4-D)

● Instemul DTA 22 (oleyl amine salt of 2,4-D + oleyllinoleylamine 

salt of 2,4,5-T)

● Instemul DTA 66 Concentrate (oleyl amine salt of 2,4-D + 

oleyllinoleylamine salt of 2,4,5-T)

● Isooctyl 2,4-dichlorophenoxyacetate (isooctyl ester of 2,4-D)

● Isooctyl alcohol, (2,4-dichlorophenoxy) acetate (isooctylester of 

2,4-D)

● Jet-Weed Killer Power Pellets (2,4-D + silvex [2-(2,4,5-

trichlorophenoxy)propionicacid])

● Kansel (2,4-D + dicamba [2-methoxy-3,6-dichlorobenzoic acid])

● Kilbrush 8-16 Ester (butyl esters of 2,4-D and 2,4,5-T)

● Knoxweed (eptam [S-ethyl dipropylthiocarbamate] + 10 E 2,4-D)

● Kro-Foot-Kil (dimethylamine salts of 2,4-D + 

phenylmercuricacetate)

● Krotilin (chlorocrotyl ester of 2,4-D)

● Krotiline (chlorocrotyl ester of 2,4-D)

● Lawn Weed Killer (triethanolamine salt of 2,4-D)

● Lawn Weed-Rhap (2-ethylhexyl esters of 2,4-D and 2,4,5-T)

● Lawn-Keep (2,4-D, form unspecified)

● Lebanon Deluxe Weed and Feed with 2,4-D and Banvel D 

(dimethylaminesalts of 2,4-D, dicamba [3,6-dichloro-2-methoxybenzoic acid]and related acids)

● Lebanon Weedeth (dimethylamine salt of 2,4-D, 

dimethylaminesalt of dicamba [3,6-dichloro-2-methoxy-benzoic 

acid] and relatedacid)

● Limit (chloro-N,N-diallylacetamide + 2,4-D)

● Line Rider 22 (butyl esters of 2,4-D and 2,4,5-T)

● Line Rider Invert D/T (isooctyl esters of 2,4-D and 2,4,5-T)

● Line Rider Invert D/T Concentrate (isooctyl esters of 2,4-Dand 

2,4,5-T)

● Line Rider LV-21 (isooctyl esters of 2,4-D and 2,4,5-T)

● Line Rider LV-4D (isooctyl ester of 2,4-D)

● Line Rider LV-6D (isooctyl ester of 2,4-D)

● Liqweedate (2-methoxy-4,6-bis(isopropylamine)-s-triazine 
+isooctyl esters of 2,4-D and 2,4,5-T)

● Liqweedate-2 (2-methoxy-4,6-bis(isopropylamine)-s-triazine+ 

isooctyl ester of 2,4-D)

● Lironox (butyl ester of 2,4-D)

● Lithate 2,4-D (lithium salt of 2,4-D)

● Lo-Estasol (butoxyethanol ester of 2,4-D)

● Machete (alkanolamine salts [of the ethanol and 

isopropanolseries] of 2,4-D)

● Macondray (2,4-D, form unspecified)

● Manco Kill-Weed (dimethylamine salt of 2,4-D)

● Manco Super Kill-Weed (isooctyl esters of 2,4-D and 2,4,5-T)

● Mecopar (diethanolamine salts of MCPP [2-(2-methyl-4-

chlorophenoxy)propionicacid] and 2,4-D)

● MFA 40% Butyl Ester Weed Killer (butyl ester of 2,4-D)

● MFA LO-V Super Brush Killer (octyl esters of 2,4-D and 2,4,5-

T)

● MFA LO-V Super Brush Killer (octyl esters of 2,4-D and 2,4,5-

T)

● MFA No. 4 Weed Killer (butyl ester of 2,4-D)

● MFA No. 6 Weed Killer (butyl ester of 2,4-D)

● MFA Super Brush Kill (butyl esters of 2,4-D and 2,4,5-T)

● Miller's 4# Ester (butyl ester of 2,4-D)

● Miller's 6# Ester (butyl ester of 2,4-D)

● Miller's Lo Vol 4# 2,4-D (isooctyl ester of 2,4-D)

● Milorganite Plus 2,4-D (2,4-D, form unspecified)

● Miracle (2,4-D, form unspecified)

● Monosan (2,4-D, form unspecified)

● Monsanto 2,4-D 2,4,5-T Amine brush Killer (dimethylamine 

saltof 2,4-D + triethylamine salt of 2,4,5-T)

● Monsanto 2,4-D 2,4,5-T Amine Brush Killer (triethylamine 

saltsof 2,4-D and 2,4,5-T)

● Monsanto 2,4-D 2,4,5-T Butyl Ester Brush Killer

● Monsanto 2,4-D 2,4,5-T Low Volatile Ester Brush Killer 

(isooctylesters of 2,4-D and 2,4,5-T)

● Monsanto 2,4-D Amine (dimethylamine salt of 2,4-D)

● Monsanto 2,4-D Butyl Ester
● Monsanto 2,4-D Butyl Ester Concentrate

● Monsanto 2,4-D Granular (isooctyl ester of 2,4-D)

● Monsanto 2,4-D Isopropyl Ester

● Monsanto 2,4-D Low Volatile Ester (isooctyl ester of 2,4-D)

● Morselect (dimethylamine salt of 2,4-D)

● Moxone (2,4-D, form unspecified)

● Munichem Muni-Kill (mixed aliphatic hydrocarbons + 

isooctylester of 2,4-D + bromacil [5-bromo-3-sec-butyl-6-

methyluracil]+ pentachlorophenol + other chlorophenols)

● Naco LV-4D Weed Killer (isooctyl ester of 2,4-D)

● Nalkil Weed Killer 400 Liquid (isooctyl ester of 2,4-D + 

bromacil[5-bromo-3-sec-butyl-6-methyluracil] + 

pentachlorophenol + otherchlorophenols)

● Navy Brand WKB-15 (isooctyl esters of 2,4-D and 2,4,5-T)

● Navy Brand WKB-28 (butoxyethoxypropanol esters of 2,4-D 

and2,4,5-T)

● Niagara 2,4-D Weed Killer (Amine Form) (ethanol and 

propanolaminesalts of 2,4-D)

● Niagara Brush-Killer (Ester Form) (butoxyethanol esters of2,4-D 

and 2,4,5-T)

● Niagara Commercial Brush Killer (isooctyl esters of 2,4-Dand 

2,4,5-T)

● Niagara Estasol (isopropyl ester of 2,4-D)

● NSC 423 (2,4-D, form unspecified)

● Nutro Dandelion and Turf Weed Killer (2,4-D + dicamba [3,6-

dichloro-2-methoxybenzoicacid])

● Nutro Turf Weed Killer (ethylhexyl ester of 2,4-D and silvex[2-

(2,4,5-trichlorophenoxy) propionic acid])

● Nutro Weed Bomb (2,4-D + MCPP [2-methyl-4-chlorophenoxy)propionicacid])

● Olin Butyl Ester 22 Brush Killer (butyl esters of 2,4-D and2,4,5-

T)

● Olin Butyl Ester D267 Weed Killer (butyl ester of 2,4-D)

● Olin Butyl Ester D4 Weed Killer (butyl ester of 2,4-D)

● Olin Butyl Ester D6 Weed Killer (butyl ester of 2,4-D)

● Olin Isopropyl Ester D334 Weed Killer (isopropyl ester of2,4-D)
● Olin LV Ester 22 Brush Killer (2-ethylhexyl esters of 2,4-Dand 

2,4,5-T)

● Olin LV Ester D4 Weed Killer (2-ethylhexyl ester of 2,4-D)

● Ortho 2,4-D LV Ester 4 (isooctyl ester of 2,4-D)

● Ortho Brush Killer (isooctyl esters of 2,4-D and 2,4,5-T)

● Pacific Cooperatives P 2,4-D Amine Weed Killer 

(dimethylaminesalt of 2,4-D)

● Parsons 2,4-D Weed Killer (dimethylamine salt of 2,4-D)

● Parsons 2,4-D Weed Killer Butyl Ester

● Parsons 2,4-D Weed Killer Isopropyl Ester

● Parsons 2,4-D Weed Killer No. 40 (dimethylamine salt of 2,4-D)

● Parsons Corn-Tal Weed Killer (butyl, isopropyl and 

isooctylesters of 2,4-D)

● Parsons Poison Ivy and Brush Killer No. 2 (isooctyl estersof 2,4-

D and 2,4,5-T)

● Patterson's Hi-Test Butyl Ester 2,4-D Weed Killer

● Patterson's Lawn Weed Killer (isooctyl esters of 2,4-D and2,4,5-

T)

● Patterson's Super Brush Killer (butyl esters of 2,4-D and2,4,5-T)

● Patterson's Super Brush Killer Low Volatile (isooctyl estersof 2,4-

D and 2,4,5-T)

● Pax Action Weed'N Feed 18-4-4 (alkanolamine salt of 2,4-D+ 

dimethylamine salt of dicamba [3,6-dichloro-2-

methoxybenzoicacid] + nitrogen + phosphoric acid + soluble 

potash)

● Pax Total For Lawns 10-6-4 (N-Oleyl 1,3-propylenediamine 

saltof 2,4-D + dimethylamine salt of 2-(2-methyl-4-

chlorophenoxy)propionicacid + dimethyl ester of 

tetrachloroterephthalic acid + disodiummethanearsonate 

hexahydrate + heptachlor + related c

● Pennamine (2,4-D, form unspecified)

● Pennamine D (heptylamine salt of 2,4-D)

● Phenox (2,4-D, form unspecified)

● Pielik (2,4-D, form unspecified)

● Pielik E (sodium salt of 2,4-D)

● Pill Kill Kartridges for Dandelions and Broadleaf Weeds (2,4-D+ 
silvex [2-(2,4,5-trichlorophenoxy)propionic acid])

● PL Devastate Non-Selective Weed Killer (isooctyl ester of2,4-D 

+ bromacil [5-bromo-3-sec-butyl-6-methyl-uracil] + 

pentachlorophenol+ other chlorophenols)

● PL Liqui-date (isooctyl esters of 2,4-D, 2,4,5-T and silvex[2-

(2,4,5-trichlorophenoxy) propionic acid])

● Planotox (butoxyethyl ester of 2,4-D)

● Plantgard (2,4-D, form unpecified)

● Plus 2 for Grass (2,4-D + 2-(2-methyl-4-chlorophenoxy) 

propionicacid)

● Pratt Lawn Weed Killer (2,4-D + 2,4,5-T)

● Pratt's Crabgrass and Broadleaf Weed Killer (octyl 

ammoniummethyl arsonate + 2,4-D) )

● Proturf Broad Spectrum Weedicide (2,4-D + dicamba [3,6-

dichloro-2-methoxybenzoicacid])

● Proturf Broad Spectrum Weedicide II (2,4-D + 2-(2-methyl-4-

chlorophenoxy)propionicacid)

● Proturf Fertilizer Plus Dicot Weed Control (2,4-D + dicamba[3,6-

dichloro-2-methoxybenzoic acid])

● Proturf Fertilizer Plus Dicot Weed Control II (2,4-D + 2-(2-

methyl-4-chlorophenoxy)propionicacid)

● R-H Weed Rhap 20 (2,4-D)

● Real-Kill Spot Weed Killer (amine salts of 2,4-D, dicamba[3,6-

dichloro-2-methoxybenzoic acid] and MCPP [2-(2-methyl-4-

chlorophenoxy)propionic acid])

● Real-Kill Spot Weed Killer (amine salts of 2,4-D, dicamba[3,6-

dichloro-2-methoxybenzoic acid] and 2,4,5-T)

● Reasor-Hill Brush Rhap (2,4-D + 2,4,5-T)

● Red Devil Dry Weed Killer (2,4-D)

● Rhodia 2,4-D Butyl Ester 6L

● Rhodia 2,4-D Low Volatile Ester 4L (isooctyl ester of 2,4-D)

● Rhodia Low Volatile Brush Killer No. 2 (2,4-D + 2,4,5-T)

● Rid-O-Weed (isopropyl and diisopropanol amine salts of 2,4-D)

● Robot Gardener Weed and Crabgrass Killer (potassium cyanate+ 

2,4-D)

● Roundup Granular (2-chloro-N-isopropylacetanilide + 
isooctylester of 2,4-D)

● Roundup Wettable Powder (2-chloro-N-isopropylacetanilide +2,4-

D)

● S.I.R.-Ester (isooctyl esters of 2,4-D and 2,4,5-T)

● Salvik (2,4-D, form unspecified)

● Salvo (2,4-D, form unspecified)

● Science Lawn Weed-Killer (isooctyl esters of 2,4-D + 2,4,5-T)

● Scott's 4-XD Weed Control (2,4-D)

● Security Lawn Weed Killer (N-oleyl 1,3-propylenediamine saltof 

2,4-D)

● Shell 40 (butyl ester of 2,4-D)

● Sodium 2,4-D

● Sodium 2,4-dichlorophenoxyacetate

● Spontox (2,4-D, or 2,4,5-T, forms unspecified)

● Spritz-Hormit (sodium salt of 2,4-D)

● Stull's Low Volatile Brush Killer No. 4 (isooctyl esters of2,4-D 

and 2,4,5-T)

● Stull's Low Volatile Weed Killer (isooctyl ester of 2,4-D)

● Stull's Stu-Ester Low Volatile (isooctyl ester of 2,4,5-T)

● Super Crab-E-Rad + 2 (dodecylammonium methanearsonate + 

octylammoniummethanearsonate + octylammonium salt of 2,4-

D)

● Super D Weedone (diethylamine salts of 2,4-D and dicamba [3,6-

dichloro-2-methoxybenzoicacid])

● Super Dal-E-Rad + 2 (dodecylammonium methanearsonate + 

octylammoniummethanearsonate + octylammonium salt of 2,4-

D)

● Sure Death 2,4-D Amine Weed Killer (dimethylamine salt of2,4-

D)

● Sure Death 40% Butyl Ester Type Weedkiller (butyl ester of2,4-

D)

● Sure Death Lawn Weed Killer (2-ethyl 4-methylpentanol and2-

ethylhexanol esters of 2,4-D and 2,4,5-

trichlorophenoxypropionicacid)

● Sure Death No. 4 Butyl Ester Weed Killer (butyl ester of 2,4-D)

● Sure Death No. 6 Butyl Ester Weed Killer (butyl ester of 2,4-D)
● Sure Death No. 6-D Low Vol 2,4-D (2-ethyl 4 

methylpentanoland 2-ethylhexanol esters of 2,4-D)

● Sure-Death Low-Vol 2,4-D #4 (2-ethylpentanol and 2-

ethylhexanolesters of 2,4-D)

● Swift's Gold Bear 2-2 Brush Kill (isooctyl esters of 2,4-Dand 

2,4,5-T)

● Swift's Gold Bear 40 (triethylamine salt of 2,4-D)

● Swift's Gold Bear 44 Ester (isopropyl ester of 2,4-D)

● Swift's Gold Bear Woody Plant Control (isooctyl esters of2,4-D 

and 2,4,5-T)

● T-H Ded-Weed ME-6 (butyl ester of 2, 4-D)

● T-H Ded-Weed ME-9 (butyl ester of 2,4-D)

● Techne 2,4-D Amine Weed Killer (dimethylamine salt of 2,4-D)

● Techne 40% Butyl Ester type Weed Killer (butyl ester of 2,4-D)

● Techne Butyl Ester Weed Killer No.4 (butyl ester of 2,4-D)

● Techne Butyl Ester Weed Killer No.6 (butyl ester of 2,4-D)

● Techne Low-Vol 2,4-D No.4 (2-ethylpentanol and 2-

ethylhexanolesters of 2,4-D)

● Termicide 5-15 (triethanolamine salt of 2,4-D + 

triethanolaminemethanearsonate)

● The Andersons Broadleaf Weed Killer (dimethylamine salt of2,4-

D + isooctyl ester of silvex [2-(2,4,5-

trichlorophenoxy)propionicacid])

● The Andersons Weed and Feed (dimethylamine salt of 2,4-D 

+isooctyl ester of silvex [2-(2,4,5-

trichlorophenoxy)propionicacid])

● The Crop Rider (butyl ester of 2,4-D)

● The Line Rider (2-ethylhexyl esters of 2,4-D and 2,4,5-T)

● Thorokil (2,4-D + bromacil [5-bromo-3-sec-butyl-6-

methyluracil]+ pentachlorophenol)

● Tobacco States Brand Ester 210 (isooctyl ester of 2,4-D)

● Tobacco States Brand Ester 410 Concentrate (2-ethylhexyl 

esterof 2,4-D)

● Tobacco States Brand Ester Brush Killer 2-2 (butyl estersof 2,4-

D and 2,4,5-T)

● Tobacco States Brand Low-Vol Brush Killer 2-20 (isooctyl 
estersof 2,4-D and 2,4,5-T)

● Tordon 101 Mixture (triisopropanol amine salts of 2,4-D and4-

amino-3,5,6-trichloropicolinic acid)

● Transamine OA-1.5D-1.5T (N,N-dimethyloleyllinoleylamine 

saltsof 2,4-D and 2,4,5-T)

● Transamine OA-3D (N,N-dimethyloleyllinoleylamine salt of 2,4-

D)

● Tributon (2,4-D + 2,4,5-T, forms unspecified)

● Triple Tonic (dimethylamine salts and propylene glycol 

butylether esters of 2,4-D + nitrogen + phosphoric acid + soluble 

potash)

● Turf Builder Plus 2 (2,4-D + 2-(2-methyl-4-chlorophenoxy)-

propionicacid

● U 46 (2,4-D + 2,4,5-T, forms unspecified)

● U 46 DP (2,4-D, form unspecified)

● U 46 Spezial (2,4-D + 2,4,5-T, forms unspecified)

● U-5043 (2,4-D, form unspecified)

● Unico 2,4-D Ester Weed Killer (butyl ester of 2,4-D)

● Unico 2,4-D Lo-V Ester Weed Killer (2-ethylhexyl ester of2,4-D)

● Unico Brush Killer (butyl esters of 2,4-D and 2,4,5-T)

● Unico Brush Killer A (butyl ester of 2,4-D + isooctyl esterof 

2,4,5-T)

● Unico Lo-V Brush Killer (2-ethylhexyl esters of 2,4-D and2,4,5-

T)

● Unico Turf Treeter Lawn Weed Killer (dimethylamine salts of2,4-

D and dicamba [3,6-dichloro-2-methoxy-benzoic acid])

● Utility Brush Killer No. 2 (isooctyl esters of 2,4-D and 2,4,5-T)

● Vaughan's Liquid K.O. (octyl ammonium salt of 2,4-D + 

octyland dodecyl ammonium methylarsonate)

● Veg-I-Kill (isooctyl ester of 2,4-D + bromacyl [5-bromo-3-secbutyl-6-methyluracyl]+ pentachlorophenol + others 

chlorophenols)

● Veon BK (dimethylamine salts of 2,4-D and 2,4,5-T)

● Vergemaster (2,4-D, form unspecified)

● Verton 2-D (2,4,-D, form unspecified)

● Verton 2D (propylene glycol butyl ether ester of 2,4-D)
● Verton 4D (propylene glycol butyl ether ester of 2,4-D)

● Verton CE (propylene glycol butyl ether esters of 2,4-D and2,4,5-

T)

● Verton CE Herbicide (propylene glycol butyl ether esters of2,4-D 

and 2,4,5-T)

● Verton D (2,4-D, form unspecified)

● Vi-Par (diethanolamine salts of 2-(2-methyl-4-chlorophenoxy)-

propionicacid and 2,4-D)

● Vidon 638 (2,4-D, unspecified)

● Visko-Rhap 2,4-D Low Volatile Ester 4L (isooctyl ester of2,4-D)

● Visko-Rhap A-1D (oleylamine salt of 2,4-D)

● Visko-Rhap A-3D (N,N-dimethyl oleyllinoleylamine salt of 24-

D)

● Visko-Rhap Low Drift Herbicides (2,4-D, form unspecified)

● Visko-Rhap Low Volatile 1.5D-1.5T (2-ethylhexyl esters of2,4-D 

and 2,4,5-T)

● Visko-Rhap Low Volatile 1D-1T (2-ethylhexyl esters of 2,4-

Dand 2,4,5-T)

● Visko-Rhap Low Volatile 4L (2,4-D, form unspecified)

● Visko-Rhap Low Volatile Ester 1D-1T (2-ethylhexyl esters of2,4-

D and 2,4,5-T)

● Visko-Rhap Low Volatile Ester 2D (2-ethylhexyl ester of 2,4-D)

● Visko-Rhap Oil-Soluble Amine A-3D (N,Ndimethyloleyllinoleylaminesalt of 2,4-D)

● Wasco Brush Killer (2-ethylhexyl esters of 2,4-D and 2,4,5-T)

● Weed and Brush Off Amine Formula 400 

(diethylethanolaminesalts of 2,4-D and 2,4,5-T)

● Weed Broom (anhydrous disodium methanearsonate + lithium 

saltof bromacil [5-bromo-3-sec-butyl-6-methyluracil] + 

anhydrous sodiumsalt of 2,4-D)

● Weed Killer 646 (butyl ester of 2,4-D)

● Weed-Ag-Bar (2,4-D, form unspecified)

● Weed-B-Gon (2,4-D, form unspecified)

● Weed-Ban (amines [form unspecified] of 2,4-D and dicamba [3,6-

dichloro-2-methoxybenzoicacid])

● Weed-Bane Amine (2,4-D, form unspecified)
● Weed-Bane Ester (2,4-D, form unspecified)

● Weed-Nix Lawn Food with 2,4-D and Banvel D 

(dimethylaminesalts of 2,4-D, dicamba [3,6-dichloro-2-methoxybenzoic acid]and related acids)

● Weed-No-More (2,4-D ester, form unspecified)

● Weed-Out Lawn Weed Control with 2,4-D and Silvex 

(dimethylaminesalt of 2,4-D + isooctyl ester of silvex [2-(2,4,5-

trichlorophenoxy)propionicacid])

● Weed-Rhap (2,4-D, form unspecified)

● Weed-Rhap A-4 (2,4-D)

● Weed-Rhap A-4D (dimethylamine salt of 2,4-D)

● Weed-Rhap B-2.67D (butyl ester of 2,4-D)

● Weed-Rhap B-266 (2,4-D)

● Weed-Rhap B-4 (2,4-D)

● Weed-Rhap B-4D (butyl ester of 2,4-D)

● Weed-Rhap B-6D (butyl ester of 2,4-D)

● Weed-Rhap I-3.34 (2,4-D)

● Weed-Rhap I-3.34D (isopropyl ester of 2,4-D)

● Weed-Rhap Low Volatile 4D (2-ethylhexyl ester of 2,4-D)

● Weed-Rhap Low Volatile 5D (2-ethylhexyl ester of 2,4-D)

● Weed-Rhap Low Volatile F4D For Mixing with Fertilizer (2-

ethylhexylester of 2,4-D)

● Weed-Rhap Low Volatile-Granular D (2-ethylhexyl ester of 2,4-

D)

● Weed-Rhap LV-4-0 (2,4-D)

● Weed-Rhap LV-4D (butoxyethanol ester of 2,4-D)

● Weedar (2,4-D or 2,4,5-T, forms unspecified)

● Weedar 64 (dimethylamine salt of 2,4-D)

● Weedar Amine Brush Killer (dimethylamine salt of 2,4-D + 

triethylaminesalt of 2,4,5-T)

● Weedez Wonder Bar (triethylamine salt of 2,4-D)

● Weedone (2,4-D or 2,4,5-T, forms unspecified)

● Weedone 48 (2,4-D, form unspecified)

● Weedone 638 (2,4-D)

● Weedone 638 (butoxyethanol ester of 2,4-D)

● Weedone Aero-Concentrate 96 (butyl ester of 2,4-D)
● Weedone Aero-Concentrate E (butyl ester of 2,4-D)

● Weedone Brush Killer 32 (butoxyethanol esters of 2,4-D 

and2,4,5-T)

● Weedone Brush Killer 64 (butoxyethanol esters of 2,4-D 

and2,4,5-T)

● Weedone Brush Killer 977 (butoxyethanol esters of 2,4-D 

and2,4,5-T)

● Weedone Brush Killer 977 Concentrate (butoxyethanol estersof 

2,4-D and 2,4,5-T)

● Weedone Concentrate 48 (ethyl ester of 2,4-D)

● Weedone Industrial Brush Killer (butoxyethanol esters of 2,4-

Dand 2,4,5-T)

● Weedone LV-6 (butoxyethanol ester of 2,4-D)

● Weedone LV4 (butoxyethanol ester of 2,4-D)

● Weedone-170 (2,4-D, form unspecified)

● Woodbury Pre-Merge Granular 20 2,4-D (2-ethylhexanol esterof 

2,4-D)

● Woodbury Woodkill Ester Conc. (butyl esters of 2,4-D and 2,4,5-

T)

● Woodkill Ester Concentrate (butyl esters of 2,4-D and 2,4,5-T)

● Zehrung 2,4-D Selective Amine Weed Killer (dimethylamine 

saltof 2,4-D)

● Zehrung Weed Blitz (triethanolamine salts of 2,4-D and 2,4,5-T)

● Zep R-61 Weed Killer (dimethylamine salts of 2,4-D and 2,4,5-

T)

Synonyms for 2,4,5-T and esters

● Abco Improved W.K-245 (isooctyl ester of 2,4,5-T)

● Abco W.K-DT 133 (isooctyl esters of 2,4-D and 2,4,5-T)

● Abco WKS-65 Brush Killer (isooctyl esters of 2,4-D, 2,4,5-Tand 

silvex [2-(2,4,5-trichloro-phenoxy)propionic acid])

● Acetic acid, (2,4,5-trichlorophenoxy)-

● Acide trichloro-2,4,5 phenoxyacetique

● Acido(2,4,5-tricloro-fenossi)-acetico

● Acme Poison Ivy Killer (dimethylamine salt of 2,4-D + 

triethylaminesalt of 2,4,5-T)
● Acme Weed-No-More Spotter (dimethylamine salt of 2,4-D + 

triethylaminesalt of 2,4,5-T)

● Agent Orange (n-butyl esters of 2,4-D and 2,4,5-T)

● Agent Purple (n-butyl esters of 2,4-D and 2,4,5-T + isobutylester 

of 2,4,5-T)

● Allied Chemical Low Volatile 1-1/3-2/3 Brush Killer (2,4-D+ 

2,4,5-T + isooctyl esters of 2,4-D and 2,4,5-T)

● Amchem 2,4,5-T Low Volatile Ester Brush Killer (isooctyl 

esterof 2,4,5-T)

● Amchem 2,4-D 2,4,5-T Low Volatile Ester Brush Killer 

(isooctylesters of 2,4-D and 2,4,5-T)

● Amchem 6DT. Low Volatile Ester Brush Killer (isooctyl estersof 

2,4-D and 2,4,5-T)

● Amchem 6T Low Volatile Ester Brush Killer (isooctyl esterof 

2,4,5-T)

● Amchem Amine 2,4,5-T for Rice (triethylamine salt of 2,4,5-T)

● Amchem Emulsamine Brush Killer (alkyl C_1_2 + C_1_4 

aminesalts of 2,4-D and 2,4,5-T)

● Amchem Isooctyl-DT (isooctyl esters of 2,4-D and 2,4,5-T)

● Amchem Isooctyl-DT6 (isooctyl esters of 2,4-D and 2,4,5-T)

● Amchem Isooctyl-T (isooctyl ester of 2,4,5-T)

● Amchem Isooctyl-T6 (isooctyl ester of 2,4,5-T)

● Amine 4T (2,4,5-T, form unspecified)

● Amine 4T2 (triethylamine salt of 2,4,5-T)

● Amoco 2,4,5-T Amine (triethylamine salt of 2,4,5-T)

● Amoco 2,4,5-T LV Ester (isooctyl ester of 2,4,5-T)

● Amoco Brush Killer (isooctyl esters of 2,4-D and 2,4,5-T)

● Antrol 2,4-D and 2,4,5-T Weed and Brush Killer 

(alkalonaminesalts [of the ethanol and isopropanol series] of 2,4-

D + triethylaminesalt of 2,4,5-T)

● Associated Sales Low Volatile 2,4,5-T Brush Killer (isooctylester 

of 2,4,5-T)

● Balcom's Brush Killer Number 4 (isooctyl ester of 2,4,5-T)

● Balcom's G-K-20 (2-ethylhexyl esters of 2,4-D and 2,4,5-T)

● Balcom's T-D Special Weed Killer (isooctyl esters of 2,4-Dand 

2,4,5-T)
● Breck's Lawn Weed Killer (butoxyethoxypropanol esters of 2,4-

Dand 2,4,5-T)

● Brulin's Brush Killer (butyl esters of 2,4-D and 2,4,5-T)

● Brush Killer 50-50 (butyl esters of 2,4-D and 2,4,5-T)

● Brush Killer T (butyl esters of 2,4,5-T)

● Brush Killer TX (isooctyl esters of 2,4,5-T)

● Brush Killer X (isooctyl esters of 2,4-D and 2,4,5-T)

● Brush-Blitz (isooctyl ester of 2,4,5-T)

● Brush-O-Cide (isooctyl esters of 2,4-D + 2,4,5-T)

● Brush-Off 445 Low Volatile Brush Killer (2,4,5-T, form 

unspecified)

● Brush-Off No. 438 Conc. 2-2 LV Brush Killer (isooctyl estersof 

2,4-D and 2,4,5-T)

● Brush-Rhap A-2D-2T (dimethylamine salt of 2,4-D + 

triethylaminesalt of 2,4,5-T)

● Brush-Rhap A-4T (triethylamine salt of 2,4,5-T)

● Brush-Rhap Amine A-2D-2T (dimethylamine salt of 2,4-D + 

triethylaminesalt of 2,4,5-T)

● Brush-Rhap B-1.33D - 0.67T (butyl esters of 2,4-D and 2,4,5-T)

● Brush-Rhap B-2-2 (2,4-D + 2,4,5-T)

● Brush-Rhap B-2D-2T (butyl esters of 2,4-D and 2,4,5-T)

● Brush-Rhap B-4 (2,4,5-T)

● Brush-Rhap B-4T (butyl ester of 2,4,5-T)

● Brush-Rhap Injection Fluid Low Volatile 2D-2T (2-

ethylhexylesters of 2,4-D and 2,4,5-T)

● Brush-Rhap Injection Fluid Low Volatile 3D-3T (2-

ethylhexylesters of 2,4-D and 2,4,5-T)

● Brush-Rhap Injection Fluid Low Volatile 4T (2-ethylhexyl 

esterof 2,4,5-T)

● Brush-Rhap Injection Fluid-B (2,4,5-T)

● Brush-Rhap Low Volatile 2D-2T (2-ethylhexyl esters of 2,4-

Dand 2,4,5-T)

● Brush-Rhap Low volatile 3D-2T (2-ethylhexyl esters of 2,4-Dand 

2,4,5-T)

● Brush-Rhap Low Volatile 3D-3T (2-ethylhexyl esters of 2,4-

Dand 2,4,5-T)
● Brush-Rhap Low Volatile 4T (2-ethylhexyl ester of 2,4,5-T)

● Brush-Rhap Low Volatile 5T (2-ethylhexyl ester of 2,4,5-T)

● Brush-Rhap Low Volatile 6T (2-ethylhexyl ester of 2,4,5-T)

● Brush-Rhap LV 2D-2T (2-ethylhexyl esters of 2,4-D and 2,4,5-T)

● Brush-Rhap LV Injection Fluid-0 (2,4,5-T)

● Brush-Rhap LV-2-2-0 (2,4-D + 2,4,5-T)

● Brush-Rhap LV-4-0 (2,4,5-T)

● Brush-Rhap LV-40 (isooctyl esters of 2,4,5-T)

● Brush-Rhap LV-4T (2-ethylhexyl ester of 2,4,5-T)

● Brush-Rhap LV-6T (2-ethylhexyl ester of 2,4,5-T)

● Brush-Rhap LV-OXY-4T (2,4,5-T, form unspecified)

● Brush-Rhap OXY-4T (butoxyethanol ester of 2,4,5-T)

● Butyl 2,4,5-trichlorophenoxyacetate

● Certified C-300 Selective Weed Killer (isooctyl esters of2,4-D 

and 2,4,5-T)

● Chem-Pels Plus (isooctyl esters of 2,4-D and 2,4,5-T)

● Chem-Weed 2,4,5-T (butoxyethoxypropanol ester of 2,4,5-T 

+2,4,5-T)

● Chemform Butoxy Brush Killer (butoxyethoxypropanol estersof 

2,4-D and 2,4,5-T)

● Chempar Low Volatile Brush Killer No. 2 (2,4,5-T + 2,4-D)

● Chipco Turf Herbicide "D" and "T" (dimethylaminesalt of 2,4-D 

+ triethylamine salt of 2,4,5-T)

● Chipco Turf Herbicide "T" (triethylamine salt of2,4,5-T)

● Chipman 2,4,5-T 76 (L.V.) (2,4,5-T, form unspecified)

● Chipman 2,4,5-T Amine 4L (triethylamine salt of 2,4,5-T)

● Chipman 2,4,5-T Low Volatile Ester 4L (isooctyl ester of 2,4,5-

T)

● Chipman 2,4,5-T Low Volatile Ester 6L (isooctyl ester of 2,4,5-

T)

● Chipman Amine Brush Killer (triethylamine salts of 2,4-D 

and2,4,5-T)

● Chipman Brush Killer 128 (2,4-D + 2,4,5-T, forms unspecified)

● Chipman Brush Killer 128 L.V. (2,4-D + 2,4,5-T, forms 

unspecified)

● Chipman Brush Killer 128 Regular (2,4-D + 2,4,5-T, forms 
unspecified)

● Chipman Brush Killer 76 (isooctyl esters of 2,4-D and 2,4,5-T)

● Chipman Low Volatile Brush Killer No. 2 (isooctyl esters of2,4-

D and 2,4,5-T)

● Chipman Low Volatile Brush Killer No. 3 (isooctyl esters of2,4-

D and 2,4,5-T)

● Chipman LVE-4L (isooctyl esters of 2,4,5-T)

● Chipman LVE-6L (isooctyl esters of 2,4,5-T)

● Clover Killer (butoxyethanol ester of 2,4,5-T)

● Commercial Brush Killer (isooctyl esters of 2,4-D and 2,4,5-T)

● Crop Rider 248 (2-ethylhexyl ester of 2,4-D)

● Crop Rider Amine 4T (triethylamine salt of 2,4,5-T)

● Crop Rider Amine 4T-2 (triethylamine salt of 2,4,5-T)

● Cross Country Poison Ivy Killer (butoxyethoxypropanol estersof 

2,4-D and 2,4,5-T)

● Dacamine (N-oleyl 1,3-propylenediamine salts of 2,4-D and2,4,5-

T)

● Dacamine 1D/1T (N-oleyl 1,3-propylenediamine salts of 2,4-

Dand 2,4,5-T)

● Dacamine 2D/2T (N-oleyl 1,3-propylenediamine salts of 2,4-

Dand 2,4,5-T)

● Dacamine 4T (N-oleyl 1,3-propylenediamine salt of 2,4,5-T)

● Dacamine T (N-oleyl 1,3-propylenediamine salt of 2,4,5-T)

● De Witt S-77 Weed Killer (dimethylamine salts of 2,4-D 

and2,4,5-T)

● De-Pester Ded-Weed 50-50 Brush-Kil (2,4,5-T)

● De-Pester Ded-Weed for Lawns (2,4-D + 2,4,5-T + Kerosene)

● De-Pester Ded-Weed LV-6 (2,4,5-T)

● De-Pester Ded-Weed LV-9 (2,4,5-T)

● De-Pester Ded-Weed T6 Brush Kil (amyl ester of 2,4,5-T)

● Ded-weed Brush Killer (2,4,5-T, form unspecified)

● Ded-weed for Lawns, New Improved (isooctyl esters of 2,4-Dand 

2,4,5-T)

● Ded-weed LV-6 Brush Kil (2,4,5-T, form unspecified)

● Destruxol Weed Killer "D" (isooctyl esters of 2,4-Dand 2,4,5-T)

● Diamond Alkali Chemicals 2-2 2-Ethyl Hexyl Brush Killer (2-
ethylhexylesters of 2,4-D and 2,4,5-T)

● Diamond Alkali Chemicals Technical 2-Ethyl Hexyl-T (2-

ethylhexylester of 2,4,5-T)

● Diamond Alkali Chemicals The Line Rider (2-ethylhexyl estersof 

2,4-D and 2,4,5-T)

● Diamond Shamrock Amine 2D/2T (dimethylamine salts of 2,4-

Dand 2,4,5-T)

● Diamond Shamrock Amine 4T (triethylamine salt of 2,4,5-T)

● Diamond Shamrock Dormant Cane Concentrate LV-6T-OS 

(isooctylester of 2,4,5-T)

● Diamond Shamrock Dormant Cane LV 3D/3T-OS (isooctyl 

estersof 2,4-D and 2,4,5-T)

● Diamond Shamrock LO-VOL 2D/2T (isooctyl esters of 2,4-D 

and2,4,5-T)

● Diamond Shamrock LO-VOL 4T (isooctyl ester of 2,4,5-T)

● Diamond Shamrock LO-VOL 6T (isooctyl ester of 2,4,5-T)

● Dinoxol (butoxyethanol esters of 2,4-D and 2,4,5-T)

● Dinoxol 64 (butoxyethanol esters of 2,4-D and 2,4,5-T)

● Dinoxol Super-6 (butoxyethanol esters of 2,4-D and 2,4,5-T)

● Dormant Cane Concentrate (2-ethylhexyl ester of 2,4,5-T)

● Dow 2,4,5-T Amine Weed Killer (triethylamine salt of 2,4,5-T)

● Dow Brush Killer 50-50 (butyl esters of 2,4-D and 2,4,5-T)

● Dow Brush Killer TX (butoxypropyl esters of 2,4,5-T)

● Dow Brush Killer X (isooctyl esters of 2,4-D and 2,4,5-T)

● Emulsamine 2,4,5-T (dodecyl- and tetradecylamine salts of2,4,5-

T)

● Emulsamine Brush Killer (dodecyl- and tetradecylamine saltsof 

2,4-D and 2,4,5-T)

● Emulsavert 100 (2,4-D + 2,4,5-T + N,N-dimethyloleylamine 

saltsof 2,4-D and 2,4,5-T)

● Emulsavert 248 (2,4-D + 2,4,5-T + N,N-dimethyloleylamine 

saltsof 2,4-D and 2,4,5-T)

● Envert-DT (butoxyethanol esters of 2,4-D and 2,4,5-T)

● Envert-T (butoxyethanol ester of 2,4,5-T)

● Estercide T-2 (2,4,5-T, form unspecified)

● Estercide T-245 (2,4,5-T, form unspecified)
● Esteron 245 (old formulation) (isopropyl and mixed amyl estersof 

2,4,5-T)

● Esteron 245 (propylene and polypropylene butyl ether estersof 

2,4,5-T)

● Esteron 245 Concentrate (propylene glycol butyl ether estersof 

2,4,5-T)

● Esteron 245 Herbicide (propylene and polypropylene glycolbutyl 

ether esters of 2,4,5-T)

● Esteron 245 O.S. (propylene glycol butyl ether esters of 2,4,5-T)

● Esteron Brush Killer (old formulation) (isopropyl esters of2,4-D 

and 2,4,5-T)

● Esteron Brush Killer (propylene glycol butyl ether estersof 2,4-D 

and 2,4,5-T)

● Esteron Brush Killer O.B. (propylene glycol butyl ether estersof 

2,4-D and 2,4,5-T)

● Feed No Weed (triethylamine salts of 2,4-D and 2,4,5-T)

● Felco 2,4,5-T Brush Killer (butyl ester of 2,4,5-T)

● Felco Super Brush Killer (butyl esters of 2,4-D and 2,4,5-T)

● Fence Rider "45" (isooctyl esters of 2,4-D and 2,4,5-T)

● Fence Rider 22 (butyl esters of 2,4-D and 2,4,5-T)

● Fence Rider 3.34-T Brush Killer (isopropyl ester of 2,4,5-T)

● Fence Rider 4T Brush Killer (butyl ester of 2,4,5-T)

● Fence Rider 6T Brush Killer (butyl ester of 2,4,5-T)

● Fence Rider LV-22 (2-ethylhexyl esters of 2,4-D and 2,4,5-T)

● Fence Rider LV-3D/3T (2-ethylhexyl esters of 2,4-D and 2,4,5-

T)

● Fence Rider LV-4T Brush Killer (2-ethylhexyl ester of 2,4,5-T)

● Fence Rider LV-6T Brush Killer (2-ethylhexyl ester of 2,4,5-T)

● Forron (2,4,5-T, form unspecified)

● Fortex (2,4,5-T, form unspecified)

● Fruitone A (2,4,5-T)

● GCC-425 (isooctyl esters of 2,4-D, 2,4,5-T and 2-(2,4,5-

trichlorophenoxy)propionicacid)

● GCC-429 (isooctyl esters of 2,4-D, 2,4,5-T and 2-(2,4,5-

trichlorophenoxy)propionicacid)

● General Chemical 2,4,5-T Amine (triethylamine salt of 2,4,5-T)
● Gormel's Brush Killer (propylene glycol butyl ether estersof 2,4-

D and 2,4,5-T)

● Gormel's Weed and Clover Killer (isooctyl esters of 2,4-Dand 

2,4,5-T)

● Green Cross Celatox 50/30 (2,4,5-T + MCP [(4-chloro-2-methylphenoxy)aceticacid])

● Green Cross Vegetation Killer (monuron [3-(p-chlorophenyl)-1,1-

dimethylurea]+ 2,4-D + 2,4,5-T)

● Green Light 2,4-D, 2,4,5-T Weed Killer (isooctyl esters of2,4-D 

and 2,4,5-T)

● Green Light Weed Killer (alkanolamine salts [of the ethanoland 

isopropanol series] of 2,4-D + triethylamine salt of 2,4,5-T)

● Greenfield Broadleaf Weed and Crab Grass Killer 

(trifluralin[alpha,alpha,alpha-trifluoro-2,6-dinitro-N,N-dipropyl-ptoluidine]+ disodium methylarsonate + sodium salts of 2,4-D and 

2,4,5-T)

● Greenfield Crab Grass and Broadleaf Weed Killer 

(trifluralin[alpha,alpha,alpha-trifluoro-2,6-dinitro-N,N-dipropyl-ptoluidine]+ disodium methylarsonate hexahydrate + isooctyl 

esters of 2,4-Dand 2,4,5-T)

● Greenfield Crabgrass and Dandelion Killer (disodium 

methanearsonate+ trifluralin [alpha,alpha,alpha-trifluoro-2,6-

dinitro-N,N-dipropyl-p-toluidine]+ sodium salts of 2,4-D and 

2,4,5-T)

● Greenfield Weeds As It Feeds For Lawns (isooctyl esters of2,4-D 

and 2,4,5-T)

● Greever's Low Volatile Brush Killer (isooctyl esters of 2,4-Dand 

2,4,5-T)

● Hercules (isooctyl esters of 2,4,5-T)

● HH Poison Ivy Killer (triethylamine salt of 2,4,5-T)

● Hormoslyr 64 (2,4-D + 2,4,5-T)

● Hub States Selective Weed and Brush Killer Amine Formula 

400(diethylethanolamine salts of 2,4-D and 2,4,5-T)

● Instemul DTA 22 (oleyl amine salt of 2,4-D + oleyllinoleylamine 

salt of 2,4,5-T)

● Instemul DTA 66 Concentrate (oleyl amine salt of 2,4-D + 
oleyllinoleylamine salt of 2,4,5-T)

● Instemul TA 120 Concentrate (oleyllinoleyl amine salt of 2,4,5-

T)

● Instemul TA 40 (oleyllinoleyl amine salt of 2,4,5-T)

● Inverton 245 (2,4,5-T, form unspecified)

● Kansel (2,4,5-T + propylene glycol butyl ether esters of 2,4,5-T)

● Kilbrush 8-16 Ester (butyl esters of 2,4-D and 2,4,5-T)

● Kilex 3 (butyl ester of 2,4,5-T)

● L.V. Brush Rhap-4 (isooctyl ester of 2,4,5-T)

● Lawn Weed-Rhap (2-ethylhexyl esters of 2,4-D and 2,4,5-T)

● Line Rider 22 (butyl esters of 2,4-D and 2,4,5-T)

● Line Rider 4T (butyl ester of 2,4,5-T)

● Line Rider Amine 4T-2 (alkyl amine salt of 2,4,5-T)

● Line Rider Invert D/T (isooctyl esters of 2,4-D and 2,4,5-T)

● Line Rider Invert D/T Concentrate (isooctyl esters of 2,4-Dand 

2,4,5-T)

● Line Rider Invert T (isooctyl ester of 2,4,5-T)

● Line Rider Invert T Concentrate (isooctyl ester of 2,4,5-T)

● Line Rider LV-21 (isooctyl esters of 2,4-D and 2,4,5-T)

● Line Rider LV-4T (2-ethylhexyl ester of 2,4,5-T)

● Line Rider LV-6T (2-ethylhexyl ester of 2,4,5-T)

● Liqweedate (2-methoxy-4,6-bis(isopropylamine)-s-triazine 

+isooctyl esters of 2,4-D and 2,4,5-T)

● LO-VOL 4T (2,4,5-T, form unspecified)

● Manco Super Kill-Weed (isooctyl esters of 2,4-D and 2,4,5-T)

● MFA 2,4,5-T Butyl Ester

● MFA LO-V 2,4,5-T (octyl ester of 2,4,5-T)

● MFA LO-V Super Brush Killer (octyl esters of 2,4-D and 2,4,5-

T)

● MFA Super Brush Kill (butyl esters of 2,4-D and 2,4,5-T)

● Monsanto 2,4,5-T Amine (triethylamine salt of 2,4,5-T)

● Monsanto 2,4,5-T Butyl Ester (isobutyl and n-butyl estersof 2,4,5-

T)

● Monsanto 2,4,5-T Low Volatile Ester (isooctyl ester of 2,4,5-T)

● Monsanto 2,4-D 2,4,5-T Amine Brush Killer (dimethylamine 

saltof 2,4-D + triethylamine salt of 2,4,5-T)
● Monsanto 2,4-D 2,4,5-T Amine Brush Killer (triethylamine 

saltsof 2,4-D and 2,4,5-T)

● Monsanto 2,4-D 2,4,5-T Butyl Ester Brush Killer

● Monsanto 2,4-D 2,4,5-T Low Volatile Ester Brush Killer 

(isooctylesters of 2,4-D and 2,4,5-T)

● n-Butyl(2,4,5-trichlorophenoxy)acetate

● n-Butylester Kyselini 2,4,5-trichlorfenoxyoctove

● Navy Brand WKB-15 (isooctyl esters of 2,4-D and 2,4,5-T)

● Navy Brand WKB-28 (butoxyethoxypropanol esters of 2,4-D 

and2,4,5-T)

● Niagara Brush-Killer (Ester Form) (butoxyethanol esters of2,4-D 

and 2,4,5-T)

● Niagara Commercial Brush Killer (isooctyl esters of 2,4-Dand 

2,4,5-T)

● Olin Butyl Ester 22 Brush Killer (butyl esters of 2,4-D and2,4,5-

T)

● Olin LV Ester 22 Brush Killer (2-ethylhexyl esters of 2,4-Dand 

2,4,5-T)

● Ortho Brush Killer (isooctyl esters of 2,4-D and 2,4,5-T)

● Parsons 2,4,5-T Brush Killer (2,4,5-T)

● Parsons Poison Ivy and Brush Killer No. 2 (isooctyl estersof 2,4-

D and 2,4,5-T)

● Patterson's 2,4,5-T Low Volatile and Brush Killer (isooctylester 

of 2,4,5-T)

● Patterson's Lawn Weed Killer (isooctyl esters of 2,4-D and2,4,5-

T)

● Patterson's Super Brush Killer (butyl esters of 2,4-D and2,4,5-T)

● Patterson's Super Brush Killer Low Volatile (isooctyl estersof 2,4-

D and 2,4,5-T)

● Phorfox (2,4,5-T, form unspecified))

● PL Liqui-date (isooctyl esters of 2,4-D, 2,4,5-T and silvex[2-

(2,4,5-trichlorophenoxy) propionic acid])

● Pratt Lawn Weed Killer (2,4-D + 2,4,5-T)

● Real-Kill Spot Weed Killer (amine salts of 2,4-D, dicamba[3,6-

dichloro-2-methoxybenzoic acid] and 2,4,5-T)

● Reasor-Hill Brush Rhap (2,4-D + 2,4,5-T)
● Reddon (propylene glycol butyl ether esters of 2,4,5-T)

● Reddox (2,4,5-T, form unspecified)

● Rhodia Low Volatile Brush Killer No. 2 (2,4-D + 2,4,5-T)

● S.I.R.-Ester (isooctyl esters of 2,4-D and 2,4,5-T)

● Science Lawn Weed-Killer (isooctyl esters of 2,4-D + 2,4,5-T)

● Stull's Hardwood Spray (isooctyl ester of 2,4,5-T)

● Stull's Low Volatile Brush Killer No. 4 (isooctyl esters of2,4-D 

and 2,4,5-T)

● Sure Death 2,4,5-T Conc. #4 (butyl ester of 2,4,5-T)

● Sure Death 2,4,5-T Conc. (2-ethyl 4-methylpentanol and 2-

ethylhexanolesters of 2,4,5-T)

● Swift's Gold Bear 2-2 Brush Kill (isooctyl esters of 2,4-Dand 

2,4,5-T)

● Swift's Gold Bear 55 Brush Kill (isooctyl ester of 2,4,5-T)

● Swift's Gold Bear Woody Plant Control (isooctyl esters of2,4-D 

and 2,4,5-T)

● 2,4,5-T Amine (dimethylamine salt of 2,4,5-T)

● 2,4,5-T Low Volatile Ester 6L (2,4,5-T, form unspecified)

● 2,4,5-T, butoxyethanol ester

● 2,4,5-T, butyl ester

● 2,4,5-T, isooctyl esters

● 2,4,5-T, oleic-1,3-propylenediamine salt

● 2,4,5-T, propyleneglycol butyl ether esters

● 2,4,5-T, triethylamine salt

● 2,4,5-T-dimethylamine salt

● 2,4,5-Trichlorophenoxyacetic acid

● T-5 Brush Kil (2,4,5-T, form unspecified)

● T-H Ded-Weed LV-6 (2,4,5-T)

● T-H Ded-Weed LV-9 (2,4,5-T)

● Techne 2,4,5-T Concentrate No.4 (butyl ester of 2,4,5-T)

● The Line Rider (2-ethylhexyl esters of 2,4-D and 2,4,5-T)

● Tobacco States Brand Ester Brush Killer 2-2 (butyl estersof 2,4-

D and 2,4,5-T)

● Tobacco States Brand Low-Vol Brush Killer 2-20 (isooctyl 

estersof 2,4-D and 2,4,5-T)

● Tormona (2,4,5-T, form unspecified)
● Transamine OA-1.5D-1.5T (N,N-dimethyloleyllinoleylamine 

saltof 2,4-D and 2,4,5-T)

● Transamine OA-3T (N,N-dimethyloleyllinoleylamine salt of 

2,4,5-T)

● Trelease (butoxyethanol ester of 2,4,5-T)

● Tributon (2,4-D + 2,4,5-T, forms unspecified)

● (2,4,5-Trichloor-fenoxy)-azunzuur

● (2,4,5-Trichlor-phenoxy)-essigsaevre

● (2,4,5-Trichlorophenoxy)acetic acid

● Trinixol (2,4,5-T, form unspecified)

● Trinoxol (butoxyethanol ester of 2,4,5-T)

● Trinoxol Super-6 (butoxyethanol ester of 2,4,5-T)

● Trioxon (2,4,5-T, form unspecified)

● Trioxone (butyl ester of 2,4,5-T)

● U 46 (2,4-D + 2,4,5-T, forms unspecified)

● U 46 Spezial (2,4-D + 2,4,5-T, forms unspecified)

● Unico 2,4,5-T Lo-V Ester Brush Killer (2-ethylhexyl esterof 

2,4,5-T)

● Unico Brush Killer (butyl esters of 2,4-D and 2,4,5-T)

● Unico Brush Killer A (butyl ester of 2,4-D + isooctyl esterof 

2,4,5-T)

● Unico Lo-V Brush Killer (2-ethylhexyl esters of 2,4-D and2,4,5-

T)

● Utility Brush Killer No. 2 (isooctyl esters of 2,4-D and 2,4,5-T)

● Veon (2,4,5-T, form unspecified)

● Veon 100 (triethylamine salt of 2,4,5-T)

● Veon 245 (triethylamine salt of 2,4,5-T)

● Veon BK (dimethylamine salts of 2,4-D and 2,4,5-T)

● Verton 2-T (2,4,5-T, form unspecified)

● Verton 2T (2,4,5-T, form unspecified)

● Verton 2T Herbicide (propylene glycol butyl ether esters of2,4,5-

T)

● Verton CE (propylene glycol butyl ether esters of 2,4-D and2,4,5-

T)

● Verton CE Herbicide (propylene glycol butyl ether esters of2,4-D 

and 2,4,5-T)
● Verton T (propylene glycol butyl ether esters of 2,4,5-T)

● Visko-Rhap H Low Volatile 2T (2-ethylhexyl ester of 2,4,5-T)

● Visko-Rhap Low Volatile 1.5D-1.5T (2-ethylhexyl esters of2,4-D 

and 2,4,5-T)

● Visko-Rhap Low Volatile 1D-1T (2-ethylhexyl esters of 2,4-

Dand 2,4,5-T)

● Visko-Rhap Low Volatile 2T (2-ethylhexyl ester of 2,4,5-T)

● Visko-Rhap Low Volatile 3T (2-ethylhexyl ester of 2,4,5-T)

● Visko-Rhap Low Volatile Ester 1D-1T (2-ethylhexyl esters of2,4-

D and 2,4,5-T)

● Visko-Rhap Low Volatile Ester 2T (2-ethylhexyl ester of 2,4,5-

T)

● Wasco Brush Killer (2-ethylhexyl esters of 2,4-D and 2,4,5-T)

● Weed and Brush Off Amine Formula 400 

(diethylethanolaminesalts of 2,4-D and 2,4,5-T)

● Weed-Rhap A-4T (triethylamine salt of 2,4,5-T)

● Weedar (2,4-D or 2,4,5-T, forms unspecified)

● Weedar 2,4,5-T (triethylamine salt of 2,4,5-T)

● Weedar Amine Brush Killer (dimethylamine salt of 2,4-D + 

triethylaminesalt of 2,4,5-T)

● Weedone (2,4-D or 2,4,5-T, forms unspecified)

● Weedone (butoxyethanol ester of 2,4,5-T)

● Weedone 2,4,5-T (2,4,5-T, form unspecified)

● Weedone 2,4,5-T Special Air Spray Formula (butoxyethanol 

esterof 2,4,5-T)

● Weedone Brush Killer 32 (butoxyethanol esters of 2,4-D 

and2,4,5-T)

● Weedone Brush Killer 64 (butoxyethanol esters of 2,4-D 

and2,4,5-T)

● Weedone Brush Killer 977 (butoxyethanol esters of 2,4-D 

and2,4,5-T)

● Weedone Brush Killer 977 Concentrate (butoxyethanol estersof 

2,4-D and 2,4,5-T)

● Weedone Industrial Brush Killer (butoxyethanol esters of 2,4-

Dand 2,4,5-T)

● Woodbury Woodkill Ester Conc. (butyl esters of 2,4-D and 2,4,5-
T)

● Woodkill Ester Concentrate (butyl esters of 2,4-D and 2,4,5-T)

● Zehrung 2,4,5-T blackberry Vine Killer (isopropyl ester of2,4,5-

T)

● Zehrung Weed Blitz (triethanolamine salts of 2,4-D and 2,4,5-T)

● Zep R-61 Weed Killer (dimethylamine salts of 2,4-D and 2,4,5-

T)

Synonyms for MCPA

● (4-Chloro-ortho-toloxy)acetic acid

● (4-Chloro-ortho-tolyloxy)acetic acid

● [(4-Chloro-ortho-tolyl)oxy]acetic acid

● 2,4-MCPA

● 2-Methyl-4-chlorophenoxyacetic acid

● 2M-4CH

● 2M4KH

● 4-Chloro-ortho-cresoxyacetic acid

● Agritox

● Agroxon

● Agroxone

● AK-2M

● Anicon kombi

● Anicon M

● B-Selektonon M

● Banlene plus

● Banvel M

● Basagran-M

● BH MCPA

● Bordermaster

● Brominal M

● Brominal plus

● Bronate

● Cambilene

● Cekherbex

● Chiptox

● Chlorotoloxyacetic acid

● Chwastox
● Cornox M

● Ded-Weed

● Dicopur-M

● Dicotex

● Dikotes

● Dow MCP amine weed killer

● Emcepan

● Empal

● Empral

● Hedapur M52

● Hedarex M

● Hedonal M

● Herbicide M

● Hormotuho

● Hormotuho X super

● Hornotuha

● Kilsem

● Krezone

● Legumex DB

● Leuna M

● Leyspray

● Linormore

● M40

● MCP

● Mephanac

● Metaxon

● Methoxone

● Netazol

● Okultin M

● Phenoxylene plus

● Phenoxylene super

● Raphone

● Razol dock killer

● Rhomenc

● Rhomene

● Rhonox
● Seppic MMD

● Trasan

● U 46

● U 46 M-Fluid 4

● U 46 M-Fluid 6

● Ustinex

● Verdone

● Vesakontuho MCPA

● Weed-Rhap

● Weedar

● Weedar MCPA concentrate

● Weedar sodium MCPA

● Weedone MCPA ester

● Zelan

Synonyms for 2,4-DP

● 2-(2,4-Dichlorophenoxy)-propionic acid

● Dichlorprop

Synonyms for Silvex

● Fenoprop

● 2-(2,4,5-Trichlorophenoxy)propionic acid

● 2,4,5-TP

Synonyms for MCPP

● 2-(4-Chloro-ortho-tolyloxy)propionic acid

● Mecoprop

Last updated: 2 March 1998
CHOLESTEROL

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 161)

CAS No.: 57-88-5

Chem. Abstr. Name: Cholest-5-en-ol (3β) 

A. Evidence for carcinogenicity to humans (inadequate) 

Intake of dietary cholesterol was greater in premenopausal cases than controls in a case-control 

study of diet and breast cancer; however, this finding was not statistically significant, and the 

association was less strong than that with dietary fat [ref: 1]. In a reanalysis of the same data, 

dietary cholesterol did not have an effect independent of saturated fat intake [ref: 2]. Further, in a 

cohort study of 89 538 US nurses, there was no increased risk of breast cancer associated with 

dietary fat or dietary cholesterol [ref: 3]. Dietary cholesterol intake was greater in cases than in 

controls in a case-control study of colorectal cancer, but the risk ratios were lower than for saturated 

fat intake [ref: 4]. Risk ratios were also elevated for dietary cholesterol and colon cancer in a second 

case-control study, although they were lower for rectal cancer and risk ratios were elevated to a 

greater extent for dietary protein [ref: 5]. In a study in which cholesterol intake of Seventh-Day 

Adventists was compared with that of lacto-ovo-vegetarians and nonvegetarians, differences for 

colon cancer risk were not 'striking' [ref: 6]. However, a study using food disappearance data from 

20 countries showed that, when dietary cholesterol was controlled for, the partial correlations of 

dietary fat and fibre with colon cancer mortality were no longer significant. Cross-classification 

showed a significant, main effect for cholesterol but not for fat or fibre [ref: 7]. 

Dietary cholesterol was associated with increased risk of lung cancer in a case-control study. The 

association was found in all subjects, in smoking subjects and in males, but not in females [ref: 8]. 

Dietary cholesterol was also found to be slightly associated with increased risk of bladder cancer in a 

further case-control study [ref: 9]. These studies involved the use of relatively restricted dietary 

questionnaires, and it was not possible to determine whether the association with dietary cholesterol 

was part of a stronger association with other dietary factors with which the intake of cholesterol is 

associated. 

Dietary cholesterol was analysed in relation to cancer mortality in a ten-year follow-up of the 

Honolulu Heart Program in the USA. There was no significant association, but data for individual 

cancer sites were not reported [ref: 10]. 

The available data on serum cholesterol levels and cancer have been considered [ref: 11], and 

subsequently reported independently [ref: 12]. It was concluded that observational studies afford 

substantial evidence that preclinical cancer causes a lowering of blood cholesterol, and limited, but 

biologically plausible evidence that males with naturally low blood cholesterol levels are at increased 

risk of colon cancer. Since then, there have been reports of seven studies primarily related to followup of cohorts established for the study of cardiovascular disease [ref: 13-20]. A study of 4035 

residents of California, USA, aged 40-89, showed no association between plasma cholesterol and 

cancer morbidity or mortality over a seven-year period for either men or women for any cancer site 

[ref: 13]. In a five-year follow-up of 10 940 participants in the Hypertension Detection and Followup Program in the USA, a small but statistically significant inverse relationship was found between 

baseline serum cholesterol level and cancer incidence. When cases diagnosed in the first two years 

were excluded, the association was similar in magnitude but no longer statistically significant. The 

numbers of cases did not permit analysis by cancer site [ref: 14]. Up to six years of follow-up 

(mean, three years) were reported for 10 000 middle-aged men in the Malmö; Preventive Program 

in Sweden [ref: 15]. Serum cholesterol was inversely related to cancer mortality (44 deaths) - a 

relationship seen also for the 25 cancer deaths that occurred more than 2.5 years after screening 

[ref: 15]. Serum urate levels at screening were correlated with early but not late (more than 2.5 

years after screening) cancer mortality. As urate levels might indicate proliferation of cancer cells, 

the association of raised serum cholesterol with late deaths may be due to another mechanism than 

cancer present at the time of screening [ref: 16]. 
In the Busselton community study in Western Australia, 1564 subjects have been followed for 13 

years. In men aged 60-74, but not in men aged 40-59 or in women, a negative association between 

serum cholesterol level and cancer mortality was found [ref: 17]. It was not indicated if the 

association persisted when early cancer deaths were excluded. In New Zealand, 630 Maoris aged 25-

74 were followed for over 17 years. A significant inverse relationship between cancer mortality and 

serum cholesterol was found for men and women considered together. The relative risk in the pooled 

data, derived by comparing the approximate 10th and 90th percentiles of serum cholesterol 

concentration, decreased from 3.0 to 2.4 after excluding deaths in the first five years [ref: 18]. 

Fifteen years of follow-up of 11 325 healthy men aged 40-59 in the Seven Countries Study has also 

been reported. Among 477 cancer deaths five or more years after cholesterol measurement, there 

was a significant excess of deaths from lung cancer in the lower 20% of the cholesterol distribution 

in the populations. Nevertheless, regional comparisons of cancer mortality showed highest cancer 

rates in northern Europe, where the cholesterol levels were highest [ref: 19]. In contrast, in a cohort 

study in Sweden of 92 000 subjects less than 75 years old examined in 1963-1965 and followed by 

linkage to the Swedish Cancer Registry until 1979, there was a positive association between serum 

cholesterol level and risk of rectal cancer in men. When serum cholesterol and β-lipoprotein levels 

were considered together, the risk for men with elevated serum cholesterol (equal or higher than 2.5 

g/l) and β-lipoprotein (equal or higher than 2.2 g/l), relative to those with lower levels, was 1.6 for 

colon cancer (95% confidence interval, 1.2-2.2) and 1.7 for rectal cancer (1.2-2.4) [ref: 20]. In the 

largest study so far reported, the incidence of cancer was determined in 160 135 male and female 

members of a prepaid health plan in California, USA, for whom serum cholesterol levels were 

determined as part of a multiphasic health examination. Follow-up was for eight to 16 years. No 

consistent association of low cholesterol with cancer incidence was found, although cancer incidence 

was highest in those in the lowest quintile of serum cholesterol levels in the first two years after the 

measurement [ref: 21]. 

Five case-control studies have been reported in which serum cholesterol was assessed [ref: 22-26]. 

A case-control study of 37 cases of primary brain tumours and two controls per case found elevated 

levels of serum cholesterol in the cases compared to the controls. The difference was not reduced by 

controlling for potential confounders (including weight) [ref: 22]. In the second study, serum 

cholesterol was measured in 244 patients with adenomatous polyps of the colon, 182 patients with 

Dukes' A or B colon cancer and 688 hospital controls. The mean serum cholesterol levels were lower 

for the Dukes' B cases, accounting for most of the difference. There was no difference in mean levels 

between those with adenomatous polyps and their controls. After adjustment for nutritional status 

using serum albumin level, however, there was no difference between any of the groups [ref: 23]. 

In a nested case-control study within a cohort, 245 newly-diagnosed cases of large-bowel cancer in 

members of a prepaid health care plan and five matched controls for each case were compared, on 

the basis of serum cholesterol measurements performed as part of a multiphasic health examination 

prior to the diagnosis of the cases. No direct or inverse relationship between serum cholesterol and 

large-bowel cancer was found [ref: 24]. A fourth case-control study was based on a cohort of 18 995 

people examined at a health centre between 1970-1973, where medical records were found for 100 

of 176 cancer cases who had died by 1979, for 393 of 900 control subjects still alive in 1979, and for 

69 of 153 people who had died of cardiovascular disease in the same period. Serum cholesterol 

levels in the cancer cases were significantly lower than those in controls only in the two-year period 

prior to death and were inconsistently depressed three to six or seven to 16 years prior to death 

[ref: 25]. In a fifth study, a positive association was found between serum cholesterol levels and the 

prevalence of adenomatous polyps at colonoscopy performed in 842 patients. The odds ratio for 

large-bowel adenoma between the highest and lowest quintiles of serum cholesterol was 1.9 (95% 

confidence interval, 1.1-3.5) after adjustment for age and 2.0 (1.1-3.6) after adjustment for bodymass index [ref: 26]. Serum cholesterol was assessed in relation to disease-free survival of 279 

colon cancer patients. There was an 11% (nonsignificant) lower cumulative disease-free survival at 

five years in those with serum cholesterol levels below the median than in those with levels above 

the median [ref: 27]. In a further study, family history of cancer was found to be positively 

associated with serum cholesterol levels in young adults [ref: 28]. 

Thus, although studies of cohorts assembled to study cardiovascular disease risk continue to show 

associations of low serum cholesterol with cancer incidence and mortality, the studies designed 

specifically to assess the relationship do not in general confirm the association. When site-specific 

data are available, they are not consistent. Nevertheless, a plausible mechanism exists - namely, 

that those who maintain a low serum cholesterol in face of a possibly elevated fat intake increase 

the concentration of cholesterol metabolites (especially bile acids) in the intestine and thus increase 

their risk for colon cancer [ref: 29]. 
B. Evidence for carcinogenicity to animals (inadequate) 

Cholesterol was tested for carcinogenicity in mice by administration in the diet, by subcutaneous 

administration and by bladder implantation. These studies were all inadequate for evaluation. 

Cholesterol has also been tested in combination with various carcinogens, but the results were 

inadequate to assess the carcinogenesis-enhancing potential of the compound [ref: 11]. Feeding of 

cholesterol to rats exposed to a mammary carcinogen did not affect the incidence of mammary 

tumours [ref: 30], while feeding after administration of a colon carcinogen resulted in a lower 

incidence of colon tumours [ref: 31]. 

C. Other relevant data

No data were available on the genetic and related effects of cholesterol in humans. Cholesterol did 

not transform Syrian hamster embryo cells and was not mutagenic to bacteria [ref: 32]. 

Overall evaluation

Cholesterol is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 10 (1976); Vol. 31 (1983)

References

1. Miller, A.B., Kelley, A., Choi, N.W., Matthews, V., Morgan, R.W., Munan, L., Burch, J.D., Feather, 

J., Howe, G.R. & Jain, M. (1978) A study of diet and breast cancer. Am. J. Epidemiol., 107, 499-509 

2. Howe, G.R. (1985) The use of polytomous dual response data to increase power in case-control 

studies: an application to the association between dietary fat and breast cancer. J. chron. Dis., 38, 

663-670 

3. Willett, W.C., Stampfer, M.J., Colditz, G.A., Rosner, B.A., Hennekens, C.H. & Speizer, F.E. (1987) 

Dietary fat and the risk of breast cancer. New Engl. J. Med., 316, 22-28 

4. Jain, M., Cook, G.M., Davis, F.G., Grace, M.G., Howe, G.R. & Miller, A.B. (1980) A case-control 

study of diet and colo-rectal cancer. Int. J. Cancer, 26, 757-768 

5. Potter, J.D. & McMichael, A.J. (1986) Diet and cancer of the colon and rectum: a case-control 

study. J. natl Cancer Inst., 76, 557-569 

6. Turjman, N., Calkins, B., Phillips, R., Goodman, G.T. & Nair, P.P. (1984) Dietary intake of plant 

sterols and cholesterol among population groups at different risks for colon cancer (Abstract No. 

3330). Fed. Proc., 43, 855 

7. Liu, K., Stamler, J., Moss, D., Garside, D., Persky, V. & Soltero, I. (1979) Dietary cholesterol, fat 

and fibre, and colon-cancer mortality. An analysis of international data. Lancet, ii, 782-785 

8. Hinds, M.W., Kolonel, L.N., Hankin, J.H. & Lee, J. (1983) Dietary cholesterol and lung cancer risk 

in a multiethnic population in Hawaii. Int. J. Cancer, 32, 727-732 

9. Risch, H.A., Burch, J.D., Miller, A.B., Hill, G.B., Steele, R. & Howe, G.R. (1987) Dietary factors 

and the incidence of cancer of the urinary bladder. Am. J. Epidemiol. (in press) 
10. McGee, D., Reed, D., Stemmerman, G., Rhoads, G., Yano, K. & Feinleib, M. (1985) The 

relationship of dietary fat and cholesterol to mortality in 10 years: the Honolulu Heart Program. Int. 

J. Epidemiol., 14, 97-105 

11. IARC Monographs, 31, 95-132, 1983 

12. McMichael, A.J., Jensen, O.M., Parkin, D.M. & Zaridze, D.G. (1984) Dietary and endogenous 

cholesterol and human cancer. Epidemiol. Rev., 6, 192-216 

13. Wingard, D.L., Criqui, M.H., Holdbook, M.J. & Barrett-Connor, E. (1984) Plasma cholesterol and 

cancer morbidity and mortality in an adult community. J. chron. Dis., 37, 401-406 

14. Morris, D.L., Borhani, N.O., Fitzsimons, E., Hardy, R.J., Hawkins, C.M., Kraus, J.F., Labarthe, 

D.R., Mastbaum, L. & Payne, G.H. (1983) Serum cholesterol and cancer in the hypertension 

detection and follow-up program. Cancer, 52, 1754-1759 

15. Petersson, B. & Trell, E. (1983) Premature mortality in middle-aged men: serum cholesterol as 

risk factor. Klin. Wochenschr., 63, 795-801 

16. Petersson, B. & Trell, E. (1983) Raised serum urate concentration as risk factor for premature 

mortality in middle aged men: Relation to death from cancer. Br. med. J., 287, 7-9 

17. Cullen, K., Stenhouse, N.S., Wearne, K.L. & Welborn, T.A. (1983) Multiple regression analysis of 

risk factors for cardiovascular disease and cancer mortality in Busselton, Western Australia - 13-year 

study. J. chron. Dis., 36, 371-377 

18. Salmond, C.E., Beaglehole, R. & Prior, I.A.M. (1985) Are low cholesterol values associated with 

excess mortality? Br. med. J., 290, 422-424 

19. Keys, A., Aravanis, C., Blackburn, H., Buzina, R., Dontas, A.S., Fidanza, F., Karvonen, M.J., 

Menotti, A., Nedeljkovic, S., Punsar, S. & Toshima, H. (1985) Serum cholesterol and cancer 

mortality in the Seven Countries Study. Am. J. Epidemiol., 121, 870-883 

20. Törnberg, S.A., Holm, L.-E., Cartensen, J.M. & Eklund, G.A. (1986) Risks of cancer of the colon 

and rectum in relation to serum cholesterol and beta-lipoprotein. New Engl. J. Med., 315, 1629-1633 

21. Hiatt, R.A. & Fireman, B.H. (1986) Serum cholesterol and the incidence of cancer in a large 

cohort. J. chron. Dis., 39, 861-870 

22. Abramson Z.H. & Kark, J.D. (1985) Serum cholesterol and primary brain tumours: a casecontrol study. Br. J. Cancer, 52, 93-98 

23. Neugut, A.I., Johnsen, C.M. & Fink, D.J. (1986) Serum cholesterol levels in adenomatous polyps 

and cancer of the colon. A case-control study. J. Am. med. Assoc., 255, 365-367 

24. Sidney, S., Friedman, G.D. & Hiatt, R.A. (1986) Serum cholesterol and large bowel cancer. A 

case-control study. Am. J. Epidemiol., 124, 33-38 

25. Gerhardsson, M., Rosenqvist, U., Ahlbom, A. & Carlson, L.A. (1986) Serum cholesterol and 

cancer - a retrospective case-control study. Int. J. Epidemiol., 15, 155-159 

26. Mannes, G.A., Maier, A., Thieme, C., Wiebecke, B. & Paumgartner, G. (1986) Relation between 

the frequency of colorectal adenoma and the serum cholesterol level. New Engl. J. Med., 315, 1634-

1638 
27. Tartter, P.I., Slater, G., Papatestas, A.E. & Aufses, A.H., Jr (1984) Cholesterol, weight, height, 

Quetelet's index, and colon cancer recurrence. J. surg. Oncol., 27, 232-235 

28. Reed, T., Wagener, D.K., Donahue, R.P. & Kuller, L.H. (1986) Family history of cancer related to 

cholesterol level in young adults. Genet. Epidemiol., 3, 63-71 

29. Broitman, S.A. (1981) Cholesterol excretion and colon cancer. Cancer Res., 41, 3738-3740 

30. Cohen, L.A. & Chan, P.-C. (1982) Dietary cholesterol and experimental mammary cancer 

development. Nutr. Cancer, 4, 99-106 

31. Cohen, B.I., Raicht, R.F. & Fazzini, E. (1982) Reduction of N-methyl-N-nitrosourea-induced colon 

tumors in the rat by cholesterol. Cancer Res., 42, 5050-5052 

32. IARC Monographs, Suppl. 6, 166-167, 1987 

Synonyms

● (-)-Cholesterol 

● 5,6-Cholesten-3β-ol 

● 5-Cholesten-3β-ol 

● Cholest-5-en-3β-ol 

● Cholesterin 

● Cholesterine 

● Cholesterol base H 

● Cholesteryl alcohol 

● Cordulan 

● ∆5(-cholesten-3β-ol) 

● Dusoline 

● Dusoran 

● Dythol 

● β-Hydroxycholest-5-ene 

● Hydrocerin 

● Kathro 

● Lanol 

● Nimco cholesterol base H 

● Nimco cholesterol base No. 7l2 

● Provitamin D 

● Super hartolan 

● Tegolan 

Last updated: 9 March 1998 
CHRYSOIDINE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 169)

CAS No.: 532-82-1

Chem. Abstr. Name: 4-(Phenylazo)-1,3-benzenediamine, monohydrochloride 

A. Evidence for carcinogenicity to humans (inadequate) 

A report of bladder cancer in three amateur anglers with exposure to chrysoidine-dyed maggots 

[ref: 1] stimulated reports of four further cases [ref: 2,3] and two case-control studies [ref: 4,5]. A 

study in Yorkshire, UK, used an existing large-scale bladder cancer case-control study (over 900 

pairs) and made further enquiries regarding fishing, maggots and dyes used on or in the maggots. 

The relative risks were 0.7 (95% confidence interval, 0.2-2.3) based on five exposed cases for the 

use of bronze (surface-coloured) maggots, and 2.0 (0.6-6.2) based on nine exposed cases for 

yellow maggots (ready or self-coloured) [ref: 4]. A study in the West Midlands, UK, was smaller 

(202 pairs) but showed a higher percentage of use of dyed maggots (14% of cases, 8% of controls). 

A three-fold excess risk was noted for the use of bronze maggots for more than five years [ref: 5]. 

This study almost certainly included five cases from the previous case reports that stimulated the 

case-control studies, but this factor is unlikely to remove the statistically significant excess risk. 

B. Evidence for carcinogenicity to animals (limited) 

Chrysoidine was tested for carcinogenicity in single experiments in mice and rats by oral 

administration only. In mice, it produced liver-cell adenomas and carcinomas, leukaemia and 

reticulum-cell sarcomas. The experiment on rats was inadequately reported [ref: 6]. 

C. Other relevant data

No data were available on the genetic and related effects of chrysoidine in humans. It was 

mutagenic to bacteria [ref: 7]. 

Overall evaluation

Chrysoidine is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 8 (1975)

References

1. Searle, C.E. & Teale, J. (1982) Chrysoidine-based bait: a possible carcinogenic hazard to anglers? 

Lancet, i, 564 

2. Massey, J.A., Feneley, R.C.L. & Abrams, P.H. (1984) Maggots dyed with chrysoidine. Br. med. J., 

289, 1451-1452 

3. Sole, G.M. (1984) Maggots dyed with chrysoidine: a possible risk to anglers. Br. med. J., 289, 

1043-1044 
4. Cartwright, R.A., Robinson, M.R.G., Glashan, R.W., Gray, B.K., Hamilton-Stewart, P., Cartwright, 

S.C. & Barnham-Hall, D. (1983) Does the use of stained maggots present a risk of bladder cancer to 

coarse fishermen? Carcinogenesis, 4, 111-113 

5. Sole, G. & Sorahan, T. (1985) Coarse fishing and risk of urothelial cancer. Lancet, i, 1477-1479 

6. IARC Monographs, 8, 91-96, 1975 

7. IARC Monographs, Suppl. 6, 176-177, 1987 

Synonyms

● 2,4-Diaminoazobenzene hydrochloride 

● 4-(Phenylazo)-m-phenylenediamine, hydrochloride 

● 4-(Phenylazo)-m-phenylenediamine, monohydrochloride 

● Astra chrysoidine R 

● Basic Orange 2 

● Basic Orange 2, monohydrochloride 

● Brasilazina Orange Y 

● Brilliant oil Orange Y base 

● Calcozine chrysoidine Y 

● Calcozine Orange YS 

● Chrysoidin 

● Chrysoidin FB 

● Chrysoidin YN 

● Chrysoidine [II] 

● Chrysoidine A 

● Chrysoidine B 

● Chrysoidine C crystals 

● Chrysoidine crystals 

● Chrysoidine G 

● Chrysoidine GN 

● Chrysoidine GS 

● Chrysoidine HR 

● Chrysoidine J 

● Chrysoidine M 

● Chrysoidine Orange 

● Chrysoidine PRL 

● Chrysoidine PRR 

● Chrysoidine SL 

● Chrysoidine special [biological stain and indicator] 

● Chrysoidine SS 

● Chrysoidine Y 

● Chrysoidine Y base new 

● Chrysoidine Y crystals 

● Chrysoidine Y ex 

● Chrysoidine Y special 

● Chrysoidine YGH 

● Chrysoidine YL 

● Diazocard chrysoidine G 

● Elcozine chrysoidine Y 

● Leather Orange HR 

● Nippon kagaku chrysoidine 

● Pure chrysoidine YBH 

● Pure chrysoidine YD 

● Pyracryl Orange Y 

● Solvent Orange 3 

● Sugai chrysoidine 

● Tertrophene brown CG 
Last updated: 9 March 1998 
CISPLATIN

(Group 2A)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 170) 

CAS No.: 15663-27-1

Chem. Abstr. Name: Platinum, diamminedichloro-, (SP-4-2)- 

A. Evidence for carcinogenicity to humans (inadequate)

No epidemiological study of cisplatin as a single agent was available to the Working Group. 

Occasional case reports of exposure to cisplatin, especially in the presence of concurrent therapy 

with other putative carcinogens, such as ionizing radiation, alkylating agents and other potent 

oncotherapeutic drugs, do not constitute evidence of carcinogenesis [ref: 1-3]. 

B. Evidence for carcinogenicity to animals (sufficient)

Multiple intraperitoneal administrations of cisplatin to mice significantly increased the incidence and 

number of lung adenomas. Similar treatments caused a significant increase in the incidence of skin 

papillomas in mice given promoting treatment of croton oil applied to the skin. The incidences of 

epidermoid carcinomas and of both malignant and benign tumours in internal organs were increased 

by the same treatment, but were not significantly different from those in controls [ref: 1,4]. In two 

studies, multiple intraperitoneal injections of cisplatin to rats induced leukaemia [ref: 5,6]. 

C. Other relevant data

In one study, cisplatin-adriamycin combination chemotherapy induced sister chromatid exchanges in 

peripheral blood lymphocytes of patients treated with this agent. In another study, antigenicity 

against cisplatin-DNA adducts was demonstrated in blood cells of treated patients [ref: 7].

Cisplatin induced structural chromosomal aberrations and sister chromatid exchanges in cells of 

rodents treated in vivo, but it did not induce dominant lethal mutations in mice. It transformed 

Syrian hamster embryo cells; it induced chromosomal aberrations, micronuclei and sister chromatid 

exchanges in both human and rodent cells in vitro, and mutation and DNA damage (including DNA 

cross-links) in rodent cells in vitro. In Drosophila, cisplatin induced aneuploidy and dominant lethal 

and sex-linked recessive lethal mutations. It induced chromosomal aberrations and mutation in 

plants. Cisplatin induced mutation, gene conversion and DNA damage in fungi and mutation and 

DNA damage in bacteria [ref: 7]. 

Overall evaluation

Cisplatin is probably carcinogenic to humans (Group 2A).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 26 (1981) 

References

1. IARC Monographs, 26, 151-164, 1981

2. Mead, G.M., Green, J.A., Macbeth, F.R., Williams, C.J., Whitehouse, J.M.A. & Buchanan, R. (1983) 
Second malignancy after cisplatin, vinblastin, and bleomycins (PVB) chemotherapy: a case report. 

Cancer Treat. Rep., 67, 410

3. Pedersen-Bjergaard, J., Rørth, M., Avnstrøm, S., Philip, P. & Hou-Jensen, K. (1985) Acute 

nonlymphocytic leukemia following treatment of testicular cancer and gastric cancer with 

combination chemotherapy not including alkylating agents: report of two cases. Am. J. Hematol., 

18, 425-429

4. Leopold, W.R., Batzinger, R.P., Miller, E.C., Miller, J.A. & Earhart, R.H. (1981) Mutagenicity, 

tumorigenicity, and electrophilic complexes of 1,2-diaminocyclohexane. Cancer Res., 41, 4368-4377

5. Kempf, S.R. & Ivankovic, S. (1986) Chemotherapy-induced malignancies in rats after treatment 

with cisplatin as single agent and in combination: preliminary results. Oncology, 43, 187-191

6. Kempf, S.R. & Ivankovic, S. (1986) Carcinogenic effect of cisplatin(cis-diamminedichloroplatinum(II), CDDP) in BD IX rats. J. Cancer Res. clin. Oncol., 111, 133-136

7. IARC Monographs, Suppl. 6, 178-181, 1987 

Synonyms

● CDDP 

● Cisplatyl 

● DDP 

● cis-DDP 

● cis-Diamminedichloroplatinum 

● cis-Diaminodichloroplatinum [II] 

● cis-Diamminedichloroplatinum [II] 

● cis-Diammineplatinum [II]-chloride 

● cis-Dichlorodiaminoplatinum 

● cis-Dichlorodiaminoplatinum [II] 

● cis-Dichlorodiammineplatinum 

● cis-Dichlorodiammineplatinum [II] 

● NSC 119875 

● PDD 

● Platinol 

● cis-Platinous diaminodichloride 

● cis-Platinum 

● cis-Platinum diaminodichloride 

● cis-Platinum[II] diaminodichloride 

● cis-Platinum diamminedichloride 

● cis-Platinum[II] diamminedichloride 

● Platinum diamminodichloride 

Last updated: 11 February 1998 
CLOMIPHENE CITRATE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 172)

Clomiphene

CAS No.: 911-45-4

Chem. Abstr. Name: 2-[4-(2-Chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethylethanamine 

Clomiphene citrate

CAS No.: 50-41-9

Chem. Abstr. Name: 2-[4-(2-Chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethylethanamine2-hydroxy-1,2,3-propanetricarboxylate (1:1) 

A. Evidence for carcinogenicity to humans (inadequate) 

Only case reports of benign and malignant tumours occurring at various sites are available [ref: 1-

5]. These include testicular tumours in three young men who had received clomiphene as part of 

hormonal treatment for oligospermia [ref: 2], a hepatoblastoma in a female infant whose mother 

had received clomiphene citrate as treatment for infertility [ref: 3], a liver-cell adenoma in a woman 

who had received clomiphene citrate for oligomenorrhoea [ref: 4], and unilateral testicular 

neoplasms in two of 650 oligospermic men who had received monthly treatments with clomiphene 

citrate (daily for three weeks followed by a week of rest) for six to 12 months [ref: 5]. 

B. Evidence for carcinogenicity to animals (inadequate) 

Clomiphene citrate was tested in an inadequate experiment in newborn rats by single subcutaneous 

injection; reproductive-tract abnormalities, including uterine and ovarian tumours, were reported 

[ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of clomiphene citrate in humans. It did not 

induce chromosomal aberrations or micronuclei in bone-marrow cells of mice treated in vivo [ref: 

6]. 

Overall evaluation

Clomiphene citrate is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 21 (1979)

References

1. IARC Monographs, 21, 551-561 

2. Neoptolemos, J.P., Locke, T.J. & Fossard, D.P. (1981) Testicular tumour associated with hormonal 

treatment for oligospermia. Lancet, ii, 754 

3. Melamed, I., Bujanover, Y., Hammer, J. & Spirer, Z. (1982) Hepatoblastoma in an infant born to 
a mother after hormonal treatment for steriligy. New Engl. J. Med., 307, 820 

4. Carrasco, D., Barrachina, M., Prieto, M. & Berenguer, J. (1983) Clomiphene citrate and liver cell 

adenoma. New Engl. J. Med., 310, 1120-1121 

5. Nilsson, A. & Nilsson, S. (1985) Testicular germ cell tumors after clomiphene therapy for 

subfertility. J. Urol., 134, 560-562 

6. IARC Monographs, Suppl. 6, 184-185, 1987 

Synonyms for Clomiphene

● Chloramiphene 

● 2-para-(2-Chloro-1,2-diphenylvinyl)-phenoxy]triethylamine 

● 2-para-(β-Chloro-α-phenylstyryl)phenoxy]triethylamine 

● Clomifene 

● Clomiphene B 

Synonyms for Clomiphene citrate

● Clomiphene dihydrogen citrate 

● 2-[p-(2-Chloro-1,2-diphenylvinyl)phenoxy]triethylamine citrate (1:1) 

● Clomid 

● Clomifeno 

● Clomivid 

● Clomphid 

● Chloramiphene 

● Dyneric 

● Genozym 

● Ikaclomin 

● Mer-41 

● MRL 41 

● MRL/41 

● NSC 35770 

● Omifin 

● Racemic clomiphene citrate 

Last updated: 9 March 1998 
COAL GASIFICATION

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 173) 

A. Evidence for carcinogenicity to humans (sufficient)

Case reports of tumours of the skin (including the scrotum), bladder and respiratory tract in 

association with employment in industries involving the destructive distillation of coal suggested a 

link between work in that industry and human cancer. Descriptive epidemiological studies based on 

death certificates corroborated these early suggestions [ref: 1]. 

A series of detailed analytical epidemiological studies of the British gas industry add further weight 

to the hypothesis that work in such coal gasification plants carries a risk for tumours of the lung, 

bladder and scrotum. There appeared to be a relationship between elevated relative risk of tumours 

and work in retort houses, particularly when the job had entailed exposure to fumes emanating 

from the retorts [ref: 1]. 

B. Other relevant data

No data were available to the Working Group. 

Overall evaluation

Coal gasification is carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 34 (1984)

Reference

1. IARC Monographs, 34, 65-99, 1984 

Last updated: 9 February 1998 
COAL-TAR PITCHES

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 174) 

A. Evidence for carcinogenicity to humans (sufficient)

A mortality analysis in the UK from 1946 showed a greatly increased risk for scrotal cancer among 

patent-fuel workers; furthermore, a large number of case reports describe the development of skin 

(including the scrotum) cancer in workers exposed to coal-tars or coal-tar pitch [ref: 1]. Several 

epidemiological studies have shown excesses of lung and bladder cancer among workers exposed to 

pitch fumes in aluminium production plants [ref: 2]. A slight excess of lung cancer was found among 

furnace and maintenance workers exposed to coal-tar pitch fumes in a calcium carbide production 

plant [ref: 3]. A cohort study of US roofers indicated an increased risk for cancer of the lung and 

suggested increased risks for cancers of the oral cavity, larynx, oesophagus, stomach, skin and 

bladder and for leukaemia. Some support for excess risks of lung, laryngeal and oral-cavity cancer 

is provided by other studies of roofers. One study showed a small excess of bladder cancer in tar 

distillers and in patent-fuel workers. An elevated risk of cancer of the renal pelvis was seen in 

workers exposed to 'petroleum or tar or pitch' [ref: 1]. One study of millwrights and welders 

exposed to coal-tars and coal-tar pitches in a stamping plant showed significant excesses of 

leukaemia and of cancers of the lung and digestive organs [ref: 4]. 

B. Evidence for carcinogenicity to animals (sufficient)

Application of coal-tar pitches and extracts of coal-tar pitches to the skin of mice produced 

malignant skin tumours. Extracts of coal-tar pitches had both initiating and promoting activities in 

mouse skin [ref: 1,5,6]. 

C. Other relevant data

No data were available on the genetic and related effects of coal-tar pitches in humans. 

Extracts of coal-tar pitches and 'coal-tar' paints (formulated with coal-tar pitches) were mutagenic 

to Salmonella typhimurium in the presence of an exogenous metabolic system. Extracts of 

emissions from a roofing-tar pot (coal-tar pitch-based tar) enhanced viral transformation in Syrian 

hamster embryo cells but did not cause DNA strand breaks. The same material induced sister 

chromatid exchanges and mutation in cultured rodent cells, both in the presence and absence of an 

exogenous metabolic system, and was mutagenic to S. typhimurium in the presence of an 

exogenous metabolic system [ref: 7]. 

Overall evaluation

Coal-tar pitches are carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 35 (1985)

References

1. IARC Monographs, 35, 83-159, 1985 

2. IARC Monographs, 34, 37-64, 1984 
3. Kjuus, H., Andersen, A. & Langard, S. (1986) Incidence of cancer among workers producing 

calcium carbide. Br. J. ind. Med., 43, 237-242 

4. Silverstein, M., Maizlish, N., Park, R. & Mirer, F. (1985) Mortality among workers exposed to coal 

tar pitch volatiles and welding emissions: an exercise in epidemiologic triage. Am. J. publ. Health, 

75, 1283-1287 

5. Robinson, M., Bull, R.J., Munch, J. & Meier, J. (1984) Comparative carcinogenic and mutagenic 

activity of coal tar and petroleum asphalt paints used in potable water supply systems. J. appl. 

Toxicol., 4, 49-56 

6. Niemeier, R.W., Thayer, P.S., Menzies, K.T., von Thuna, P., Moss, C.E. & Burg, J. (1987) A 

comparison of the skin carcinogenicity of condensed roofing asphalt and coal tar pitch fumes. In: 

Proceedings of the International Symposium on Polynuclear Aromatic Hydrocarbons, Columbus, OH, 

Battelle (in press) 

7. IARC Monographs, Suppl. 6, 186, 1987 

Last updated: 9 February 1998 
COAL-TARS

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 175) 

Coal-tars

CAS No.: 8007-45-2

Chem. Abstr. Name: Coal-tars 

Coal-tars [high-temperature]

CAS No.: 65996-89-6

Chem. Abstr. Name: Tar, coal, high-temp. 

Coal-tars [low-temperature]

CAS No.: 65996-90-9

Chem. Abstr. Name: Tar, coal, low-temp. 

A. Evidence for carcinogenicity to humans (sufficient)

There have been a number of case reports of skin cancer in patients who used tar ointments for a 

variety of skin diseases [ref: 1,2]. A mortality analysis in the UK from 1946 showed a greatly 

increased scrotal cancer risk for patent-fuel workers. Furthermore, a large number of case reports 

describe the development of skin (including the scrotum) cancer in workers exposed to coal-tar or 

coal-tar pitches [ref: 1]. Several epidemiological studies have shown an excess of lung cancer 

among workers exposed to coal-tar fumes in coal gasification and coke production [ref: 3,4]. One 

study showed a small excess of bladder cancer in tar distillers and in patent-fuel workers. An 

elevated risk of cancer of the renal pelvis was seen in workers exposed to 'petroleum or tar or pitch' 

[ref: 1. One study of millwrights and welders exposed to coal-tars and coal-tar pitches in a stamping 

plant showed significant excesses of leukaemia and of cancers of the lung and digestive organs [ref: 

5]. 

B. Evidence for carcinogenicity to animals (sufficient)

Coal-tars from blast furnaces, coke ovens and coal gasification plants, as well as pharmaceutical 

coal-tars, were tested for carcinogenicity by skin application in mice, producing skin tumours. 

Pharmaceutical coal-tars and tars from coal gasification plants also produced skin tumours when 

applied to the ears of rabbits. Pharmaceutical coal-tars applied to the skin of rats produced lung 

tumours but not skin tumours. Inhalation of tar from coke ovens produced benign and malignant 

lung tumours in mice and rats and skin tumours in mice [ref: 1,3,4]. 

C. Other relevant data

An increased frequency of chromosomal aberrations was observed in peripheral lymphocytes of coaltar workers, both smokers and nonsmokers. Extracts of urine from patients undergoing combined 

treatment with coal-tar preparations and ultraviolet light were mutagenic to Salmonella typhimurium

[ref: 6]. 

Coal-tar induced transformation of Syrian hamster embryo cells. Samples of therapeutic coal-tar, 

extracts of coal-tar shampoos, an industrial coal-tar and vapours emitted from a coal-tar sample at 

37 °C were mutagenic to S. typhimurium in the presence of an exogenous metabolic system [ref: 

6]. 

Overall evaluation
Coal-tars are carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 35 (1985)

References

1. IARC Monographs, 35, 83-159, 1985 

2. Stern, R.S., Scotto, J. & Fears, T.R. (1985) Psoriasis and susceptibility to nonmelanoma skin 

cancer. J. Am. Acad. Dermatol., 12, 67-73 

3. IARC Monographs, 34, 65-99, 1984 

4. IARC Monographs, 34, 101-131, 1984 

5. Silverstein, M., Maizlish, N., Park, R. & Mirer, R. (1985) Mortality among workers exposed to coal 

tar pitch volatiles and welding emissions: an exercise in epidemiologic triage. Am. J. publ. Health, 

75, 1283-1287 

6. IARC Monographs, Suppl. 6, 186, 1987 

Synonyms for Coal-tars

● Carbo-cort 

● Crude coal tar 

● Estar 

● Lavatar 

● Pix carbonis 

● Polytar bath 

● Supertah 

● Syntar 

● Zetar 

Synonym for Coal-tars [high-temperature]

● Tar decanter sludge 

Synonym for Coal-tars [low-temperature]

● Coal oil 

Last updated: 9 February 1998 
COKE PRODUCTION

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 176) 

A. Evidence for carcinogenicity to humans (sufficient)

In the first half of the century, case reports of tumours of the skin (including the scrotum), bladder 

and respiratory tract, in association with employment in industries involving the destructive 

distillation of coal, suggested a link between that industry and human cancer. Despite their 

methodological shortcomings, descriptive epidemiological studies based on death certificates 

corroborated these early suggestions [ref: 1]. 

Later studies carried out in Japan, Sweden, the UK and the USA identified the lung as the site at 

which the excess cancer rates occurred most commonly among workers in coke production. All but 

two of the pertinent analytical epidemiological cohort studies provided evidence that work in coke 

production carries a significantly elevated risk of lung cancer. The two studies showing no lung 

cancer excess suffered from serious methodological limitations. The risk was evident in comparison 

with both the general population and non-coke production workers, and the extent of the increased 

relative risk estimates varied from three to seven fold. In those studies in which the relevant 

information was available, differences in smoking habits were shown not to have severely 

confounded the risk estimates [ref: 1]. 

Excess risk of kidney cancer has been repeatedly associated with work in coke plants. In one study 

in the USA, a seven-fold increase in risk was seen for workers employed for five years or more at 

coke ovens. In single studies, excess risks were reported for cancers of the large intestine and 

pancreas [ref: 1]. 

The largest study was conducted on a cohort of some 59 000 steel workers in the Pittsburgh area 

(USA) [ref: 1]. The study has recently been extended up to 1975 and the dose-response analysis of 

exposure to coal-tar pitch volatiles and lung cancer reviewed. Coke-oven workers (both white and 

nonwhite) exhibited a large, statistically significant increase in lung cancer mortality that was 

strongly associated with duration of exposure to coke-oven fumes and intensity of exposure, as 

documented by comparing topside- with side-oven experience. Significantly elevated mortality from 

prostatic and kidney cancer was also noted, but without clear evidence of an exposure-response 

relationship. Non-oven workers had no excess of lung cancer but a significantly increased mortality 

from cancer of the large intestine and pancreas. Cumulative exposure indices of exposure to coal-tar 

pitch volatiles were calculated and increasing lung cancer risk with increasing estimated exposure 

was found [ref: 2,3]. A possible causative agent is coal-tar fumes. 

Overall evaluation

Coke production is carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 34 (1984)

B. Other relevant data

An increase in the incidence of sister chromatid exchanges was observed in cultured peripheral 

blood lymphocytes from 12 nonsmoking coke-oven workers in a steel plant, when they were 

compared to a group of age-matched controls. Urine samples from nonsmoking coke-plant workers 

were mutagenic to Salmonella typhimurium in the presence of an exogenous metabolic system. In a 

second study of coke-plant workers, the mutagenic activity in S. typhimurium of extracts of urine 
samples collected after work was not statistically different from that of samples taken before work. 

Antigenicity against benzo[a]pyrene diol epoxide-DNA adducts has been demonstrated in peripheral 

blood lymphocytes of coke-oven workers [ref: 4]. 

References

1. IARC Monographs, 34, 101-131, 1984 

2. Redmond, C.K. (1983) Cancer mortality among coke oven workers. Environ. Health Perspect., 52, 

67-73 

3. Rockette, H.E. & Redmond, C.K. (1985) Selection, follow-up and analysis in the coke oven study. 

Natl Cancer Inst. Monogr., 67, 89-94 

4. IARC Monographs, Suppl. 6, 187, 1987 

Last updated: 9 February 1998 
CREOSOTES

(Group 2A)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 177) 

CAS No.: 8001-58-9

Chem. Abstr. Name: Creosote oil/wash oil 

A. Evidence for carcinogenicity to humans (limited)

In a number of case reports, the development of skin cancer in workers exposed to creosote is 

described. One study involved a review of 3753 cases of cutaneous epithelioma from 1920 to 1945 

and showed that 35 cases (12 of which were of the scrotum) had had exposure to creosote. Most 

cases occurred in workers handling creosotes or creosoted wood during timber treatment. A 

mortality analysis of workers in many occupations indicated an increased risk of scrotal cancer for 

creosote-exposed brickmakers [ref: 1]. 

B. Evidence for carcinogenicity to animals (sufficient)

Creosotes, creosote oils and anthracene oils were tested for carcinogenicity in mice by skin 

application, producing skin tumours, including carcinomas. One of the creosotes also produced lung 

tumours in mice after skin application [ref: 1]. 

C. Other relevant data

No occupationally related increase in mutagenicity was detected in the urine of creosote workers, 

but urine from rats administered creosote was mutagenic to Salmonella typhimurium in the 

presence of an exogenous metabolic system [ref: 2].

Creosote enhanced transformation of Syrian hamster embryo cells initiated with benzo[a]pyrene in 

a two-stage transformation assay, and creosote and a coal-tar/creosote mixture gave positive 

results in the mouse lymphoma L5178Y system. Creosote, vapour emitted from creosote at 37 °C 

and a coal-tar/creosote mixture were mutagenic to S. typhimurium in the presence of an exogenous 

metabolic system [ref: 2]. 

Overall evaluation

Creosotes are probably carcinogenic to humans (Group 2A).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 35 (1985)

References

1. IARC Monographs, 35, 83-159, 1985

2. IARC Monographs, Suppl. 6, 188, 1987 

Last updated: 11 February 1998 
CYCLAMATES

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 178)

Calcium cyclamate

CAS No.: 139-06-0

Chem. Abstr. Name: Cyclohexylsulfamic acid, calcium salt 

Cyclamic acid

CAS No.: 100-88-9

Chem. Abstr. Name: Cyclohexylsulfamic acid 

Cyclohexylamine

CAS No.: 108-91-8

Chem. Abstr. Name: Cyclohexanamine 

Sodium cyclamate

CAS No.: 139-05-9

Chem. Abstr. Name: Cyclohexylsulfamic acid, monosodium 

A. Evidence for carcinogenicity to humans (inadequate) 

The evidence that the risk of cancer is increased among users of artificial sweeteners is inconsistent 

[ref: 1]. Since the positive report of Howe et al. [ref: 2], reports have become available on six casecontrol studies and on one population study of bladder cancer. 

The largest was a population-based study in ten areas of the USA, with 3010 bladder cases and 5783 

controls. The relative risk for bladder cancer associated with use of artificial sweeteners was 1.0 

(95% confidence interval, 0.9-1.1) among men and 1.1 (0.9-1.3) among women. Significant trends 

of increasing risk with increasing average daily consumption were found in certain subgroups 

examined a priori on the basis of the results of animal experiments; these subgroups were female 

nonsmokers and male heavy smokers [ref: 3]. Subsequent, independent re-analysis of the same 

data by a different statistical technique (multiple logistic regression) confirmed the original findings 

overall but cast doubt on the significance of the findings in the two subgroups because of 

inconsistent dose-response trends, especially among the male heavy smokers [ref: 4]. In response, 

the original investigators noted that the inconsistency derived from the development of risk scores 

which, in their opinion, were not correctly derived, as two relevant variables had been omitted [ref: 

5]. In a subsequent report on data from one of the areas participating in this study, the use of 

hospital and population controls was compared. A higher proportion of hospital controls was found to 

have used artificial sweeteners than population controls [ref: 6]. This had been postulated earlier 

[ref: 2] as a possible reason for the negative findings of a hospital-based case-control study [ref: 7]. 

Bias resulting from use of prevalent rather than incident cases [ref: 8] has been suggested as a 

possible reason for the negative findings of another hospital based case-control study [ref: 9]. 

Two other case-control studies have also shown increased risks among subgroups. In one, conducted 

simultaneously in Japan, the UK and the USA, the relative risks among women in the US component 

of the study associated with 'any' use of diet drinks and of sugar substitutes were 1.6 and 1.5, 

respectively, and 2.6 and 2.1, respectively, for nonsmokers [ref: 10]. In the other two areas, 

however, a history of use of sugar substitutes, primarily saccharin, was not associated with an 

elevated bladder cancer risk [ref: 11]. In the other study, conducted in West Yorkshire, UK, although 

elevated risks were found for saccharin takers who were nonsmokers, the risks associated with 

cyclamate use were not examined [ref: 12]. 

Two studies in Denmark [ref: 13,14], one in the USA [ref: 15] and a further case-control study in 

Canada [ref: 16], however, gave negative results. In one of the Danish studies, incidence of bladder 
cancer at ages 20-34 among people born 1941-1945 (when use of saccharin was high in Denmark) 

was compared with that among those born 1931-1940. The risk for men was 1.0 (0.7-1.6) and that 

for women, 0.3 (0.1-1.0) [ref: 13]. The other two studies were population-based case-control 

studies of bladder cancer. In Denmark, the relative risk for people of the two sexes combined was 

0.78 (0.58-1.05) [ref: 14]. In a study in the USA of bladder cancer in women aged 20-49, the odds 

ratio for regular use of artificially sweetened beverages, table-top sweetener or both was 1.1 (0.7-

1.7) [ref: 15]. In Canada, the odds ratio for use of cyclamate was 1.09 (0.60-1.97) in males and 

0.92 (0.63-1.36) in females. In neither study were the increased risks seen in subgroups in other 

studies replicated. 

In the USA, in a study of 1862 patients hospitalized for cancer and of 10 874 control patients, a 

greater proportion of artificial sweetener users was among women found only with cancer of the 

stomach. Little information was available on urinary-tract cancer. No overall association was found 

between artificial sweetener use and cancer [ref: 17]. 

B. Evidence for carcinogenicity to animals (limited) 

Sodium cyclamate was tested for carcinogenicity both alone and in combination with other chemicals 

in different animal species and by several routes of administration. Following its oral administration 

to two strains of mice, an increased incidence of lymphosarcomas was observed in female mice of 

one strain; a few bladder tumours were seen in rats exposed orally. Several other experiments in 

mice, rats, hamsters and monkeys were inadequate for evaluation. A 10:1 mixture of sodium 

cyclamate:sodium saccharin was given to mice in one multigeneration experiment and to rats in two 

single-generation experiments: transitional-cell carcinomas were induced in the bladders of male 

rats of one strain given the highest dose [ref: 1]. In a similar two-generation experiment in rats, no 

treatment-related tumour was observed [ref: 18]. Instillation of low doses of N-methyl-Nnitrosourea into the bladder of rats fed sodium cyclamate for long periods resulted in a dose-related 

induction of transitional-cell neoplasms of the bladder. After subcutaneous injection of rats with 

sodium cyclamate, no tumour was observed at the site of injection, the only site for which tumour 

incidence was reported. A significant increase in the incidence of bladder carcinomas was observed in 

mice given bladder implants of pellets containing sodium cyclamate [ref: 1]. Transplacental 

application of cyclamate to rats did not produce an increase in tumour incidence at any site [ref: 19]. 

Calcium cyclamate did not alter tumour incidence when tested by oral administration in a twogeneration experiment in rats but produced local tumours in another experiment following its 

subcutaneous injection [ref: 1]. 

Cyclohexylamine was tested by oral administration at several dose levels in different strains of mice 

and rats, and in one multigeneration study in mice. No tumour related to treatment was observed 

[ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of calcium cyclamate, dicyclohexylamine or 

cyclohexylamine in humans. In a single study, eight persons ingesting sodium cyclamate (70 mg/kg 

per day) did not exhibit chromosomal aberrations in their lymphocytes [ref: 20]. 

Calcium cyclamate induced chromosomal aberrations in bone-marrow cells of gerbils, but not in bonemarrow cells or spermatogonia of rats treated in vivo. It did not induce dominant lethal mutations in 

rats or mice or micronuclei or sperm abnormalities in mice treated in vivo. It induced chromosomal 

aberrations in human lymphocytes but not in rat kangaroo cells in culture. It did not induce 

aneuploidy in Drosophila, but contradictory results were reported in assays for sex-linked recessive 

lethal mutations and heritable translocations. Calcium cyclamate was not mutagenic to bacteria [ref: 

20]. 

Sodium cyclamate did not induce dominant lethal mutations or chromosomal aberrations in 

spermatogonia or spermatocytes of mice treated in vivo. It induced sister chromatid exchanges and 

chromosomal aberrations in cultured human lymphocytes and chromosomal aberrations in cultured 

Chinese hamster cells. It did not induce aneuploidy or sex-linked recessive lethal mutations in 

Drosophila or chromosomal aberrations in plants [ref: 20]. 
Cyclohexylamine did not induce dominant lethal mutations in one study in rats, but contradictory 

results were obtained in mice. It gave weakly positive results in the mouse spot test. 

Cyclohexylamine induced chromosomal aberrations in lymphocytes but not in bone-marrow cells of 

hamsters and lambs or in spermatogonia of hamsters and mice treated in vivo. In treated rats, 

chromosomal aberrations were induced in spermatogonia but not in leucocytes, and contradictory 

results were obtained for bone-marrow cells. Cyclohexylamine induced sister chromatid exchanges in 

cultured human lymphocytes, but, again, conflicting results were obtained concerning the induction 

of chromosomal aberrations. Cyclohexylamine enhanced virus-induced transformation of Syrian 

hamster embryo cells and induced chromosomal aberrations in cultured rat kangaroo cells. It did not 

induce somatic or sex-linked recessive lethal mutations, aneuploidy or heritable translocations in 

Drosophila and was not mutagenic and did not induce prophage in bacteria. In host-mediated 

assays, it did not induce mutation in bacteria or chromosomal aberrations in human leucocytes [ref: 

20]. 

Dicyclohexylamine induced chromosomal aberrations in cultured human lymphocytes. It was not 

mutagenic to bacteria [ref: 20]. 

Overall evaluation

Cyclamates are not classifiable as to their carcinogenicity to humans (Group 3). 

For definition of the italicized terms, see Preamble Evaluation.

Subsequent evaluation: Vol. 73 (1999)

Also see previous evaluation: Vol. 22 (1980)

References

1. IARC Monographs, 22, 55-109, 171-185, 1980 

2. Howe, G.R., Burch, J.D., Miller, A.B., Cook, G.M., Estève, J., Morrison, B., Gordon, P., Chambers, 

L.W., Fodor, G. & Winsor, G.M. (1980) Tobacco use, occupation, coffee, various nutrients and 

bladder cancer. J. natl Cancer Inst., 64, 701-713 

3. Hoover, R.M. & Strasser, P.H. (1980) Artificial sweeteners and human bladder cancer. Preliminary 

results. Lancet, i, 837-840 

4. Walker, A.M., Dreyer, N.A., Friedlander, E., Loughlin, J., Rothman, K.J. & Kohn, H.I. (1982) An 

independent analysis of the National Cancer Institute study on non-nutritive sweeteners and bladder 

cancer. Am. J. publ. Health, 72, 376-381 

5. Hoover, R. & Hartge, P. (1982) Non-nutritive sweeteners and bladder cancer. Am. J. publ. Health, 

72, 382-383 

6. Silverman, D.T., Hoover, R.N. & Swanson, G.M. (1983) Artificial sweeteners and lower urinary 

tract cancer: hospital vs. population controls. Am. J. Epidemiol., 117, 326-334 

7. Wynder, E.L. & Stellman, S.D. (1980) Artificial sweetener use and bladder cancer: a case-control 

study. Science, 207, 1214-1216 

8. Goldsmith, D.F. (1982) Calculation of potential bias in the odds ratio illustrated by a study of 

saccharin use and bladder cancer. Environ. Res., 27, 298-306 

9. Kessler I.I. & Clark, J.P. (1978) Saccharin, cyclamate, and human bladder cancer. No evidence of 
an association. J. Am. med. Assoc., 240, 349-355 

10. Morrison, A.S. & Buring, J.E. (1980) Artificial sweeteners and cancer of the lower urinary tract. 

New Engl. J. Med., 302, 537-541 

11. Morrison, A.S., Verhoek, W.G., Leck, I., Aoki, K., Ohno, Y. & Obata, K. (1982) Artificial 

sweeteners and bladder cancer in Manchester, UK, and Nagoya, Japan. Br. J. Cancer, 45, 332-336 

12. Cartwright, R.A., Adib, R., Glashan, R. & Gray, B.K. (1981) The epidemiology of bladder cancer 

in West Yorkshire. A preliminary report on non-occupational aetiologies. Carcinogenesis, 2, 343-347 

13. Jensen, O.M. & Kamby, C. (1982) Intra-uterine exposure to saccharine and risk of bladder 

cancer in man. Int. J. Cancer, 29, 507-509 

14. Møller-Jensen, O., Knudsen, J.B., Sørensen, B.L. & Clemmesen, J. (1983) Artificial sweeteners 

and absence of bladder cancer risk in Copenhagen. Int. J. Cancer, 32, 577-582 

15. Piper, J.M., Matanoski, G.M. & Tonascia, J. (1986) Bladder cancer in young women. Am. J. 

Epidemiol., 123, 1033-1042 

16. Risch, H.A., Burch, J.D., Miller, A.B., Hill, G.B., Steele, R. & Howe, G.R. (1987) Dietary factors 

and the incidence of cancer of the urinary bladder. Am. J. Epidemiol. (in press) 

17. Morrison, A.S. (1979) Use of artificial sweeteners by cancer patients. J. natl Cancer Inst., 62, 

1397-1399 

18. Schmähl, D. & Habs, M. (1984) Investigations on the carcinogenicity of the artificial sweeteners 

sodium cyclamate and sodium saccharin in rats in a two-generation experiment. Arzneimittel.-

Forsch., 34, 604-606 

19. Schmähl, D. & Habs, M. (1980) Absence of carcinogenic response to cyclamate and saccharin in 

Sprague-Dawley rats after transplacental application. Arzneimittel.-Forsch., 30, 1905-1906 

20. IARC Monographs, Suppl. 6, 188-195, 240-241, 1987 

Synonyms for Calcium cyclamate

● Calcium cyclohexane sulphamate 

● Calcium cyclohexylsulphamate 

● Cyclamate calcium 

● Cyclohexanesulphamic acid, calcium salt 

● Cyclohexylsulphamic acid, calcium salt 

● Cyclan 

● Cylan 

● Dietil 

● Sucaryl calcium 

Synonyms for Cyclamic acid

● Cyclamate 

● Cyclohexanesulphamic acid 

● Cyclohexylamidosulphuric acid 

● Cyclohexylaminesulphonic acid 

● Cyclohexylsulphamic acid 

● N-Cyclohexylsulphamic acid 

● Hexamic acid 

● Sucaryl 
● Sucaryl acid 

Synonyms for Cyclohexylamine

● Aminocyclohexane 

● Aminohexahydrobenzene 

● CHA 

● Hexahydroaniline 

● Hexahydrobenzenamine 

Synonyms for Sodium cyclamate salt

● Assugrin feinsuss 

● Assugrin vollsuss [also contains saccharin] 

● Asugryn 

● Cyclamate sodium 

● Cyclohexanesulphamic acid, monosodium salt 

● Cyclohexylsulphamate sodium 

● Cyclohexylsulphamic acid, monosodium salt 

● Dulzor-etas 

● Hachi-sugar 

● Izbiosuc 

● Natreen [also contains saccharin] 

● Sodium cyclohexanesulphamate 

● Sodium cyclohexyl amidosulfate 

● Sodium cyclohexylsulphamate 

● Sodium cyclohexylsulphamidate 

● Sodium N-cyclohexylsulphamate 

● Sodium sucaryl 

● Sucaryl sodium 

● Succaril [also contains saccharin] 

● Sucrosa 

● Sucrun 7 

● Suessette 

● Suestamin 

● Sugarin 

● Sugaron 

Last updated: 30 September 1999 
CYCLOPHOSPHAMIDE

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 182) 

Cyclophosphamide

CAS No.: 6055-19-2

Chem. Abstr. Name: 2H-1,3,2-Oxazaphosphorin-2-amine, N,N-bis(2-chloroethyl)-tetrahydro-, 2-

oxide monohydrate 

Cyclophosphamide [anhydrous form]

CAS No.: 50-18-0 

A. Evidence for carcinogenicity to humans (sufficient)

Many cases of cancer have been reported following therapy with cyclophosphamide [ref: 1]. 

Excess frequencies of bladder cancer following therapy with cyclophosphamide for nonmalignant 

diseases have been clearly demonstrated in two epidemiological studies [ref: 1,2]. Three recent 

studies confirmed that cyclophosphamide is also a leukaemogen. Among 602 patients treated 

predominantly with cyclophosphamide for non-Hodgkin's lymphoma in Denmark, nine cases of acute 

nonlymphocytic leukaemia (ANLL) or preleukaemia were observed, compared to 0.12 expected on 

the basis of incidence rates in the general population [ref: 3]. In the USA, three cases of ANLL or 

preleukaemia were observed among 333 women treated only with cyclophosphamide for ovarian 

cancer; 1.2 were expected [ref: 4]. In the German Democratic Republic, a case-control study was 

carried out of leukaemia arising as a second primary malignancy following breast or ovarian cancer. 

Relative risks of 1.5, 3.3 and 7.3 were estimated in association with cumulative doses of < 10 g, 10-

29 g and > 30 g of cyclophosphamide, respectively [ref: 5]. 

Cyclophosphamide is a far less potent leukaemogen than 1,4-butanediol dimethanesulphonate 

(myleran) when used following surgery for lung cancer [ref: 6]. Similarly, melphalan produces a 

much higher incidence of leukaemia than cyclophosphamide when used in the therapy of multiple 

myeloma [ref: 7] and ovarian cancer [ref: 4] 

B. Evidence for carcinogenicity to animals (sufficient)

Cyclophosphamide has been tested for carcinogenicity by oral administration and by intravenous 

and intraperitoneal injection in rats and by subcutaneous and intraperitoneal injection in mice. It 

produced benign and malignant tumours at various sites, including the bladder, in rats after its oral 

or intravenous administration, and benign and malignant tumours at the site of injection and at 

distant sites in mice following its subcutaneous injection. There was some evidence of its 

carcinogenicity to mice and rats following intraperitoneal injection [ref: 1]. A study in which 

cyclophosphamide was given intraperitoneally to rats in combination with methotrexate and 5-

fluorouracil resulted in induction of tumours in the nervous system, haematopoietic and lymphatic 

tissues, the urinary bladder and adrenal glands; however, because of lack of matched controls, it 

could not be concluded whether tumour inducation was due to a combined effect of the three 

chemicals or of any one of them [ref: 8]. 

C. Other relevant data

Cyclophosphamide is metabolized to an alkylating intermediate. Increased incidences of 

chromosomal aberrations and sister chromatid exchanges were observed in peripheral blood 

lymphocytes and, in one study, in bone-marrow cells of patients treated with cyclophosphamide for 

a variety of malignant and nonmalignant diseases [ref: 9]. 
Cyclophosphamide has been tested extensively for genetic effects in a wide variety of tests in vivo

and in vitro, giving consistently positive results. It bound to DNA in kidney, lung and liver of mice 

and induced dominant lethal mutations, chromosomal aberrations, micronuclei, sister chromatid 

exchanges, mutation and DNA damage in rodents treated in vivo. In human cells in vitro, it induced 

chromosomal aberrations, sister chromatid exchanges and DNA damage. In rodent cells in vitro, it 

induced transformation, chromosomal aberrations, sister chromatid exchanges, mutation and 

unscheduled DNA synthesis. In Drosophila, it induced aneuploidy, heritable translocations and 

somatic and sex-linked recessive lethal mutations. In fungi, it induced aneuploidy, mutation, 

recombination, gene conversion and DNA damage. In host-mediated assays, it induced 

chromosomal aberrations and sister chromatid exchanges in human lymphoid cells, mutation and 

sister chromatid exchanges in Chinese hamster cells, gene conversion in yeast, and mutation in 

bacteria. It was active in body-fluid assays of urine from humans and rodents exposed in vivo, and 

in one study using plasma serum rats [ref: 9]. 

Overall evaluation

Cyclophosphamide is carcinogenic to humans (Group 1). 

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 9 (1975); Vol. 26 (1981)

References

1. IARC Monographs, 26, 165-202, 1981 

2. Kinlen, L.J. (1985) Incidence of cancer in rheumatoid arthritis and other disorders after 

immunosuppressive treatment. Am. J. Med., 78 (Suppl. 1A), 44-49 

3. Pedersen-Bjergaard, J., Ersbøll, J., Sørensen, H.M., Keiding, N., Larsen, S.O., Philip, P., Larsen, 

M.S., Schultz, H. & Nissen, N.I. (1985) Risk of acute nonlymphocytic leukemia and preleukemia in 

patients treated with cyclophosphamide for non-Hodgkin's lymphomas. Comparison with results 

obtained in patients treated for Hodgkin's disease and ovarian carcinoma with other alkylating 

agents. Ann. int. Med., 103, 195-200 

4. Greene, M.H., Harris, E.L., Gershenson, D.M., Malkasian, G.D., Jr, Melton, L.J., III, Dembo, A.J., 

Bennett, J.M., Moloney, W.C. & Boice, J.D., Jr (1986) Melphalan may be a more potent leukemogen 

than cyclophosphamide. Ann. int. Med., 105, 360-367 

5. Haas, J.F., Kittelmann, B., Mehnert, W.H., Staneczek, W., Mohner, M., Kaldor, J.M. & Day, N.E. 

(1987) Risk of leukaemia in ovarian tumour and breast cancer patients following treatment by 

cyclophosphamide. Br. J. Cancer, 55, 213-218 

6. Stott, H., Fox, W., Girling, D.J., Stephens, R.J. & Galton, D.A.G. (1977) Acute leukaemia after 

busulphan. Br. med. J., ii, 1513-1517 

7. Cuzick, J., Erskine, S., Edelman, D. & Galton, D.A.G. (1987) A comparison of the incidence of 

myelodysplastic syndrome and acute myeloid leukaemia following melphalan and cyclophosphamide 

treatment for myelomatosis. A report to the Medical Research Council's Working Party on leukaemia 

in adults. Br. J. Cancer, 55, 523-529 

8. Habs, M., Schmahl, D. & Lin, P.Z. (1981) Carcinogenic activity in rats of combined treatment with 

cyclophosphamide, methotrexate and 5-fluorouracil. Int. J. Cancer, 28, 91-96 

9. IARC Monographs, Suppl. 6, 196-205, 1987 
Synonyms

● Asta B 518 

● B 518 

● B 518-Asta 

● 2-[Bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxaza-phosphorine 2-oxide monohydrate 

● 2-[Bis(β-chloroethyl)amino]-1-oxa-3-aza-2-phosphacyclohexan-2-oxide monohydrate 

● 1-Bis(2-chloroethyl)amino-1-oxo-2-aza-5-oxaphosphoridin monohydrate 

● N,N-Bis(2-chloroethyl)-N'-(3-hydroxypropyl)phosphorodiamidic acid intramolecular ester 

monohydrate 

● Bis(2-chloroethyl)phosphamide cyclic propanolamide ester monohydrate 

● Bis(2-chloroethyl)phosphoramide cyclic propanolamide ester monohydrate 

● N,N-Bis(2-chloroethyl)-N',O-propylenephosphoric acid ester diamide monohydrate 

● N,N-Bis(β-chloroethyl)-N',O-propylenephosphoric acid ester diamide monohydrate 

● N,N-Bis(β-chloroethyl)-N',O-trimethylenephosphoric acid ester diamide monohydrate 

● Ciclofosfamide 

● Clafen 

● Claphene 

● CP monohydrate 

● Cyclophosphamid monohydrate 

● 2-[Di(2-chloroethyl)amino]-1-oxa-3-aza-2-phosphacyclohexane 2-oxide monohydrate 

● Cyclophospham 

● Cyclophosphan 

● Cyclophosphane 

● Cytophosphan 

● Cytoxan 

● Endoxan 

● Endoxana 

● Endoxan-ASTA 

● Enduxan 

● Genoxal 

● Mitoxan 

● NSC 26271 

● Procytox 

● Sendoxan 

● Syklofosfamid 

● Zytoxan 

Last updated: 9 February 1998 
DACARBAZINE

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 184) 

CAS No.: 4342-03-4

Chem. Abstr. Name: 1H-Imidazole-4-carboxamide, 5-(3,3-dimethyl-1-triazenyl)- 

A. Evidence for carcinogenicity to humans (inadequate)

No epidemiological study of dacarbazine as a single agent was available to the Working Group. 

Occasional case reports of exposure to dacarbazine, especially in the presence of concurrent therapy 

with other putative carcinogens, such as ionizing radiation, alkylating agents and other potent 

oncotherapeutic drugs, do not constitute evidence of carcinogenesis [ref: 1].

In a large systematic follow-up of patients with Hogdkin's disease treated with an intensive 

chemotherapeutic combination including dacarbazine (plus adriamycin, vinblastine and bleomycin) 

but no alkylating agent, preliminary evidence suggested no excess of acute nonlymphocytic 

leukaemia in the first decade after therapy [ref: 2]. 

B. Evidence for carcinogenicity to animals (sufficient)

Following its oral or intraperitoneal administration to rats, dacarbazine produced tumours at various 

sites, including mammary gland, thymus, spleen and brain, in as little as 18 weeks after initial 

exposure [ref: 1]. After its intraperitoneal administration to rats at the end of pregnancy, 

dacarbazine produced tumours, the majority of which were malignant neurinomas, in offspring [ref: 

3]. Dacarbazine produced tumours at various sites, including lung, haematopoietic tissue and 

uterus, after intraperitoneal administration to mice [ref: 1]. 

C. Other relevant data

Dacarbazine did not induce sister chromatid exchanges in lymphocytes of treated patients in one 

study. It gave weakly positive results for induction of sister chromatid exchanges in Chinese 

hamster cells in vitro and was mutagenic to cultured rodent cells and to bacteria [ref: 4]. 

Overall evaluation

Dacarbazine is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 26 (1981)

References

1. IARC Monographs, 26, 203-212, 1981

2. Valagussa, P., Santoro, A., Bellani, F.F., Franchi, F., Banfi, A. & Bonadonna, G. (1982) Absence of 

treatment-induced second neoplasms after ABVD in Hodgkin's disease. Blood, 59, 488-494

3. Zeller, W.J. (1980) Prenatal carcinogenic action of 5-(3,3-dimethyl-1-triazeno)imidazole-4-

carboxamide (DTIC) in the offspring of BD IX rats (Ger.). Arch. Geschwulstforsch., 50, 306-308
4. IARC Monographs, Suppl. 6, 208-209, 1987 

Synonyms

● Deticene 

● DIC 

● 5-(3,3-Dimethyl-1-triazeno)imidazole-4-carboxamide 

● 5-(3,3-Dimethyltriazeno)imidazole-4-carboxamide 

● 4-(Dimethyltriazeno)imidazole-5-carboxamide 

● 5-(Dimethyltriazeno)imidazole-4-carboxamide 

● Dimethyl(triazeno)imidazolecarboxamide 

● 5-(3,3-Dimethyl-1-triazenyl)-1H-imidazole-4-carboxamide 

● DTIC 

● DTIC-Dome 

● NSC 45388 

Last updated: 2 March 1998 
DAPSONE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 185)

CAS No.: 80-08-0

Chem. Abstr. Name: Benzenamine, 4,4'-sulfonylbisA. Evidence for carcinogenicity to humans (inadequate) 

Cases of cancer have been reported in patients treated with dapsone for dermatitis herpetiformis 

[ref: 1] and leprosy [ref: 2]. Several follow-up studies have been undertaken of patients with 

leprosy, some of whom were treated with dapsone [ref: 1,3-6]. Increased mortality from cancer, 

restricted to males (standardized mortality ratio [SMR], 1.5; 95% confidence interval, 1.1-1.9), has 

been observed only in the most recent of them. The excess was most evident for cancers of the oral 

cavity and bladder and for lymphoma in males (SMRs, 4.5, 4.0 and 3.0, respectively) and for 

dapsone users. Possible confounding effects of tobacco and alcohol intake could not be addressed, 

but there was no substantial increase in mortality from lung cancer [ref: 6]. 

B. Evidence for carcinogenicity to animals (limited) 

Dapsone has been tested by oral administration in mice and rats, by intraperitoneal administration 

in mice and by prenatal and lifetime oral exposure in mice and rats. In three different studies in 

rats, high doses of dapsone induced mesenchymal tumours of the spleen in males (and of the 

peritoneum in two studies). An increased incidence of tumours of the thyroid was found in rats of 

each sex in one study and in males in a further study. The experiment in mice involving 

intraperitoneal administration of dapsone could not be evaluated. The other two experiments in 

mice did not provide evidence of carcinogenicity [ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of dapsone in humans. It was not 

mutagenic to bacteria [ref: 7]. 

Overall evaluation

Dapsone is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 24 (1980)

References

1. IARC Monographs, 24, 59-76, 1980 

2. Troy, J.L., Grossman, M.E. & Walther, R.R. (1980) Squamous-cell carcinoma arising in a leprous 

neurotrophic ulcer. Report of a case. J. Dermatol. Surg. Oncol., 6, 659-661 

3. Oleinick, A. (1968) Survival among leprosy patients with special consideration of cancer as a 

cause of death. Int. J. Lepr., 36, 318-327 
4. Kolonel, L.N. & Hirohata, T. (1977) Leprosy and cancer: a retrospective cohort study in Hawaii. J. 

natl Cancer Inst., 58, 1577-1581 

5. Tokudome, S., Kono, S., Ikeda, M., Kuratsune, M. & Kumamaru, S. (1981) Cancer and other 

causes of death among leprosy patients. J. natl Cancer Inst., 67, 285-289 

6. Brinton, L.A., Hoover, R., Jacobson, R.R. & Fraumeni, J.F., Jr (1984) Cancer mortality among 

patients with Hansen's disease. J. natl Cancer Inst., 72, 109-114 

7. IARC Monographs, Suppl. 6, 210-211, 1987 

Synonyms

● Avlosulfon 

● Avlosulphone 

● Bis(4-aminophenyl)sulfone 

● Bis(p-aminophenyl)sulfone 

● Bis(p-aminophenyl)sulphone 

● Bis-(4-aminophenyl)sulphone 

● Croysulfone 

● Croysulphone 

● DADPS 

● Dapson 

● Dapsonum 

● DDS 

● DDS [pharmaceutical] 

● DDS [VAN] 

● 4,4'-Diaminodiphenyl sulfone 

● 4,4'-Diaminodiphenyl sulphone 

● Di(4-aminophenyl)sulfone 

● Di(4-aminophenyl)sulphone 

● Di(p-aminophenyl)sulfone 

● Di(p-aminophenyl)sulphone 

● Diamino-4,4'-diphenyl sulfone 

● p,p-Diaminodiphenyl sulfone 

● p,p-Diaminodiphenyl sulphone 

● Diamino-4,4'-diphenyl sulphone 

● Diaphenylsulfon 

● Diaphenylsulfone 

● Diaphenylsulphon 

● Diaphenylsulphone 

● Diphenasone 

● Diphone 

● Disulone 

● Dubronax 

● Dumitone 

● Eporal 

● F1358 

● Maloprim 

● Metabolite C 

● Novophone 

● Sulfona 

● Sulfona-Mae 

● Sulfone UCB 

● 1,1'-Sulfonylbis(4-aminobenzene) 

● 4,4'-Sulfonylbisaniline 

● p,p-Sulfonyldianiline 

● p,p-Sulphonyldianiline 

● Sulphadione 

● Sulphon-mere 

● 1,1'-Sulphonylbis(4-aminobenzene) 

● 4,4'-Sulfonylbisbenzamine 
● p,p-Sulphonylbisbenzamine 

● p,p-Sulfonylbisbenzamine 

● p,p-Sulfonylbisbenzenamine 

● 4,4'-Sulfonyldianiline 

● 4,4'-Sulphonylbisbenzamine 

● 4,4'-Sulphonylbisbenzenamine 

● p,p-Sulphonylbisbenzenamine 

● 4,4'-Sulphonyldianiline 

● Sulphonyldianiline 

● Tarimyl 

● Udolac 

Last updated: 9 March 1998 
ortho-DICHLOROBENZENE

(Group 3) 

and para-DICHLOROBENZENE

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p.192) 

ortho-Dichlorobenzene

CAS No.: 95-50-1

Chem. Abstr. Name: Benzene, 1,2-dichloropara-Dichlorobenzene

CAS No.: 106-46-7

Chem. Abstr. name: Benzene, 1,4-dichloroA. Evidence for carcinogenicity to humans (inadequate for ortho- and para-dichlorobenzene)

One report of a series of five cases has suggested an association between leukaemia and exposure 

to dichlorobenzenes [ref: 1]. 

B. Evidence for carcinogenicity to animals (inadequate for ortho-dichlorobenzene; sufficient for 

para-dichlorobenzene)

ortho-Dichlorobenzene was tested in mice and rats by gastric intubation; no evidence of 

carcinogenicity was observed [ref: 2]. A study by inhalation in several species was considered 

inadequate [ref: 1].

para-Dichlorobenzene was tested in mice and rats by gastric intubation; it caused renal tubular-cell 

adenocarcinomas in male rats and hepatocellular carcinomas in male and female mice [ref: 3]. It 

was also tested in mice and rats by inhalation; no increase in the incidence of tumours was noted, 

but the duration of exposure was limited [ref: 4]. 

C. Other relevant data

No data were available on the genetic and related effects of ortho- or para-dichlorobenzene in 

humans. ortho-Dichlorobenzene was not mutagenic to fungi or bacteria. para-Dichlorobenzene was 

mutagenic to fungi but not to bacteria [ref: 5]. 

Overall evaluation

para-Dichlorobenzene is possibly carcinogenic to humans (Group 2B).

ortho-Dichlorobenzene is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Subsequent evaluation: Vol. 73 (1999)

Also see previous evaluations: Vol. 7 (1974); Vol. 29 (1982)

References
1. IARC Monographs, 29, 213-238, 1982

2. National Toxicology Programme (1985) Toxicology and Carcinogenesis Studies of 1,2-

Dichlorobenzene (o-Dichlorobenzene) (CAS No. 95-50-1) in F344/N Rats and B6C3F1 Mice (Gavage 

Studies) (NTP TR 255; NIH Publ. No. 86-2511), Research Triangle Park, NC

3. National Toxicology Program (1987) Toxicology and Carcinogenesis Studies of 1,4-

Dichlorobenzene (CAS No. 106-46-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies) (NTP TR 

No. 319; NIH Publ. No. 86-2575), Research Triangle Park, NC

4. Loeser, E. & Litchfield, M.H. (1983) Review of recent toxicology studies on p-dichlorobenzene. 

Food chem. Toxicol., 21, 825-832

5. IARC Monographs, Suppl. 6, 222-225, 1987 

Synonyms for ortho-Dichlorobenzene

● Chloroben 

● Chloroden 

● Cloroben 

● DCB 

● 1,2-Dichlorobenzene 

● o-Dichlorobenzene 

● Dilatin DB 

● Dizene 

● Dowtherm E 

● ODB 

● ODCB 

● Termitkil 

Synonyms for para-Dichlorobenzene

● para-Chlorophenyl chloride 

● Di-chloricide 

● 1,4-Dichlorobenzene 

● p-Dichlorobenzene 

● Di-cloricide 

● Evola 

● Paracide 

● Paradi 

● Paradow 

● Paramoth 

● Parazene 

● PDB 

● PDCB 

● Persia-perazol 

● Santochlor 

Last updated: 30 September 1999 
3,3'-DICHLOROBENZIDINE

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 193) 

3,3'-Dichlorobenzidine

CAS No.: 91-94-1

Chem. Abstr. Name: (1,1'-Biphenyl)-4,4'-diamine, 3,3'-dichloro3,3'-Dichlorobenzidine Dihydrochloride

CAS No.: 612-83-9

Chem. Abstr. Name: (1,1'-Biphenyl)-4,4'-diamine, 3,3'-dichloro-, dihydrochloride

A. Evidence for carcinogenicity to humans (inadequate)

Three retrospective epidemiological studies of workers exposed to 3,3'-dichlorobenzidine gave no 

evidence of carcinogenicity, but the studies were of insufficient quality or statistical power to permit 

confident exclusion of this possibility. Because 3,3'-dichlorobenzidine and benzidine may be made in 

the same plant, 3,3'-dichlorobenzidine may have contributed to the incidence of bladder cancer 

attributed to benzidine [ref: 1]. 

B. Evidence for carcinogenicity to animals (sufficient)

3,3'-Dichlorobenzidine was tested for carcinogenicity in mice, rats, hamsters and dogs by oral 

administration, in rats by subcutaneous administration and in mice by transplacental exposure. 

Following its oral administration, it produced liver-cell tumours in mice, hepatocellular carcinomas in 

dogs, mammary and Zymbal-gland tumours in rats and carcinomas of the urinary bladder in 

hamsters and dogs. Increased incidences of leukaemias were observed in rats following oral 

administration and in mice following transplacental exposure [ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of 3,3'-dichlorobenzidine in humans. It has 

been reported to induce unscheduled DNA synthesis in cultured human cells. It was mutagenic to 

bacteria [ref: 2]. 

Overall evaluation

3,3'-Dichlorobenzidine is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 4 (1974) ; Vol. 29 (1982) 

References

1. IARC Monographs, 29, 239-256, 1982

2. IARC Monographs, Suppl. 6, 226-227, 1987 

Synonyms for 3,3-Dichlorobenzidine
● DCB 

● 4,4'-Diamino-3,3'-dichlorobiphenyl 

● 4,4'-Diamino-3,3'-dichlorodiphenyl 

● Dichlorobenzidine 

● ortho,ortho'-Dichlorobenzidine 

● Dichlorobenzidine base 

● 3,3'-Dichlorobenzidine base 

● 3,3'-Dichlorobiphenyl-4,4'-diamine 

● 3,3'-Dichloro-4,4'-biphenyldiamine 

● 3,3'-Dichloro-4,4'-diaminobiphenyl 

● 3,3'-Dichloro-4,4'-diamino(1,1-biphenyl) 

● Curithane C126 

Last updated: 2 March 1998 
DIELDRIN

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 196)

CAS No.: 60-57-1 

A. Evidence for carcinogenicity to humans (inadequate) 

Mean tissue levels of dieldrin were reported to be elevated in one necropsy study of 50 cancer 

patients compared to 42 control subjects [ref: 1]. Mean serum levels were not generally found to be 

elevated in cancer patients compared with controls in one study [ref: 2], but not in another [ref: 3]. 

Follow-up for four to 29 years (mean, 24 years) of 233 workers employed for four to 27 years 

(mean, 11 years) in the manufacture of aldrin, dieldrin and endrin revealed nine deaths from cancer 

with 12 expected (standardized mortality ratio [SMR], 75; 95% confidence interval, 25-125) [ref: 

4,5]. In a similar study, 90% of 1155 men employed in the manufacture of aldrin, dieldrin and 

endrin were followed for 13 years or more. Mortality from all cancers was not increased (SMR, 82; 

56-116), although there were apparent increases in mortality from cancers of the oesophagus, 

rectum and liver based on very small numbers [ref: 6]. 

B. Evidence for carcinogenicity to animals (limited) 

Dieldrin has been tested by oral administration in mice, rats, trout, hamsters, dogs and monkeys. In 

mice, it produced benign and malignant liver neoplasms [ref: 1,7-10]; no carcinogenic effect was 

observed in feeding studies using several strains of rats [ref: 1,8,11], trout [ref: 12] and hamsters 

[ref: 13], the latter having been given relatively high doses. Feeding studies in dogs and monkeys 

were inadequate for evaluation [ref: 1]. Dietary administration to trout of dieldrin enhanced the 

incidence of liver tumours induced by dietary administration of aflatoxin B1 [ref: 12]. 

C. Other relevant data

In one study, chromosomal aberrations were not found in peripheral blood lymphocytes of workers 

exposed to dieldrin [ref: 14]. 

Dieldrin did not induce dominant lethal mutations in mice or chromosomal aberrations in bonemarrow cells of Chinese hamsters treated in vivo. It induced unscheduled DNA synthesis in 

transformed human fibroblasts but not in rat hepatocytes; it did not induce single-strand breaks in 

Chinese hamster V79 cells. Dieldrin inhibited intercellular communication in human and rodent cell 

systems. It did not induce sex-linked recessive lethal mutations in Drosophila, was not mutagenic to 

bacteria and did not induce breakage of plasmid DNA [ref: 14]. 

Overall evaluation

Dieldrin is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 5 (1974)

References

1. IARC Monographs, 5, 125-156, 1974 
2. Caldwell, G.G., Cannon, S.B., Pratt, C.B. & Arthur, R.D. (1981) Serum pesticide levels in patients 

with childhood colorectal carcinoma. Cancer, 48, 774-778 

3. Davis, J.E., Barquet, A., Morgade, G. & Raffionelli, A. (1975) Epidemiologic studies of DDT and 

dieldrin residues and their relationship to human carcinogenesis. In: Proceedings of an International 

Symposition on Recent Advances in Assessing Health Effects of Environmental Pollution, Vol. 2 (EUR 

5360), Luxembourg, Commission of the European Communities, pp. 695-702 

4. van Raalte, H.G.S. (1977) Human experience with dieldrin in perspective. Ecotoxicol. environ. 

Saf., 1, 203-210 

5. Ribbens, P.H. (1985) Mortality study of industrial workers exposed to aldrin, dieldrin and endrin. 

Int. Arch. occup. environ. Health, 56, 75-79 

6. Ditraglia, D., Brown, D.P., Namekata, T. & Iverson, N. (1981) Mortality study of workers 

employed at organochlorine pesticide manufacturing plants. Scand. J. Work Environ. Health, 7 

(Suppl. 4), 140-146 

7. Tennekes, H.A., Wright, A.S., Dix, K.M. & Koeman, J.H. (1981) Effects of dieldrin, diet, and 

bedding on enzyme function and tumor incidence in livers of male CF-1 mice. Cancer Res., 41, 3615-

3620 

8. National Cancer Institute (1978) Bioassays of Aldrin and Dieldrin for Possible Carcinogenicity 

(Tech. Rep. Ser. No. 21; DHEW Publ. No. (NIH) 78-821), Bethesda, MD, Carcinogenesis Testing 

Program, Division of Cancer Cause and Prevention 

9. Ruebner, B.H., Gershwin, M.E., Hsieh, L. & Dunn, P. (1980) Ultrastructure of spontaneous 

neoplasms induced by diethylnitrosamine and dieldrin in the C3H mouse. J. environ. Pathol. Toxicol., 

4, 237-254 

10. Meierhenry, E.F., Ruebner, B.H., Gershwin, M.E., Hsieh, L.S. & French, S.W. (1983) Dieldrininduced Mallory bodies in hepatic tumors of mice of different strains. Hepatology, 3, 90-95 

11. National Cancer Institute (1978) Bioassay of Dieldrin for Possible Carcinogenicity (Tech. Rep. 

Ser. No. 22; DHEW Publ. No. (NIH) 78-822), Bethesda, MD, Carcinogenesis Testing Program, 

Division of Cancer Cause and Prevention 

12. Hendricks, J.D., Putnam, T.P. & Sinnhuber, R.O. (1979) Effect of dietary dieldrin on aflatoxin B1

carcinogenesis in rainbow trout (Salmo gairdneri). J. environ. Pathol. Toxicol., 2, 719-728 

13. Cabral, J.R.P., Hall, R.K., Bronczyk, S.A. & Shubik, P. (1979) A carcinogenicity study of the 

pesticide dieldrin in hamsters. Cancer Lett., 6, 241-246 

14. IARC Monographs, Suppl. 6, 242-244, 1987 

Synonyms

● ENT 16,225 

● HEOD 

● 1,2,3,4,10,10-Hexachloro-6,7-epoxy-1,4,4a,5,6,7,8,8a-octahydro-1,4,5,8-dimethanonaphthalene(endo-exo isomer) 

● 1,2,3,4,10,10-Hexachloro-6,7-epoxy-1,4,4a,5,6,7,8,8a-octahydro-endo-exo-1,4:5,8-

dimethanonaphthalene 

● 1,2,3,4,10,10-Hexachloro-6,7-epoxy-1,4,4a,5,6,7,8,8a-octahydro-endo-1,4-exo-5,8-

dimethano-
naphthalene 

● 1,2,3,4,10,10-Hexachloro-6,7-epoxy-1,4,4a,5,6,7,8,8a-octahydro-1,4-endo-exo-5,8-

dimethanonaphthalene 

● 1,2,3,4,10,10-Hexachloro-6,7-epoxy-1,4,4a,5,6,7,8,8a-octahydro-1,4-endo,exo-5,8-

dimethanonaphthalene 

● 1,2,3,4,10,10-Hexachloro-6,7-epoxy-1,4,4a,5,6,7,8,8a-octahydro-exo-1,4-endo-5,8-

dimethanonaphthalene 

● 1,2,3,4,10,10-Hexachloro-6,7-epoxy-1,4,4a,5,6,7,8,8a-octahydro-1,4-exo-5,8-endodimethanonaphthalene 

Last updated: 9 March 1998 
DIETHYLSTILBOESTROL

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 273)

Diethylstilboestrol

CAS No.: 56-53-1

Chem. Abstr. Name: (E)-4,4'-(1,2-Diethyl-1,2-ethenediyl)bisphenol

Diethylstilboestrol dipropionate

CAS No.:130-80-3

Chem. Abstr. Name: (E)-4,4'-(1,2-Diethyl-1,2-ethenediyl)bisphenol dipropionate

A. Evidence for carcinogenicity to humans (sufficient)

Diethylstilboestrol (DES) causes clear-cell adenocarcinoma of the vagina and cervix in women 

exposed in utero. There is sufficient evidence that administration of oestrogens for the control of 

symptoms of the climacteric is causally related to an increased incidence of endometrial carcinoma; 

DES is no different from other oestrogens in this respect [ref: 1]. 

There is also clear evidence that administration of DES in large doses during pregnancy increases 

the subsequent risk of breast cancer and that DES increases the risk of testicular cancer in males 

exposed in utero. 

In four follow-up studies [ref: 2-5] of exposed and nonexposed groups of women, the possible 

effects of DES exposure during pregnancy on subsequent breast cancer risk have been evaluated. All 

have shown an increased risk in exposed women; two were randomized trials [ref: 2,3]. In one [ref: 

2], there were 32 (4.6%) breast cancers among 693 women exposed to an average total dose of 12 

g DES, and 21 (3.1%) breast cancers among 668 control (placebo) women. In the other [ref: 3], 

there were four (5.0%) breast cancers among 80 women exposed to an average total dose DES of 

16 g (plus ethisterone, average total dose, 14 g), compared to none of 76 controls; all 156 women 

were diabetic. In two studies, an exposed group and a 'matched' unexposed group were followed-up 

[ref: 4,5]. One [ref: 4] found 118 (4.4%) breast cancer cases in 2680 women exposed to a mean 

DES dose of 5 g, and 80 (3.1%) among 2566 control women. The other [ref: 5] similarly showed 38 

(2.5%) breast cancer cases among 1531 women exposed to a mean DES dose of 2 g, and 24 (1.7%) 

cases among the 1404 control women. The overall relative risk from these four studies is 1.5 (p = 

0.001). 

A further group of 408 DES-exposed women (median dose, 1.5 g) was followed up and the eight 

breast cancer cases found were contrasted to the 8.1 cases expected on the basis of local breast 

cancer incidence rates [ref: 6]. If this study is considered together with the four studies described 

above, the overall relative risk is 1.4 (p = 0.0016). 

In all five papers [ref: 2-6], the possibility is discussed that there may be a long (15-20 years) 

'latent' period before the first 'DES-induced' breast cancer would be seen. Clear evidence was found 

in a study [ref: 4] in which there was no difference in the breast cancer rates of exposed and 

unexposed women until 22 years after exposure, but an increasing difference thereafter. Similarly, 

in another study [ref: 3], there was no case in the exposed group in the first 18 years after 

exposure. In a further study [ref: 5], the relative risk was 1.3 before age 50 and 1.7 thereafter, and 

in another [ref: 6], three cases were reported with 5.1 expected before age 50 and five cases versus

3.0 expected thereafter. In contrast, however, a randomized study [ref: 2] showed 11 exposed 

cases and five nonexposed cases during the first 15 years of follow-up, compared to 21 exposed 

cases and 16 nonexposed cases thereafter. Further data are required to settle this issue. 

The four follow-up studies [ref: 2-5] of exposed and nonexposed women also included information 

on other possibly 'hormone-related' cancers. The occurrence of endometrial cancer was not 
increased in any study. The study [ref: 2] of 693 women exposed to DES and 668 controls showed 

increases in the occurrence of cancer of the ovary (4 exposed, 1 nonexposed), cancer of the cervix 

(7 exposed, 3 non-exposed) and cancer of the colon-rectum (2 exposed, 1 nonexposed); there was 

also a risk for cancer at these sites in the study of 1531 women exposed to DES and 1404 controls 

[ref: 5] (6 exposed, 2 nonexposed; 9 exposed, 6 nonexposed; 11 exposed, 7 nonexposed for the 

three sites, respectively). A third study [ref: 4] showed, in contrast, no elevation of rates for cancer 

at any other site, and there were seven deaths from cervical cancer in the control group and none in 

the exposed group, suggesting that matching in the control group was 'inadequate'; the authors 

could not identify the matching problem, and, in particular, they found that the two groups were well 

matched on educational level. The data are too few to draw any firm conclusions. 

A greater frequency of abnormalities of the reproductive tract has been found in males exposed 

prenatally to DES in comparison with nonexposed controls, although the data are few. 

Cryptorchidism, a major risk factor for testicular cancer, is one of the associated lesions [ref: 1]. 

Cancer of the testis has been investigated in five case-control studies of fetal exposure to DES [ref: 

7-11]. One [ref: 7] showed that 5.1% (4/78) of cases and 1% of controls had been exposed to 

hormones (in all likelihood DES) for bleeding; the second [ref: 8] similarly found that 5.8% (11/190) 

versus 2.3% (7/304) had had such exposure; the third [ref: 9] found 1.9% (2/108) versus 0 

(0/108) exposed to DES; the fourth [ref: 10] found 1.0% (2/202) versus 1.0% (2/206) exposed to 

DES; and the fifth [ref: 11] found 1.9% (4/211) versus 0.9% (2/214) exposed to DES. The 

combined relative risk is 2.5 (p = 0.014). 

A number of unusual tumours have been reported in women exposed to DES in utero: a fatal 

adenocarcinoma of the endometrium at age 26 [ref: 12]; a pituitary adenoma at age 18 [ref: 13]; 

an invasive squamous-cell carcinoma of the cervix at age 21 [ref: 14]; an invasive adenosquamouscell carcinoma of the cervix at age 27 [ref: 15]; and an ovarian teratoma at age 12 [ref: 16]. 

There has been no further report to add to the six cases of primary breast cancer in males with 

prostatic cancer treated with DES [ref: 1]. A case has been reported of a Leydig-cell tumour 

developing in such a man treated with DES at 1 mg per day for 2.5 years [ref 17]. There has been a 

second case report of hepatic angiosarcoma in a man treated over a long period with DES for 

prostatic cancer [ref: 1,18], and a second case report of a hepatoma in a prostatic cancer patient 

treated with DES at 3 mg per day for 4.5 years (to diagnosis of hepatoma) [ref: 1,19]. Three renal 

carcinomas have been reported after exposure to DES for prostatic cancer [ref: 20,21]. 

B. Evidence for carcinogenicity to animals (sufficient)

DES has been tested in mice, rats, hamsters, frogs and squirrel monkeys, producing tumours 

principally in oestrogen-responsive tissues [ref: 1]. Female newborn mice injected with DES 

developed epidermoid carcinomas and granular-cell myoblastomas of the cervix and squamous 

carcinomas of the vagina [ref: 22]. Mice treated prenatally with DES developed adenocarcinomas of 

the uterus, cervix and vagina, epidermoid carcinomas of the uterine cervix and vagina and ovarian 

and mammary tumours [ref: 23-28]. Female mice fed diets containing DES developed cervical and 

endometrial adenocarcinomas, mammary adenocarcinomas, osteosarcomas and mesotheliomas [ref: 

29-33]. Mice treated subcutaneously with DES had a slightly increased incidence of lymphomas and 

subcutaneous fibrosarcomas [ref: 34,35]. Prenatal exposure to DES potentiated mammary 

tumorigenesis in rats given 7,12-dimethylbenz[a]anthracene at about 50 days of age [ref: 36]. Rats 

given DES by subcutaneous pellet developed mammary and pituitary tumours. When these animals 

wee also treated with X-rays or neutrons, they developed a higher incidence of mammary tumours 

[ref: 37-39]. In other studies (subcutaneous, transplacental, oral), rats treated with DES developed 

mammary, hepatic and pituitary tumours [ref: 40-44]. When hamsters were treated prenatally with 

DES, females developed endometrial adenocarcinoma, squamous-cell papillomas of the cervix and 

vagina, and a mixed Mullerian tumour of the cervix (myosarcoma); in males, a leiomysarcoma of the 

seminal vesicles and a Cowper's gland adenoma were found [ref: 45]. Male hamsters castrated as 

adults and given DES subcutaneously developed renal tumours [ref: 46,47]. 

C. Other relevant data

No data were available on the genetic and related effects of DES in humans. 

DES induced chromosomal aberrations in bone-marrow cells of mice treated in vivo, but data on 
induction of sister chromatid exchanges and micronuclei were equivocal; it induced sister chromatid 

exchanges in one study in rats. Unusual nucleotides were found in kidney DNA following chronic 

treatment of hamsters with DES. Aneuploidy was induced in human cells in vitro, but data on 

induction of sister chromatid exchanges. chromosomal aberrations and mutation were inconclusive; 

it induced DNA strand breaks, but not unscheduled DNA synthesis, except in a single study. Tests for 

transformation in rat and Syrian hamster embryo cells gave positive results, while results for mouse 

cells were negative. Aneuploidy and DNA strand breaks were induced in rodent cells in vitro, but 

results for chromosomal aberrations and sister chromatid exchanges were equivocal; DES did not 

induce mutation or unscheduled DNA synthesis, except in a single study in Syrian hamster embryo 

cells. It did not inhibit intercellular communication of Chinese hamster V79 cells. It induced 

aneuploidy in fungi, but, in most studies, it did not induce mutation, recombination or gene 

conversion. It did not induce mutation in a variety of bacterial and insect systems, but it was 

mutagenic in plants. DNA damage was not induced in fungi or bacteria. DES induced single-strand 

breaks in bacteriophage DNA in the presence of a horseradish peroxidase activation system [ref: 

48]. 

Overall evaluation

Diethylstilboestrol is carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 6 (1974); Vol. 21 (1979)

References

1. IARC Monographs, 21, 131-134, 173-231, 1979 

2. Bibbo, M., Haenszel, W.M., Wied, G.L., Hubby, M. & Herbst, A.L. (1978) A twenty-five-year followup of women exposed to diethylstilbestrol during pregnancy. New Engl. J. Med., 298, 763-767 

3. Beral, V. & Colwell, L. (1980) Randomised trial of high doses of stilboestrol and ethisterone in 

pregnancy: Long-term follow-up of mothers. Br. med. J., 281, 1098-1101 

4. Greenberg, E.R., Barnes, A.B., Resseguie, L., Barrett, J.A., Burnside, S., Lanza, L.L., Neff, R.K., 

Stevens, M., Young, R.H. & Colton, T. (1984) Breast cancer in mothers given diethylstilbestrol in 

pregnancy. New Engl. J. Med., 311, 1393-1398 

5. Hadjimichael, O.C., Meigs, J.W., Falcier, F.W., Thompson, W.D. & Flannery, J.T. (1984) Cancer 

risk among women exposed to exogenous estrogens during pregnancy. J. natl Cancer Inst., 73, 831-

834 

6. Brian, D.D., Tilley, B.C., Labarthe, D.R., O'Fallon, W.M., Noller, K.L. & Kurland, L.T. (1980) Breast 

cancer in DES-exposed mothers. Absence of association. Mayo Clin. Proc., 55, 89-93 

7. Henderson, B.E., Benton, B., Jing, J., Yu, M.C. & Pike, M.C. (1979) Risk factors for cancer of the 

testis in young men. Int. J. Cancer, 23, 598-602 

8. Schottenfeld, D., Warshauer, M.E., Sherlock, S., Zauber, A.G., Leder, M. & Payne, R. (1980) The 

epidemiology of testicular cancer in young adults. Am. J. Epidemiol., 112, 232-246 

9. Depue, R.H., Pike, M.C. & Henderson, B.E. (1983) Estrogen exposure during gestation and risk of 

testicular cancer. J. natl Cancer Inst., 71, 1151-1155 

10. Brown, L.M., Pottern, L.M. & Hoover, R.N. (1986) Prenatal and perinatal risk factors for testicular 

cancer. Cancer Res., 46, 4812-4816 
11. Moss, A.R., Osmond, D., Bacchetti, P., Torti, F.M. & Gurgin, V. (1986) Hormonal risk factors in 

testicular cancer. A case-control study. Am. J. Epidemiol., 124, 39-52 

12. Barter, J.F., Austin, J.M., Jr & Shingleton, H.M. (1986) Endometrial adenocarcinoma after in 

utero diethylstilbestrol exposure. Obstet. Gynecol., 67 (Suppl.), 84S-85S 

13. Cunningham, J.R., Gidwani, G.P., Gupta, M.S., Duchesneau, P.M. & Schumacher, O.P. (1982) 

Prolactin-secreting pituitary adenoma: occurrence following prenatal exposure to diethylstilbestrol. 

Cleveland Clin. Q., 49, 249-254 

14. Lamb, E.J. (1977) Invasive squamous cell carcinoma of the cervix in a diethylstilbestrol-exposed 

offspring. Am. J. Obstet. Gynecol., 129, 924-925 

15. Vandrie, D.M., Puri, S., Upton, R.T. & Demeester, L.J. (1983) Adenosquamous carcinoma of the 

cervix in a woman exposed to diethylstilbestrol in utero. Obstet. Gynecol., 61 (Suppl.), 84S-87S 

16. Lazarus, K.H. (1984) Maternal diethylstilboestrol and ovarian malignancy in offspring. Lancet, i, 

53 

17. Deshmukh, A.S. & Hartung, W.H. (1983) Leydig cell tumor in patient on estrogen therapy. 

Urology, 21, 538-539 

18. Ham, J.M., Pirola, R.C. & Crouch, R.L. (1980) Hemangioendothelial sarcoma of the liver 

associated with long-term estrogen therapy in a man. Dig. Dis. Sci., 25, 879-883 

19. Brooks, J.J. (1982) Hepatoma associated with diethylstilbestrol therapy for prostatic carcinoma. 

J. Urol., 128, 1044-1045 

20. Bellet, R.E. & Squitieri, A.P. (1974) Estrogen-induced hypernephroma. J. Urol., 112, 160-161 

21. Nissenkorn, I., Servadio, C. & Avidor, I. (1979) Oestrogen-induced renal carcinoma. Br. J. Urol., 

51, 6-9 

22. Dunn, T.B. (1979) Cancer and other lesions in mice receiving estrogens. Recent Results Cancer 

Res., 66, 175-192 

23. McLachlan, J.A. (1979) Transplacental effects of diethylstilbestrol in mice. Natl Cancer Inst. 

Monogr., 51, 67-72 

24. McLachlan, J.A., Newbold, R.R. & Bullock, B.C. (1980) Long-term effects on the female mouse 

genital tract associated with prenatal exposure to diethylstilbestrol. Cancer Res., 40, 3988-3999 

25. Lamb, J.C., IV, Newbold, R.R. & McLachlan, J.A. (1981) Visualization by light and scanning 

electron microscopy of reproductive tract lesions in female mice treated transplacentally with 

diethylstilbestrol. Cancer Res., 41, 4057-4062 

26. Newbold, R.R. & MacLachlan, J.A. (1982) Vaginal adenosis and adenocarcinoma in mice exposed 

prenatally or neonatally to diethylstilbestrol. Cancer Res., 42, 2003-2011 

27. Walker, B.E. (1983) Uterine tumors in old female mice exposed prenatally to diethylstilbestrol. J. 

natl Cancer Inst., 70, 477-484 

28. Nagasawa, H., Mori, T. & Nakajima, Y. (1980) Long-term effects of progesterone or 

diethylstilbestrol with or without estrogen after maturity on mammary tumorigenesis in mice. Eur. J. 

Cancer, 16, 1583-1589 
29. Highman, B., Greenman, D.L., Norvell, M.J., Farmer, J. & Shellenberger, T.E. (1980) Neoplastic 

and preneoplastic lesions induced in female C3H mice by diets containing diethylstilbestrol or 17βestradiol. J. environ. Pathol. Toxicol., 4, 81-95 

30. Highman, B., Roth, S.I. & Greenman, D.L. (1981) Osseous changes and oesteosarcomas in mice 

continuously fed diets containing diethylstilbestrol or 17β-estradiol. J. natl Cancer Inst., 67, 653-662 

31. Greenman, D.L., Highman, B., Kodell, R.L., Morgan, K.T. & and Norvell, M. (1984) Neoplastic 

and nonneoplastic responses to chronic feeding of diethylstilbestrol in C3H mice. J. Toxicol. environ. 

Health, 14, 551-567 

32. Greenman, D.L., Kodell, R.L., Highman, B., Schieferstein, G.J. & Norvell, M. (1984) Influence of 

strain and age on the induction of mammary tumours by diethylstilboestrol in C3H mice. Food chem. 

Toxicol., 22, 871-874 

33. Greenman, D.L., Highman, B., Chen, J.J., Schieferstein, G.J. & Norvell, M.J. (1986) Influence of 

age on induction of mammary tumors by diethylstilbestrol in C3H/HeN mice with low murine 

mammary tumor virus titer. J. natl Cancer Inst., 77, 891-898 

34. Boján, F., Rédai, I. & Gomba, S. (1979) Induction of lymphomas by urethane in combination 

with diethylstilboestrol in CFLP mice. Experientia, 35, 378-379 

35. Ways, S. (1982) Local induction of fibrosarcomas by diethylstilbestrol. Int. Res. Commun. 

System med. Sci., 10, 796-797 

36. Boylan, E.S. & Calhoon, R.E. (1979) Mammary tumorigenesis in the rat following prenatal 

exposure to diethylstilbestrol and postnatal treatment with 7,12-dimethylbenz(a)anthracene. J. 

Toxicol. environ. Health, 5, 1059-1071 

37. Holtzman, S., Stone, J.P. & Shellabarger, C.J. (1979) Synergism of diethylstilbestrol and 

radiation in mammary carcinogenesis in female F344 rats. J. natl Cancer Inst., 63, 1071-1074 

38. Holtzman, S., Stone, J.P. & Shellabarger, C.J. (1981) Synergism of estrogens and X-rays in 

mammary carcinogenesis in female ACI rats. J. natl Cancer Inst., 67, 455-459 

39. Shellabarger, C.J., Chmelevsky, D., Kellerer, A.M., Stone, J.P. & Holtzman, S. (1982) Induction 

of mammary neoplasms in the ACI rat by 430-keV neutrons, X-rays, and diethylstilbestrol. J. natl 

Cancer Inst., 69, 1135-1146 

40. Sumi, C., Yokoro, K. & Matsushima, R. (1983) Induction of hepatic tumors by diethylstilbestrol 

alone or in synergism with N-nitrosobutylurea in castrated male WF rats. J. natl Cancer Inst., 70, 

937-942 

41. Phelps, C. & Hymer, W.C. (1983) Characterization of estrogen-induced adenohypophyseal 

tumors in the Fischer 344 rat. Neuroendocrinology, 37, 23-31 

42. Rothschild, T.C., Calhoon, R.E. & Boylan, E.S. (1985) Transplacental carcinogenicity of 

diethylstilbestrol (DES) in female ACI rats (Abstract No. 770). Proc. Am. Assoc. Cancer Res., 26, 195 

43. Inoh, A., Kamiya, K., Fujii, Y. & Yokoro, K. (1985) Protective effects of progesterone and 

tamoxifen in estrogen-induced mammary carcinogenesis in ovariectomized W/FU rats. Jpn. J. Cancer 

Res. (Gann), 76, 699-704 

44. Wanless, I.R. & Medline, A. (1982) Role of estrogens as promoters of hepatic neoplasia. Lab. 

Invest., 46, 313-320 
45. Rustia, M. (1979) Role of hormone imbalance in transplacental carcinogenesis induced in Syrian 

golden hamsters by sex hormones. Natl Cancer Inst. Monogr., 51, 77-87 

46. Li, J.J., Li, S.A., Klicka, J.K., Parsons, J.A. & Lam, L.K.T. (1983) Relative carcinogenic activity of 

various synthetic and natural estrogens in the Syrian hamster kidney. Cancer Res., 43, 5200-5204 

47. Li, J.J. & Li, S.A. (1984) Estrogen-induced tumorigenesis in hamsters: roles for hormonal and 

carcinogenic activities. Arch. Toxicol., 55, 110-118 

48. IARC Monographs, Suppl. 6, 250-256, 1987 

Synonyms for Diethylstilboestrol

● Acnestrol 

● Antigestil 

● Bio-des 

● 3,4-Bis(para-hydroxyphenyl)-3-hexene 

● Bufon 

● Comestrol 

● Cyren 

● Cyren A 

● Dawe's destrol 

● DEB 

● DES 

● Desma 

● Destrol 

● DiBestrol '2' Premix 

● Dicorvin 

● DiEstryl 

● α,α'-Diethylstilbenediol 

● (E)-α,α'-Diethyl-4,4'-stilbenediol 

● trans-α,α'-Diethyl-4,4'-stilbenediol 

● trans-Diethylstilbesterol 

● Diethylstilbestrol 

● trans-Diethylstilbestrol 

● trans-Diethylstilboestrol 

● 4,4'-Dihydroxydiethylstilbene 

● 4,4'-Dihydroxy-α,β-diethylstilbene 

● Distilbene 

● Domestrol 

● Estilbin 'MCO' 

● Estrobene 

● Estromenin 

● Estrosyn 

● [Follidiene] 

● Fonatol 

● Grafestrol 

● Gynopharm 

● Hi-Bestrol 

● Idroestril 

● Iscovesco 

● Menostilbeen 

● Microest 

● Milestrol 

● Neo-Oestranol I 

● Oekolp 

● Oestrogenine 

● Oestrol Vetag 

● Oestromenin 

● Oestromensyl 

● Oestromon 
● Pabestrol 

● Palestrol 

● Percutatrine oestrogenique Iscovesco 

● Rumestrol 1 

● Rumestrol 2 

● Sedestran 

● Serral 

● Sexocretin 

● Sibol 

● Sintestrol 

● Stibilium 

● Stilbestrol 

● Stilbetin 

● Stilboefral 

● Stilboestrol 

● Stilboestroform 

● Stilbofollin 

● Stilbol 

● Stilkap 

● Stil-Rol 

● Synestrin 

● Synthoestrin 

● Synthofolin 

● Syntofolin 

● Tampovagan stilboestrol 

● Tylosterone 

● Vagestrol 

Synonyms for Diethylstilboestrol dipropionate

● Clinestrol 

● Cyren B 

● Dibestil 

● α,α,'-Diethyl-4,4'-stilbenediol dipropionate 

● (E)-α,α'-Diethyl-4,4'-stilbenediol dipropionate 

● α,α'-Diethyl-4,4'-stilbenediol trans-dipropionate 

● α,α'-Diethyl-4,4'-stilbenediol dipropionyl ester 

● Diethylstilbene dipropionate 

● Diethylstilbesterol dipropionate 

● Diethylstilbestrol dipropionate 

● Diethylstilbestrol propionate 

● Diethylstilboestrol dipropionate 

● Diethylstilboestrol propionate 

● Dihydroxydiethylstilbene dipropionate 

● para,para'-Dipropionoxy-trans-α,β-diethylstilbene 

● Estilben 

● Estilbin 

● Estrobene DF 

● Estrobene DP 

● Estrogenin 

● Estrostilben 

● Euvestin 

● Gynolett 

● Horfemine 

● Neo-Oestranol II 

● Neo-Oestronol II 

● New-Oestranol 11 

● Oestrogynaedron 

● Orestol 

● Pabestrol D 

● Sinciclan 

● Stilbestrol dipropionate 

● Stilbestrol propionate 

● Stilbestronate 
● Stilboestrol dipropionate 

● Stilboestrol DP 

● Stilbofax 

● Stilronate 

● Synoestron 

● Syntestrin 

● Syntestrine 

● Willestrol 

Last updated: 9 February 1998 
3,3'-DIMETHOXYBENZIDINE

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 198) 

CAS No.: 119-90-4

A. Evidence for carcinogenicity to humans (inadequate)

3,3'-Dimethoxybenzidine (together with 3,3'-dichlorobenzidine and ortho-toluidine) has been 

prepared in the same plants as benzidine and may therefore have contributed to the bladder cancer 

risk associated with benzidine [ref: 1]. No case is on record in the USSR of an occupational urinary 

bladder neoplasm produced solely by this compound [ref: 2]. 

B. Evidence for carcinogenicity to animals (sufficient)

Following its oral administration, 3,3'-dimethoxybenzidine produced tumours in rats at various sites, 

including the bladder, intestine, skin and Zymbal gland; it produced forestomach papillomas in 

hamsters [ref: 3]. 

C. Other relevant data

3,3'-Dimethoxybenzidine has been found in the urine of workers exposed to it [ref: 3].

No data were available on the genetic and related effects of 3,3'-dimethoxybenzidine in humans. It 

induced sister chromatid exchanges in Chinese hamster cells in vitro and unscheduled DNA 

synthesis in human cells and rat hepatocytes in vitro. It was mutagenic to bacteria [ref: 4]. 

Overall evaluation

3,3'-Dimethoxybenzidine is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 4 (1974)

References

1. Clayson, D.B. (1976) Occupational bladder cancer. Prev. Med., 5, 228-244

2. Genin, V.A. (1974) Hygienic assessment of dianisidine-sulphate production from standpoint of 

carcinogenous hazard for workers (Russ.). Gig. Tr. prof. Zabol., 6, 18-22

3. IARC Monographs, 4, 41-47, 1974

4. IARC Monographs, Suppl. 6, 262-263, 1987 

Synonyms

● Bianisidine 
● 4,4'-Diamino-3,3'-dimethoxybiphenyl 

● Di-para-amino-di-meta-methoxydiphenyl 

● Dianisidine 

● ortho-Dianisidine 

● 3,3'-Dimethoxy-4,4'-diaminobiphenyl 

Last updated: 2 March 1998 
ERIONITE

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 203) 

CAS No.: 66733-21-9

A. Evidence for carcinogenicity to humans (sufficient)

Descriptive studies have demonstrated very high mortality from malignant mesothelioma, mainly of 

the pleura, in three Turkish villages where there was contamination from erionite and where 

exposure had occurred from birth [ref: 1]. 

B. Evidence for carcinogenicity to animals (sufficient)

Erionite has been tested in mice by intraperitoneal injection and in rats by inhalation, intrapleural 

and intraperitoneal administration, producing high incidences of mesotheliomas [ref: 1,2]. 

C. Other relevant data

Erionite fibres were identified in lung tissue samples in cases of pleural mesothelioma; ferruginous 

bodies were found in a much higher proportion of inhabitants in contaminated villages in Turkey 

than in those of two control villages [ref: 1]. 

No data were available on the genetic and related effects of erionite in humans. It induced 

unscheduled DNA synthesis in human cells in vitro and transformation and unscheduled DNA 

synthesis in mouse C3H 10T1/2 cells [ref: 3]. 

Overall evaluation

Erionite is carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 42 (1987)

References

1. IARC Monographs, 42, 225-239 1987 

2. Pott, F. (1987) The fibre as a carcinogenic agent (Ger.). Zbl. Bakt. Hyg. B, 184, 1-23 

3. IARC Monographs, Suppl. 6, 291-292, 1987 

Last updated: 9 February 1998 
ETHYLENE THIOUREA

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 207) 

CAS No.: 96-45-7 

A. Evidence for carcinogenicity to humans (inadequate)

In one incidence study, 1929 workers were identified as having worked at some time with ethylene 

thiourea in one of several rubber manufacturing companies and in one firm producing ethylene 

thiourea. No case of thyroid cancer was reported in this group to the regional cancer registry 

between 1957 and 1971, although less than one case would have been expected [ref: 1]. 

B. Evidence for carcinogenicity to animals (sufficient)

In three studies, ethylene thiourea produced high incidences of follicular carcinomas of the thyroid 

in rats after its oral administration; animals of each sex were affected, although male rats had a 

higher incidence. Lower doses produced thyroid follicular hyperplasia [ref: 2-6]. In mice, oral 

administration of ethylene thiourea produced liver tumours; the thyroids of these animals were not 

examined [ref: 2]. In dosed rats, either shortened survival due to thyroid tumours or altered body 

weights may have obscured a potential carcinogenic effect on the liver due to administration of 

ethylene thiourea. A feeding study in hamsters showed no effect [ref: 6]. 

C. Other relevant data

No data were available on the genetic and related effects of ethylene thiourea in humans.

Ethylene thiourea did not induce dominant lethal mutations, micronuclei or sister chromatid 

exchanges in mice or chromosomal aberrations in rats treated in vivo. It did not induce unscheduled 

DNA synthesis in human fibroblasts in vitro or chromosomal aberrations, sister chromatid 

exchanges, mutation or unscheduled DNA synthesis in rodent cells in vitro. Ethylene thiourea did 

not induce sex-linked recessive lethal mutations in Drosophila, but it induced aneuploidy and 

mutation in yeast. Studies on gene conversion and DNA damage in yeast and on mutation in 

bacteria have given conflicting results [ref: 7]. 

Overall evaluation

Ethylene thiourea is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Subsequent evaluation: Vol. 79 (2001)

Also see previous evaluation: Vol. 7 (1974)

References

1. Smith, D. (1976) Ethylene thiourea - a study of possible teratogenicity and thyroid 

carcinogenicity. J. Soc. occup. Med., 26, 92-94
2. IARC Monographs, 7, 45-52, 1974

3. Graham, S.L., Hansen, W.H., Davis, K.J. & Perry, C.H. (1973) Effects of one-year administration 

of ethylenethiourea upon the thyroid of the rat. J. agric. Food Chem., 21, 324-329

4. Graham, S.L., Davis, K.J., Hansen, W.H. & Graham, C.H. (1975) Effects of prolonged ethylene 

thiourea ingestion on the thyroid of the rat. Food Cosmet. Toxicol., 13, 493-499

5. Weisburger, E.K., Ulland, B.M., Nam, J.-M., Gart, J.J. & Weisburger, J.H. (1981) Carcinogenicity 

tests of certain environmental and industrial chemicals. J. natl Cancer Inst., 67, 75-88

6. Gak, J.-C., Graillot, C. & Truhaut, R. (1976) Difference in sensitivity of the hamster and of the rat 

with regard to the effects of the long-term administration of ethylene thiourea (Fr.). Eur. J. Toxicol., 

9, 303-312

7. IARC Monographs, Suppl. 6, 304-307, 1987 

Synonyms

● 4,5-Dihydroimidazole-2(3H)-thione 

● N,N'-Ethylenethiourea 

● 1,3-Ethylene-2-thiourea 

● ETU 

● 2-Imidazolidinethione 

● 2-Imidazoline-2-thiol 

● 2-Mercaptoimidazoline 

● NA-22 

● NA-22-D 

● Pennac CRA 

● Sodium-22 neoprene accelerator 

● 2-Thiol-dihydroglyoxaline 

● Warecure C 

Last updated: 2 March 1998 
FLUORIDES (INORGANIC, USED IN DRINKING-WATER) 

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 208) 

Sodium fluoride

CAS No.: 7681-49-4 

Fluosilicic acid

CAS No.: 16961-83-4

Chem. Abstr. Name: Silicate (2-), hexafluoro-, dihydrogen 

Sodium silicofluoride

CAS No.: 16893-85-9

Chem. Abstr. Name: Silicate (2-), hexafluoro-, disodium 

Fluorspar

CAS No.: 14542-23-5

Chem. Abstr. Name: Fluorite [CaF2] 

Stannous fluoride

CAS No.: 7783-47-3

Chem. Abstr. Name: Tin fluoride [SnF2] 

Sodium monofluorophosphate

CAS No.: 10163-15-2

Chem. Abstr. Name: Phosphorofluoridic acid, disodium salt 

A. Evidence for carcinogenicity to humans (inadequate) 

Only studies on water fluoridation and cancer were reviewed. Comparisons have been made of 

mortality from cancers at all sites and from particular types of cancer between areas with high 

concentrations of inorganic fluoride in drinking-water (either occurring naturally or as a 

consequence of fluoridation) and areas with low concentrations, or before and after fluoridation; the 

areas or groups of areas most frequently studied are Australia, Canada, China, England and Wales, 

New Zealand, Norway and the USA [ref: 1-6]. When possible, confounding of fluoride concentration 

with relevant variables such as age, sex, race and ethnic composition of the populations was taken 

into account. Fluoridation of drinking-water was introduced in the USA in 1950 [ref: 1], and thus the 

studies in the USA encompass periods of observation of 20 years or more. Studies of areas with 

different levels of naturally fluoridation cover longer periods of exposure [ref: 1,6]. The studies have 

shown no consistent tendency for people living in areas with high concentrations of fluoride in the 

water to have higher cancer rates than those living in areas with low concentrations or for cancer 

mortality rates to increase following fluoridation. 

In several studies, trends in cancer incidence or mortality in naturally or artificially fluoridated areas 

and in areas with low natural fluoride content and no artificially fluoridated water were evaluated 

according to individual cancer sites or groups of sites [ref: 1,3,4,6]. Since a large number of 

comparisons were made, some would be expected by chance alone to show differences. However, 

no consistent difference has been seen, and there have been as many significant negative 

associations between fluoridated water supplies and cancer incidence or mortality as there have 

been positive associations. 

Many studies, therefore, cover the range of doses of fluorides in drinking-water to which humans 

are exposed, and these are mutually consistent in not showing a positive association between 

exposure to fluoride and overall cancer rates or rates of different cancers. The Working Group noted 
that the studies involved were of the ecological or correlation type. The Group was therefore unable 

to classify the evidence for inorganic fluorides used in drinking-water as 'suggesting lack of 

carcinogenicity'. 

B. Evidence for carcinogenicity to animals (inadequate) 

Sodium fluoride was tested in three experiments in three different strains of mice by oral 

administration. The available data are insufficient to allow an evaluation to be made [ref: 1]. 

C. Other relevant data

Epidemiological studies have shown no association between the presence of fluorides in drinkingwater and the incidence of Down's syndrome [ref: 7]. 

Sodium fluoride did not induce DNA strand breaks in testicular cells of rats treated in vivo and did 

not cause chromosomal aberrations in bone-marrow or testicular cells or sister chromatid exchanges 

in bone-marrow cells of mice treated in vivo. It was reported to induce unscheduled DNA synthesis 

in cultured human cells, and conflicting results were obtained on the induction of chromosomal 

aberrations; it did not induce sister chromatid exchanges. It induced transformation of Syrian 

hamster embryo cells in vitro. At high doses and low cell survival, sodium fluoride induced doserelated increases in mutations in cultured mouse lymphoma cells. It did not induce aneuploidy in 

Drosophila. It induced chromosomal aberrations in plants. It did not induce gene conversion in yeast 

and was not mutagenic to bacteria [ref: 7]. 

Stannous fluoride, sodium monofluorophosphate and sodium silicofluoride did not induce sex-linked 

recessive lethal mutation in Drosophila, and sodium monoflourophosphate did not induce dominant 

lethal mutations in Drosophila [ref: 7]. 

Overall evaluation

Fluorides (inorganic, used in drinking-water) are not classifiable as to their carcinogenicity to 

humans.

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 27 (1982)

References

1. IARC Monographs, 27, 237-303, 1982 

2. Wang, B. (1981) The relationship between malignancy and fluorine content in the drinking water 

in Xilinkuolemeng, Nei Menggu (Chin.). Zhonghua Zhongliu Zazhi, 3, 19-21 

3. Neuberger, J.S. (1982) Fluoridation and cancer: an epidemiologic appraisal. J. Kansas med. Soc., 

83, 134-139 

4. Chilvers, C. (1982) Cancer mortality by site and fluoridation of water supplies. J. Epidemiol. 

Commun. Health, 36, 237-242 

5. Chilvers, C. (1983) Cancer mortality and fluoridation of water supplies in 35 US cities. Int. J. 

Epidemiol., 12, 397-404 

6. Chilvers, C. & Conway, D. (1985) Cancer mortality in England in relation to levels of naturally 

occurring fluoride in water supplies. J. Epidemiol. Commun. Health, 39, 44-47 
7. IARC Monographs, Suppl. 6, 312-315, 1987 

Synonyms for Sodium fluoride

● Antibulit 

● Cavi-Trol 

● Credo 

● Disodium difluoride 

● F1-Tabs 

● FDA 0101 

● Flozenges 

● Fluor-O-Kote 

● Fluoral 

● Fluorident 

● Fluorigard 

● Fluorineed 

● Fluorinse 

● Fluoritab 

● Fluorocid 

● Fluorol 

● Flura 

● Flura-Drops 

● Flura-Gel 

● Flura-Loz 

● Flurcare 

● Flursol 

● Fungol B 

● Gel II 

● Gelution 

● Gleem 

● Iradicav 

● Kari-rinse 

● Karidium 

● Karigel 

● Lea-cov 

● Lemoflur 

● Luride 

● Luride lozi-tabs 

● Na frinse 

● Nafeen 

● NaFpak 

● Natrium fluoride 

● Nufluor 

● Ossalin 

● Ossin 

● Pediaflor 

● Pedident 

● Pennwhite 

● Pergantene 

● Phos-flur 

● Point two 

● Predent 

● Rafluor 

● Rescue squad 

● So-flo 

● Sodium fluoride cyclic dimer 

● Sodium hydrofluoride 

● Sodium monofluoride 

● Stay-flo 

● Studafluor 

● Super-dent 

● T-Fluoride 

● Thera-flur 
● Thera-flur-N 

● Trisodium trifluoride 

● Villiaumite 

● Zymafluor 

Synonyms for Fluosilicic acid

● Dihydrogen hexafluorosilicate (2-) 

● Dihydrogen hexafluorosilicate 

● FKS 

● Fluorosilicic acid 

● Hexafluorosilicic acid 

● Hexafluosilicic acid 

● Hydrofluorosilicic acid 

● Hydrogen hexafluorosilicate 

● Hydrosilicofluoric acid 

● Sand acid 

● Silicofluoric acid 

● Silicon hexafluoride dihydride 

Synonyms for Sodium silicofluoride

● Disodium hexafluorosilicate (2-) 

● Disodium hexafluorosilicate 

● Disodium silicofluoride 

● Prodan 

● Salufer 

● Silicon sodium fluoride 

● Sodium fluorosilicate 

● Sodium fluosilicate 

● Sodium hexafluorosilicate 

● Sodium hexafluosilicate 

● Sodium silicon fluoride 

Synonyms for Fluorspar

● Acid-spar 

● Calcium difluoride 

● Calcium fluoride 

● Irtran 3 

● Liparite 

● Met-spar 

Synonyms for Stannous fluoride

● Aim 

● Cap-Tin Mouthrinse 

● Crest 

● Fluoristan 

● Gel-Kam 

● Iradicar SnF2

● Iradicar Stannous Fluoride 

● King's Gel-Tin 

● Stancare 

● Stanide 

● Tin bifluoride 

● Tin difluoride 

● Tin fluoride 

Synonyms for Sodium monofluorophosphate
● Aquafresh 

● Colgate with MFP fluoride 

● Disodium phosphorofluoridate 

● Disodium fluorophosphate 

● Disodium monofluorophosphate 

● Macleans Fluoride 

● MFP 

● Sodium fluorophosphate 

● Sodium phosphorofluoridate 

Last updated: 9 March 1998 
5-FLUOROURACIL

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 210)

CAS No.: 51-21-8

Chem. Abstr. Name: 2,4(1H,3H)-Pyrimidinedione, 5-fluoroA. Evidence for carcinogenicity to humans (inadequate)

No epidemiological study of 5-fluorouracil as a single agent was available to the Working Group. 

Occasional case reports of exposure to 5-fluorouracil, especially in the presence of concurrent 

therapy with other putative carcinogens, such as ionizing radiation, alkylating agents and other 

potent oncotherapeutic drugs, do not constitute evidence of carcinogenesis [ref: 1]. 

No increased risk of second malignancies was found among 276 patients with colorectal cancer 

randomized to low-dose (20 mg/kg bw) 5-fluoro-2'-deoxyuridine adjuvant therapy, followed for 

1774 person-years (14 second noncolorectal cancers observed, 15 expected) [ref: 2]. 

B. Evidence for carcinogenicity to animals (inadequate) 

5-Fluorouracil was tested by intravenous administration in mice and rats and by oral administration 

in rats. No evidence of carcinogenicity was found, but the studies suffered from limitations with 

regard to duration or dose [ref: 1]. It was reported that ingestion of 5-fluorouracil prevented or 

delayed the appearance of spontaneous mammary and pituitary tumours in old female rats; no 

histopathological evaluation was made of the tumours that developed [ref: 3]. A study in which 5-

fluorouracil was given intraperitoneally to rats in combination with methotrexate and 

cyclophosphamide results in induction of tumours in the nervous system, haematopoietic and 

lymphatic tissue, the urinary bladder and the adrenal glands; however, because of the lack of 

matched controls, it could not be concluded whether tumour induction was due to a combined effect 

of the three chemicals or of any one of them [ref: 4]. 

C. Other relevant data

Neither chromosomal aberrations (in two patients) nor sister chromatid exchanges (in three 

patients) were induced following administration of 5-fluorouracil [ref: 5]. 

5-Fluorouracil induced micronuclei and aneuploidy but not specific locus mutations in mice treated in 

vivo. It induced aneuploidy, chromosomal aberrations and sister chromatid exchanges in cultured 

Chinese hamster cells. It did not induce sex-linked recessive lethal mutations in Drosophila, but 

caused genetic crossing-over in fungi. Studies on mutation in bacteria were inconclusive [ref: 5]. 

Overall evaluation

5-Fluorouracil is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 26 (1981)

References
1. IARC Monographs, 26, 217-235, 1981 

2. Boice, J.D., Greene, M.H., Keehn, R.J., Higgins, G.A. & Fraumeni, J.F., Jr (1980) Late effects of 

low-dose adjuvant chemotherapy in colorectal cancer. J. natl Cancer Inst., 64, 501-511 

3. Ferguson, T. (1980) Prevention and delay of spontaneous mammary and pituitary tumors by longand short-term ingestion of 5-fluorouracil in Wistar-Furth rats. Oncology, 37, 353-356 

4. Habs, M., Schmähl, D. & Lin, P.Z. (1981) Carcinogenic activity in rats of combined treatment with 

cyclophosphamide, methotrexate and 5-fluorouracil. Int. J. Cancer, 28, 91-96 

5. IARC Monographs, Suppl. 6, 316-318, 1987 

Synonyms

● Adrucil 

● 2,4-Dioxo-5-fluoropyrimidine 

● Efudex 

● Efudix 

● Fluoroplex 

● 5-Fluoropyrimidin-2,4-diol 

● 5-Fluoro-2,4-(1H,3H)-pyrimidinedione 

● 5-Fluoro-2,4-pyrimidinedione 

● 5-Fluoropyrimidine-2,4-(1H,3H)-dione 

● 5-Fluoropyrimidine-2,4-dione 

● Fluorouracil 

● 5-Fluracil 

● Fluracilum 

● Fluoro uracil 

● Fluoro-uracile 

● Fluracil 

● Fluril 

● FU 

● 5-FU 

● NSC 19893 

● Phthoruracil 

● Ro-2-9757 

Last updated: 9 March 1998 
FURNITURE AND CABINET-MAKING

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 380) 

A. Evidence for carcinogenicity to humans (sufficient)

Employment in the furniture-making industry has been associated with nasal adenocarcinoma; an 

increased risk for other nasal cancers has also been suggested [ref: 1]. Subsequent case reports 

[ref: 2-11] and epidemiological studies [ref: 12-18] have clearly corroborated an increased risk of 

nasal adenocarcinoma among workers in the furniture and cabinet-making industry. 

A study was made of the incidence of and mortality from cancer in 5371 men employed in the 

Buckinghamshire, UK, furniture industry and followed for an average of 19 years since commencing 

work. The incidence of nasal adenocarcinoma was about 100 times that expected from the local 

population. For cancer of the bronchus, the standard registration ratio was 82 (95% confidence 

interval, 61-107), based on 53 cases, and the standardized mortality ratio (SMR) (corrected for the 

Oxford region) was 79 (59-105). However, a significant trend of increasing SMR with increasing 

dustiness of work was found. A trend of increasing SMR for bronchial cancer with increasing duration 

of work (not significant) was also found. A sample of the workforce alive in 1969 contained a lower 

percentage of current smokers than the general population, and there were slightly fewer smokers 

among the men in the dustiest jobs than in the less dusty jobs [ref: 12]. However, an update of the 

same study at the end of 1982 found no significant increase in mortality nor any trend towards 

increasing mortality with increased dustiness of work for cancer at any site apart from the nasal 

cavity [ref: 16]. 

A Swedish pilot case-control study found an odds ratio of 4.1 (1.6-10.6) for respiratory cancer other 

than nasal cancer in relation to wood work. This ratio was based on six exposed cases, four of which 

were in furniture workers (odds ratio, 6.0) [ref: 19]. In another Swedish study, 8141 furniture 

workers were followed for 19 years. Nasal adenocarcinoma was 63.4 times more common than 

expected, but no increased risk was found for laryngeal cancer, lung cancer or sinonasal cancer 

other than adenocarcinoma [ref: 17]. 

A cohort study of the Danish carpenters' and cabinet-makers' union [ref: 20] gives SMRs for lung 

cancer of 96 (68-114) in men aged 20-64 and 110 (92-127) in men aged 65-84. 

Mortality from multiple myeloma among furniture workers was investigated in a US case-control 

study of 301 male cases and 858 controls who had died from other causes. Employment in the 

furniture industry was associated with a nonsignificant excess risk (odds ratio, 1.3) of multiple 

myeloma. The risk was somewhat higher for those who had died before age 65 (odds ratio, 1.7) and 

for those born before 1905 (odds ratio, 1.5), and was significantly elevated for those born before 

1905 and who died before age 65 (odds ratio, 5.4; based on five cases; p < 0.05) [ref: 21]. 

A proportionate mortality study showed an elevated risk for death from all cancer (proportionate 

mortality ratio [PMR], 112; p < 0.01), stomach cancer (PMR, 128; p < 0.01) and non-Hodgkin's 

lymphoma (PMR, 139; p < 0.05) among woodworkers (including carpenters, cabinet-makers and 

furniture workers, lumber graders and scalers, sawyers in sawmills and woodworkers not classified 

elsewhere). In this mixed category, there was no death from sinonasal cancer [ref: 22]. 

Epidemiological data reported here and previously [ref: 1] thus provide sufficient evidence that 

nasal adenocarcinomas have been caused by employment in the furniture-making industry. The 

excess risk occurs (mainly) among those exposed to wood dust. 

According to Acheson et al. [ref: 13], the fact that woodworking machinists (who saw timber) and 

cabinet- and chain makers (who shape, finish, sand and assemble furniture) experience similar risks 

makes it unlikely that the tumours are due to a chemical agent applied to the wood at a particular 
stage of the process, but that they are more probably due to a substance in wood itself. Beech and 

oak, especially, have been incriminated, but the possibility that other hardwoods are carcinogenic 

cannot be ruled out. The carcinogenic substances in hardwood are, however, unknown. 

B. Evidence for carcinogenicity to animals (inadequate)

Among hamsters exposed by inhalation to fine particles of beech wood dust, one animal out of 22 

had a nasal tumour. In these limited studies, inhalation of wood dust did not increase the incidence 

of nasal or respiratory-tract tumours induced by N-nitrosodimethylamine [ref: 23,24]. 

C. Other relevant data

A fraction of a methanol extract of beech-wood dust was mutagenic to Salmonella typhimurium in 

the presence of an exogenous metabolic system [ref: 25]. 

Overall evaluation

Furniture and cabinet-making are carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 25 (1981)

References

1. IARC Monographs, 25, 99-138, 1981 

2. Duclos, J.-C., Dubreuil, C., Contassot, J.C., Guinchard, R. & Arnould, G. (1979) Nasal ethmoid 

adenocarcinomas in woodworkers. Clinical and forensic aspects (Fr.). Arch. Mal. prof., 40, 909-917 

3. Cecchi, F., Buiatti, E., Kriebel, D., Nastasi, L. & Santucci, M. (1980) Adenocarcinoma of the nose 

and paranasal sinuses in shoemakers and woodworkers in the province of Florence, Italy (1963-77). 

Br. J. ind. Med., 37, 222-225 

4. Merler, E., Carnevale, F., D' Andrea, F., Macaccaro, G., Pisa, R., Capitanio, A., Cavazzani, M., 

Gentile, A. & Fantoni, G. (1981) Neoplasm of the nasal cavities and the paranasal sinuses and 

occupational exposure to wood dust (Ital.). Med. Lav., 72, 87-95 

5. Marandas, P., Schwaab, G. & Cachin, Y. (1980) Wood workers and ethmoid tumours (Fr.). Ouest 

méd. 33, 1149-1153 

6. Cabal, C. & Teyssier, J.-M. (1981) Ethmoid tumours in wood workers (Fr.). Arch. Mal. prof., 42, 

303-305 

7. Duclos, J.C., Dubreuil, C., Guinchard, R. & Arnould, G. (1981) Ethmoid nasal adenocarcinomas in 

wood workers (Fr.). Arch. Mal. prof., 42, 292-294 

8. Marandas, P., Schwaab, G., Lecointre, F., Pene, F. & Vandenbrouck, C. (1981) Ethmoid tumours. 

Role of wood work and clinical aspects (Fr.). Arch. Mal. prof., 42, 294-300 

9. Klintenberg, C., Olofsson, J., Hellquist, H. & Sökjer, H. (1984) Adenocarcinoma of the ethmoid 

sinuses. A review of 28 cases with special reference to wood dust exposure. Cancer, 54, 482-488 

10. von Thürauf, J. & Hartung, M. (1984) Adenocarcinoma of the nose and paranasal sinuses in 
people employed in the wood industry in the Federal Republic of Germany (Ger.). Zbl. Arbeitsmed., 

34, 8-15 

11. Wolf, J., Hartung, M., Schaller, K.H., Kochem, W. & Valentin, H. (1986) Occurrence of 

adenocarcinoma of the nasal and paranasal sinuses in woodworkers (Ger.) Arbeitsmed. Sozialmed. 

Präventivmed., 7, 3-22 

12. Rang, E.H. & Acheson, E.D. (1981) Cancer in furniture workers. Int. J. Epidemiol., 10, 253-261 

13. Acheson, E.D., Winter, P.D., Hadfield, E. & Macbeth, R.G. (1982) Is nasal adenocarcinoma in the 

Buckinghamshire furniture industry declining? Nature, 299, 263-265 

14. Battista, G., Cavallucci, F., Comba, P., Quercia, A., Vindigni, C. & Sartorelli, E. (1983) A casereferent study on nasal cancer and exposure to wood dust in the province of Sienna, Italy. Scand. J. 

Work Environ. Health, 9, 25-29 

15. Hernberg, S., Westerholm, P., Schultz-Larsen, K., Degerth, R., Kuosma, E., Englund, A., 

Engzell, U., Sand Hansen, H. & Mutanen, P. (1983) Nasal and sinonasal cancer. Connection with 

occupational exposures in Denmark, Finland and Sweden. Scand. J. Work Environ. Health, 9, 315-

326 

16. Acheson, E.D., Pippard, E.C. & Winter, P.D. (1984) Mortality of English furniture makers. Scand. 

J. Work Environ. Health, 10, 211-217 

17. Gerhardsson, M.R., Norell, S.E., Kiviranta, H.J. & Ahlbom, A. (1985) Respiratory cancers in 

furniture workers. Br. J. ind. Med., 42, 403-405 

18. Malker, H.S.R., McLaughlin, J.K., Blot, W.J., Weiner, J.A., Malker, B.K., Ericsson, J.L.E. & Stone, 

B.J. (1986) Nasal cancer and occupation in Sweden, 1961-1979. Am. J. ind. Med., 9, 477-485 

19. Esping, B. & Axelson, O. (1980) A pilot study on respiratory and digestive tract cancer among 

woodworkers. Scand. J. Work Environ. Health, 6, 201-205 

20. Olsen, J. & Sabroe, S. (1979) A follow-up study of non-retired and retired members of the 

Danish Carpenter/Cabinet Makers' Trade Union. Int. J. Epidemiol., 8, 375-382 

21. Tollerud, D.J., Brinton, L.A., Stone, B.J., Tobacman, J.K. & Blattner, W.A. (1985) Mortality from 

multiple myeloma among North Carolina furniture workers. J. natl Cancer Inst., 74, 799-801 

22. Gallagher, R.P., Threlfall, W.J., Band, P.R. & Spinelli, J.J. (1987) Cancer mortality experience of 

woodworkers, loggers, fishermen, farmers, and miners in British Columbia. Natl Cancer Inst. 

Monogr., 69, 163-167 

23. Wilhelmsson, B., Lundh, B., Drettner, B. & Stenkvist, B. (1985) Effects of wood dust exposure 

and diethylnitrosamine. A pilot study in Syrian golden hamsters. Acta otolaryngol., 99, 160-171 

24. Drettner, B., Wilhelmsson, B. & Lundh, B. (1985) Experimental studies on carcinogenesis in the 

nasal mucosa. Acta otolaryngol., 99, 205-207 

25. IARC Monographs, Suppl. 6, 573, 1987 

Last updated: 9 February 1998 
GRISEOFULVIN 

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7:: (1987) (p. 391) 

CAS No.: 126-07-8

Chem. Abstr. Name: 2-S-trans)-7-Chloro-2',4,6-trimethoxy-6'-methylspiro[benzofuran-2(3H),1'-

(2)-cyclohexene]-3,4'-dione 

A. Evidence for carcinogenicity to animals (sufficient)

Griseofulvin induced liver tumours following its oral administration to adult mice [ref: 1-3] or its 

subcutaneous administration to infant male mice [ref: 1]. When given orally to rats and hamsters, it 

produced a significant increase in the incidence of thyroid tumours in rats but had no carcinogenic 

effect in hamsters [ref: 2]. 

Overall evaluation

Griseofulvin is possibly carcinogenic to humans (Group 2B). 

For definition of the italicized terms, see Preamble Evaluation.

Subsequent evaluation: Vol. 79 (2001)

Also see previous evaluation: Vol. 10 (1976)

References

1. IARC Monographs, 10, 153-161, 1976 

2. Rustia, M. & Shubik, P. (1978) Thyroid tumours in rats and hepatomas in mice after griseofulvin 

treatment. Br. J. Cancer, 38, 237-249 

3. Chlumská, A.A. & Janousek, V. (1981) Hepatomas after long-term administration of griseofulvin 

(Czech.). Cesk. Patol., 17, 83-87 

Synonyms

● Amudane 

● Biogrisin-FP 

● 7-Chloro-4,6-dimethoxycoumaran-3-one-2-spiro-1'-(2'-methoxy-6'-methylcyclohex-2'-en-4'-

one) 

● 7-Chloro-2',4,6-trimethoxy-6'β-methylspiro[benzofuran-2(3H),1'-(2)-cyclohexene]-3,4'-

dione 

● 7-Chloro-2',4,6-trimethoxy-6'-methyl-(2S-trans)-spiro[benzofuran-2H(3H),1'-(2)-

cyclohexene]-

3,4'-dione 

● Curling factor 

● Delmofulvina 

● Fulcin 

● Fulcine 

● Fulvicin 

● Fulvina 
● Fungivin 

● Fulvistatin 

● Greosin 

● Gricin 

● Grifulvin 

● Grisactin 

● Griscofulvin 

● Grisefuline 

● Griseo 

● (+)-Griseofulvin 

● Grisetin 

● Grisofulvin 

● Grisovin 

● Grysio 

● Guservin 

● Lamoryl 

● Likuden 

● Neo-Fulcin 

● NSC 34533 

● Poncyl 

● Spirofulvin 

● Sporostatin 

Last Updated: 2 March 1998 
GYROMITRIN

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 391)

CAS No.: 16568-02-8 

Chem. Abstr. Name: Hydrazinecarboxaldehyde, ethylidenemethylEvidence for carcinogenicity to animals (limited) 

In one study, gyromitrin was administered by intragastric intubation to mice, producing increased 

incidences of tumours of the forestomach, clitoral gland and lung in females and of tumours of the 

preputial gland in males [ref: 1]. 

Reference

1. IARC Monographs, 31, 163-170, 1983 

Overall evaluation

Gyromitrin is not classifiable as to its carcinogenicity to humans (Group 3). 

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 31 (1983)

Synonyms

● Formic acid, ethylidenemethylhydrazide 

● Acetaldehyde-N-formyl-N-methylhydrazone 

● Acetaldehyde-N-methyl-N-formylhydrazone 

● Acetaldehyde methylformylhydrazone 

● Ethylidene gyromitrin 

● Acetaldehyde formylmethylhydrazone 

Last updated: 9 March 1998 
HAEMATITE AND FERRIC OXIDE:

FERRIC OXIDE

(Group 3)

HAEMATITE

(Group 3) 

UNDERGROUND HAEMATITE MINING WITH EXPOSURE TO RADON

(Group 1) 

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 216) 

Ferric oxide

CAS No.: 1309-37-1 

Haematite

CAS No.: 1317-60-8 

A. Evidence for carcinogenicity to humans (inadequate for haematite and ferric oxide; sufficient

for underground haematite mining with exposure to radon)

Underground haematite miners have a higher incidence of lung cancer in the presence of exposure 

to radon daughters (although other agents might also contribute to the risk) than surface haematite 

miners [ref: 1-11]. Haematite mining with low-grade exposure to radon daughters and silica dust 

was not associated with excess lung cancer in a relatively large cohort [ref: 12]. The importance of 

exposure to radon daughters in the occurrence of lung cancer in haematite miners is also suggested 

by the time trend of lung cancer rates in a mining population [ref: 4]. One mining population with 

an increased lung cancer risk but with current low exposure to radon daughters might have had 

higher exposures in the past due to poorer ventilation [ref: 13,14]. 

Some studies of metal workers exposed to ferric oxide dusts have shown an increased incidence of 

lung cancer [ref: 1,15], but the influence of factors in the workplace other than ferric oxide, i.e., 

soot, silica and asbestos in foundry work, cannot be discounted. In other studies of metal and 

chemical workers exposed to ferric oxide, the incidence of lung cancer has generally not been 

increased [ref: 1,16]. 

B. Evidence for carcinogenicity to animals (inadequate for haematite; evidence suggesting lack 

of carcinogenicity for ferric oxide)

No conclusive carcinogenic effect was observed in mice, hamsters or guinea-pigs given ferric oxide 

intratracheally or by inhalation [ref: 1]. Repeated intratracheal instillation to hamsters of 

benzo[a]pyrene bound to fine ferric oxide dust particles induced squamous-cell and anaplastic 

carcinomas [ref: 17]. There was no increase in tumour yield in hamsters administered a constant 

dose of benzo[a]pyrene and increasing amounts of ferric oxide intratracheally, indicating that, 

beyond a certain ratio of benzo[a]pyrene to ferric oxide, the latter does not affect tumour yield [ref: 

18]. Administration of ferric oxide particles alone occasionally induced interstitial fibrosis, indicating 

that ferrous oxide particles act as cofactors in this system, mainly as carriers [ref: 19]. In one 

study, intrapleural inoculation of the respirable fraction of iron ore mine dust to female BALB/c mice 

resulted in an increased incidence of lung adenomas; in a second study, an increased incidence of 

lymphoma/leukaemia was observed in female C57BL/6J mice exposed chronically to the same dust. 

In neither study was the number of animals specified, nor whether the mice were killed serially or 

died; in the second study, the type of exposure was not specified [ref: 20]. In several studies in 

hamsters, ferric oxide was not carcinogenic when given alone but enhanced lung and nasal-cavity 
carcinogenesis induced by N-nitrosodiethylamine and N-nitrosodimethylamine, respectively [ref: 21-

23]. 

C. Other relevant data

No data were available on the genetic and related effects of ferric oxide in humans. It did not induce 

transformation of Syrian hamster embryo cells [ref: 24]. 

Overall evaluation

Ferric oxide is not classifiable as to its carcinogenicity to humans (Group 3).

Haematite is not classifiable as to its carcinogenicity to humans (Group 3).

Underground haematite mining with exposure to radon is carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 1 (1972) 

References

1. IARC Monographs, 1, 29-39, 1972 

2. Damber, L. & Larsson, L.-G. (1985) Underground mining, smoking, and lung cancer: a casecontrol study in the iron ore municipalities in northern Sweden. J. natl Cancer Inst., 74, 1207-1213 

3. Edling, C. (1982) Lung cancer and smoking in a group of iron ore miners. Am. J. ind. Med., 3, 

191-199 

4. Edling, C. & Axelson, O. (1983) Quantitative aspects of radon daughter exposure and lung cancer 

in underground miners. Br. J. ind. Med., 40, 182-187 

5. Icsó, J. & Szöllösová, M. (1984) The incidence of lung cancer in the miners of iron-ore mines 

(Czech). Pracov. Lék., 36, 294-298 

6. Jorgensen, H.S. (1973) A study of mortality from lung cancer among miners in Kiruna 1950-

1970. Work Environ. Health, 10, 126-133 

7. Jorgensen, H.S. (1984) Lung cancer among underground workers in the iron ore mine of Kiruna 

based on thirty years of observation. Ann. Acad. Med., 13 (Suppl.), 371-377 

8. Larsson, L.-G. & Damber, L. (1982) Interaction between underground mining and smoking in the 

causation of lung cancer: a study of nonuranium miners in northern Sweden. Cancer Detect. Prev., 

5, 385-389 

9. Radford, E.P. (1981) Radon daughters in the induction of lung cancer in underground miners. In: 

Peto, R. & Schneiderman, M., eds, Quantification of Occupational Exposure (Banbury Report 9), Cold 

Spring Harbor, NY, CSH Press, pp. 151-163 

10. Radford, E.P. & St Clair Renard, K.G. (1984) Lung cancer in Swedish iron miners exposed to low 

doses of radon daughters. New Engl. J. Med., 310, 1485-1494 
11. St Clair Renard, K.G. (1974) Respiratory cancer mortality in an iron ore mine in northern 

Sweden. Ambio, 3, 67-69 

12. Lawler, A.B., Mandel, J.S., Schuman, L.M. & Lubin, J.H. (1985) A retrospective cohort mortality 

study of iron ore (hematite) miners in Minnesota. J. occup. Med., 27, 507-517 

13. Anthoine, D., Braun, P., Cervoni, P., Schwartz, P. & Lamy, P. (1979) Should the lung cancer of 

iron miners in the Lorraine be considered an occupational disease? 270 new cases observed from 

1964-1978 (Fr.). Rev. fr. Mal. respir., 7, 63-65 

14. Pham, Q.T., Gaertner, M., Mur, J.M., Braun, P., Gabiano, M. & Sadoul, P. (1983) Incidence of 

lung cancer among iron miners. Eur. J. respir. Dis., 64, 534-540 

15. Tola, S., Koskela, R.-S., Hernberg, S. & Järvinen, E. (1979) Lung cancer mortality among iron 

foundry workers. J. occup. Med., 21, 753-760 

16. Axelson, O. & Sjöberg, A. (1979) Cancer incidence and exposure to iron oxide dust. J. occup. 

Med., 21, 419-422 

17. Saffiotti, U. (1969) Experimental respiratory tract carcinogenesis. Prog. exp. Tumor Res., 11, 

302-333 

18. Sellakumar, A.R., Montesano, R., Saffiotti, U. & Kaufman, D.G. (1973) Hamster respiratory 

carcinogenesis induced by benzo[a]pyrene and different dose levels of ferric oxide. J. natl Cancer 

Inst., 50, 507-510 

19. Stenback, F., Rowland, J. & Sellakumar, A. (1976) Carcinogenicity of benzo[a]pyrene and dusts 

in the hamster lung instilled intratracheally with titanium oxide, aluminium oxide, carbon and ferric 

oxide. Oncology, 33, 29-34 

20. Keast, D., Tam, N., Sheppard, N. & Papadimitriou, J.M. (1985) The role of tobacco smoke, iron 

ore mine dusts, viruses, and chemicals in experimental cancer. Arch. environ. Health, 40, 296-300 

21. Stenbäck, F., Ferrero, A., Montesano, R. & Shubik, P. (1973) Synergistic effect of ferric oxide on 

dimethylnitrosamine carcinogenesis in the Syrian golden hamster. Z. Krebsforsch., 79, 31-38 

22. Nettesheim, P., Creasia, D.A. & Mitchell, T.J. (1975) Carcinogenic and cocarcinogenic effects of 

inhaled synthetic smog and ferric oxide particles. J. natl Cancer Inst., 55, 159-169 

23. Feron, V.J., Emmelot, P. & Vossenaar, T. (1972) Lower respiratory tract tumours in Syrian 

golden hamsters after intratracheal instillations of diethylnitrosamine alone and with ferric oxide. 

Eur. J. Cancer, 8, 445-449 

24. IARC Monographs, Suppl. 6, 310-311, 1987 

Synonyms for Ferric oxide

● Food Yellow 11 

● Iron oxide 

● Sesquioxide of iron 

● Solvent Yellow 6 

Synonyms for Haematite

● Blood stone 
● Iron ore 

● Red iron ore 

Last updated: 9 February 1998 
HEXACHLOROBENZENE

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 219) 

CAS No.: 118-74-1

A. Evidence for carcinogenicity to humans (inadequate)

No report of a direct association between hexachlorobenzene and human cancer is available. 

Hepatocellular carcinoma has been associated with porphyria [ref: 1-5]. However, although 

abnormal porphyrin metabolism persisted at least 20 years after an epidemic of porphyria cutanea 

tarda in Turkey, caused by consumption of grain treated with hexachlorobenzene [ref: 6], no excess 

cancer occurrence has been reported in this population 25 years after the accident [ref: 7]. 

B. Evidence for carcinogenicity to animals (sufficient)

Hexachlorobenzene was tested by oral administration in one experiment in mice and in one in 

hamsters. In mice, it produced liver-cell tumours in animals of each sex; in hamsters of each sex, it 

produced hepatomas, liver haemangioendotheliomas and thyroid adenomas. An experiment 

involving intraperitoneal administration in mice was considered to be inadequate [ref: 6]. In a study 

in rats fed hexachlorobenzene in the diet, hepatomas, hepatocellular carcinomas, bile-duct 

adenomas and renal-cell adenomas were observed [ref: 8]. In a two-generation feeding study in 

rats with lower dose levels, increased incidences of parathyroid adenomas and adrenal 

phaeochromocytomas were observed in animals of each sex and liver neoplastic nodules in females 

of the F1 generation [ref: 9]. After 90 weeks' feeding of hexachlorobenzene to rats, 100% of 

surviving females and only 16% of males had developed liver tumours [ref: 10]. 

C. Other relevant data

No data were available on the genetic and related effects of hexachlorobenzene in humans. It did 

not induce dominant lethal mutations in rats treated in vivo. It did not induce chromosomal 

aberrations in cultured Chinese hamster cells or mutation in bacteria [ref: 11]. 

Overall evaluation

Hexachlorobenzene is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Subsequent evaluation: Vol. 79 (2001)

Also see previous evaluation: Vol. 20 (1979)

References

1. Kordac, V. (1972) Frequency of occurrence of hepatocellular carcinoma in patients with porphyria 

cutanea tarda in long-term follow-up. Neoplasma, 19, 135-139

2. Solis, J.A., Betancor, P., Campos, R., Enriquez de Salamanca, R., Rojo, P., Marin, I. & Schüller, A. 

(1982) Association of porphyria cutanea tarda and primary liver cancer: report of ten cases. J. 

Dermatol., 9, 131-137
3. Lithner, F. & Wetterberg, L. (1984) Hepatocellular carcinoma in patients with acute intermittent 

porphyria. Acta med. scand., 215, 271-274

4. Hardell, L., Bengtsson, N.O., Jonsson, U., Eriksson, S. & Larsson, L.G. (1984) Aetiological aspects 

on primary liver cancer with special regard to alcohol, organic solvents, and acute intermittent 

porphyria - an epidemiological investigation. Br. J. Cancer, 50, 389-397

5. Axelson, O. (1986) A review of porphyria and cancer and the missing link with human exposure 

to hexachlorobenzene. In: Morris, C.R. & Cabral, J.R.P., eds, Hexachlorobenzene: Proceedings of An 

International Symposium (IARC Scientific Publications No. 77), Lyon, International Agency for 

Research on Cancer, pp. 585-589

6. IARC Monographs, 20, 155-178, 1979

7. Peters, H.A., Gocmen, A., Cripps, D.J., Bryan, G.T. & Dogramaci, I. (1982) Epidemiology of 

hexachlorobenzene-induced porphyria in Turkey. Clinical and laboratory follow-up after 25 years. 

Arch. Neurol., 39, 744-749

8. Ertürk, E., Lambrecht, R.W., Peters, H.A., Cripps, D.J., Gocmen, A., Morris, C.R. & Bryan, G.T. 

(1986) Oncogenicity of hexachlorobenzene. In: Morris, C.R. & Cabral, J.R.P., eds, 

Hexachlorobenzene: Proceedings of an International Symposium (IARC Scientific Publications No. 

77), Lyon, International Agency for Research on Cancer, pp. 417-423

9. Arnold, D.L., Moodie, C.A., Charbonneau, S.M., Grice, H.C., McGuire, P.F., Bryce, F.R., Collins, 

C.T., Zawidzka, Z.Z., Krewski, D.R., Nera, E.A. & Munro, I.C. (1985) Long-term toxicity of 

hexachlorobenzene in the rat and the effect of dietary vitamin A. Food chem. Toxicol., 23, 779-793

10. Smith, A.G., Francis, J.E., Dinsdale, D., Manson, M.M. & Cabral, J.R.P. (1985) 

Hepatocarcinogenicity of hexachlorobenzene in rats and the sex difference in hepatic iron status and 

development of porphyria. Carcinogenesis, 6, 631-636

11. IARC Monographs, Suppl. 6, 331-332, 1987 

Synonyms

● Amatin 

● Anticarie 

● Bunt-cure 

● Bunt-no-more 

● Co-op hexa 

● Granox NM 

● HCB 

● Julin's carbon chloride 

● No Bunt 

● No Bunt 40 

● No Bunt 80 

● No Bunt liquid 

● Pentachlorophenyl chloride 

● Perchlorobenzene 

● Sanocide 

● Snieciotox 

Last updated: 2 March 1998 
HEXACHLOROCYCLOHEXANES

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 220) 

Hexachlorocyclohexane [mixed isomers]

CAS No.: 608-73-1

Chem. Abstr. Name: 1,2,3,4,5,6-Hexachlorocyclohexane 

Hexachlorocyclohexane [α-isomer]

CAS No.: 319-84-6

Chem. Abstr. Name: 1α,2α,3β,4α,5β,6α-Hexachlorocyclohexane 

Hexachlorocyclohexane [β-isomer]

CAS No.: 319-85-7

Chem. Abstr. Name: 1α,2β,3α,4β,5α,6β-Hexachlorocyclohexane 

Lindane

CAS No.: 58-89-9

Chem. Abstr. Name: 1α,2α,3β,4α,5α,6β-Hexachlorocyclohexane 

Hexachlorocyclohexane [δ-isomer]

CAS No.: 319-86-8

Chem. Abstr. Name: 1α,2α,3α,4β,5α,6β-Hexachlorocyclohexane 

Hexachlorocyclohexane [ε-isomer]

CAS No.: 6108-10-7

Chem. Abstr. Name: 1α,2α,3α,4β,5β,6β-Hexachlorocyclohexane 

Hexachlorocyclohexane [ζ-isomer]

CAS No.: 6108-11-8

Chem. Abstr. Name: 1α,2α,3α,4α,5α,6α-Hexachlorocyclohexane 

Hexachlorocyclohexane [η-isomer]

CAS No.: 6108-12-9 

Chem. Abstr. Name: 1α,2α,3α,4α,5β,6β-Hexachlorocyclohexane 

Hexachlorocyclohexane [θ-isomer]

CAS No.: 6108-13-0 

Chem. Abstr. Name: 1α,2α,3α,4α,5α,6βA. Evidence for carcinogenicity to humans (inadequate for hexachlorocyclohexanes)

Four cases of leukaemia were reported in men exposed to γ-hexachlorocyclohexane (lindane) with or 

without other chemicals [ref: 1,2]. Cases of aplastic anaemia have also been associated with 

exposure to this compound [ref: 1]. Mean tissue levels of hexachlorocyclohexanes were reported to 

be elevated in two of three studies of autopsy patients; in one of these, in four liver cancer patients, 

the level of the β-isomer was abnormally high [ref: 3-5]. Mean serum levels of βhexachlorocyclohexane were not appreciably higher in four cancer patients than in three controls 

[ref: 6]. Exposure to γ-hexachlorocyclohexane was recorded in case-control studies of soft-tissue 

sarcomas and of lymphomas [ref: 7,8] but was insufficiently frequent for any conclusion to be 

drawn. An increase in lung cancer mortality was observed in agricultural workers who had used 

hexachlorocyclohexane (unspecified) and a variety of other pesticides and herbicides (standardized 

mortality ratio, 180 [95% confidence interval, 140-240]) [ref: 9]. 
B. Evidence for carcinogenicity to animals (sufficient for technical-grade and for the α isomer; 

limited for the β and for the γ isomers)

Technical-grade, α- and β-hexachlorocyclohexane and the γ isomer (lindane) produced liver tumours 

in mice when administered orally [ref: 1,10,11]; the technical grade also produced lymphoreticular 

neoplasms [ref: 10]. In two studies in rats, an increased incidence of liver tumours was observed 

with the α isomer [ref: 1,12], and in one study in rats a few thyroid tumours were observed with 

the γ isomer [ref: 1]; other studies in rats [ref: 11,13-15] were considered to be inadequate. 

Studies in hamsters [ref: 11] and dogs [ref: 16] were also inadequate. Technical-grade 

hexachlorocyclohexane and the γ isomer were tested inadequately by skin application in mice [ref: 

1,10]. α-Hexachlorocyclohexane enhanced the incidence of liver neoplasms induced in rats by Nnitrosodiethylamine [ref: 12]. 

C. Other relevant data

In a single study, chromosomal aberrations were not found in workers involved in the production of 

γ-hexachlorocyclohexane (lindane) [ref: 17].

Technical-grade hexachlorocyclohexane, but not γ- hexachlorocyclohexane, induced dominant lethal 

mutations in mice; chromosomal aberrations were not found in bone-marrow cells of mice exposed 

to technical-grade or γ-hexachlorocyclohexane in vivo. γ-Hexachlorocyclohexane did not induce 

unscheduled DNA synthesis in human cells in vitro and did not induce micronuclei or chromosomal 

aberrations in cultured rodent cells; it induced DNA strand breaks but not unscheduled DNA 

synthesis. It inhibited intercellular communication in Chinese hamster V79 cells. It did not induce 

sex-linked recessive lethal mutations in Drosophila. α- Hexachlorocyclohexane was not mutagenic to 

yeast, but the gamma isomer induced gene conversion. Neither γ- nor β-hexachlorocyclohexane was 

mutagenic to bacteria, and α- and β-hexachlorocyclohexane did not cause DNA damage in bacteria 

[ref: 17]. 

Overall evaluation

Hexacyclohexanes are possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 5 (1974); Vol. 20 (1979) 

References

1. IARC Monographs, 20, 195-239, 1979

2. Sidi, Y., Kiltchevsky, E., Shaklai, M. & Pinkhas, J. (1983) Acute myeloblastic leukemia and 

insecticide. N.Y. State J. Med., 83, 161

3. Hoffman, W.S., Adler, H., Fishbein, W.I. & Bauer, F.C. (1967) Relation of pesticide concentrations 

in fat to pathological changes in tissues. Arch. environ. Health, 15, 758-765

4. Radomski, J.L., Deichmann, W.B., Clizer, E.E. & Rey, A. (1968) Pesticide concentrations in the 

liver, brain and adipose tissue of terminal hospital patients. Food Cosmet. Toxicol., 6, 209-220

5. Kasai, A., Asanuma, S. & Nakamura, S. (1972) Studies on organochlorine pesticide residues in 

human organs. Part III (Jpn.). Nippon Noson Igakkai Zasshi, 21, 296-297

6. Caldwell, G.G., Cannon, S.B., Pratt, C.B. & Arthur, R.D. (1981) Serum pesticide levels in patients 

with childhood colorectal carcinoma. Cancer, 48, 774-778
7. Eriksson, M., Hardell, L., Berg, N.O., Möller, T. & Axelson, O. (1981) Soft-tissue sarcomas and 

exposure to chemical substances: a case-referent study. Br. J. ind. Med., 38, 27-33

8. Hardell, L., Eriksson, M., Lenner, P. & Lundgren, E. (1981) Malignant lymphoma and exposure to 

chemicals, especially organic solvents, chlorophenols and phenoxy acids: a case-control study. Br. J. 

Cancer, 43, 169-176

9. Barthel, E. (1981) Increased risk of lung cancer in pesticide-exposed male agricultural workers. J. 

Toxicol. environ. Health, 8, 1027-1040

10. Kashyap, S.K., Nigam, S.K., Gupta, R.C., Karnik, A.B. & Chatterjee, S.K. (1979) Carcinogenicity 

of hexachlorocyclohexane (BHC) in pure inbred Swiss mice. J. environ. Sci. Health, B14, 305-318

11. Munir, K.M., Soman, C.S. & Bhide, S.V. (1983) Hexachlorocyclohexane-induced tumorigenicity 

in mice under different experimental conditions. Tumori, 69, 383-386

12. Schulte-Hermann, R. & Parzefall, W. (1981) Failure to discriminate initiation from promotion of 

liver tumors in a long-term study with the phenobarbital-type inducer α-hexachlorocyclohexane and 

the role of sustained stimulation of hepatic growth and monooxygenases. Cancer Res., 41, 4140-

4146

13. Angsubhakorn, S., Bhamarapravati, N., Romruen, K., Sahaphong, S. & Thamavit, W. (1977) 

Alpha benzene hexachloride inhibition of aflatoxin B1-induced hepatocellular carcinoma. A 

preliminary report. Experientia, 34, 1069-1970

14. Hiasa, Y., Ohshima, M., Ohmori, T. & Murata, Y. (1978) Effect of α-benzene hexachloride on 2-

fluorenylacetamide carcinogenesis in rats. Gann, 69, 423-426

15. Angsubhakorn, S., Bhamarapravati, N., Romruen, K., Sahaphong, S., Thamavit, W. & Miyamoto, 

M. (1981) Further study of alpha benzene hexachloride inhibition of aflatoxin B1

hepatocarcinogenesis in rats. Br. J. Cancer, 43, 881-883

16. Rivett, K.F., Chesterman, H., Kellett, D.N., Newman, A.J. & Worden, A.N. (1978) Effects of 

feeding lindane to dogs for periods of up to 2 years. Toxicology, 9, 273-289

17. IARC Monographs, Suppl. 6, 333-335, 1987 

Synonyms for Hexachlorocyclohexane [mixed isomers]

● Benzahex 

● Benzex 

● BHC 

● Dol 

● Dolmix 

● FBHC 

● HCCH 

● Hexachlor 

● Hexachloran 

● Hexafor 

● Hexyclan 

● Kotol 

● Soprocide 

Synonyms for Hexachlorocyclohexane [α-isomer]

● α-Benzene hexachloride 
● α-BHC 

● α-HCH 

● α-Hexachloran 

● α-Hexachlorane 

● α-Hexachlorcyclohexane 

● α-1,2,3,4,5,6-Hexachlorcyclohexane 

● α-Hexachlorocyclohexane 

● α-1,2,3,4,5,6-Hexachlorocyclohexane 

● α-Lindane 

Synonyms for Hexachlorocyclohexane [β-isomer]

● β-Benzene hexachloride 

● β-BHC 

● β-HCH 

● β-Hexachlorobenzene 

● β-Hexachlorocyclohexane 

● β-1,2,3,4,5,6-Hexachlorocyclohexane 

● β-Lindane 

Synonyms for Lindane

● Aalindan 

● Aficide 

● Agrocide 

● Agrocide III 

● Agrocide WP 

● Ameisenmittel Merck 

● Ameisentod 

● Aparasin 

● Aphtiria 

● Aplidal 

● Arbitex 

● BBH 

● Ben-Hex 

● Bentox 10 

● γ-Benzene hexachloride 

● Bexol 

● γ-BHC 

● Celanex 

● Chloresene 

● Codechine 

● DBH 

● Detmol-extrakt 

● Devoran 

● Dol granule 

● Drill tox-spezial aglukon 

● ENT 7796 

● Entomoxan 

● Forlin 

● Gamacid 

● Gamaphex 

● Gammalin 

● Gammalin 20 

● Gammaterr 

● Gammexane 

● Gexane 

● HCH 

● γ-HCH 

● Heclotox 

● Hexa 

● Hexachloran 
● Hexachloran-gamma 

● Hexachlorane 

● Hexachlorane-gamma 

● γ-Hexachlorobenzene 

● γ-Hexachlorocyclohexane 

● γ-1,2,3,4,5,6-Hexachlorocyclohexane 

● Hexatox 

● Hexaverm 

● Hexicide 

● Hexyclan 

● HGI 

● Hortex 

● Isotox 

● Jacutin 

● Kokotine 

● Kwell 

● Lendine 

● Lentox 

● Lidenal 

● Lindafor 

● Lindagam 

● γ-Lindane 

● Lindatox 

● Lindosep 

● Lintox 

● Lorexane 

● Milbol 49 

● Mszycol 

● Neo-scabicidol 

● Nexen FB 

● Nexit 

● Nexit-stark 

● Nexol-E 

● Nicochloran 

● Novigam 

● Omnitox 

● Ovadziak 

● Owadziak 

● Pedraczak 

● Pflanzol 

● Quellada 

● Sang-gamma 

● Silvanol 

● Spritz-Rapidin 

● Sprehpflanzol 

● Streunex 

● TAP 85 

● Tri-6 

● Viton 

Synonyms for Hexachlorocyclohexane [δ-isomer]

● δ-Benzene hexachloride 

● δ-BHC 

● δ-HCH 

● δ-Hexachlorocyclohexane 

● δ-1,2,3,4,5,6-Hexachlorocyclohexane 

● δ-Lindane 

Synonyms for Hexachlorocyclohexane [ε-isomer]

● ε-Benzene hexachloride 

● ε-BHC 
● ε-HCH 

● ε-Hexachlorocyclohexane 

● ε-1,2,3,4,5,6-Hexachlorocyclohexane 

● ε-Lindane 

Synonyms for Hexachlorocyclohexane [ζ-isomer]

● ζ-Hexachlorocyclohexane 

● ζ-Lindane 

Synonyms for Hexachlorocyclohexane [η-isomer]

● η-Hexachlorocyclohexane 

● η-Lindane 

Synonym for Hexachlorocyclohexane [θ-isomer]

● θ-Hexachlorocyclohexane 

● θ-Lindane 

Last updated: 2 March 1998 
HYDRALAZINE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 222)

Hydralazine

CAS No.: 86-54-4

Chem. Abstr. Name: 1(2H)-Phthalazinone hydrazone 

Hydralazine hydrochloride

CAS No.: 304-20-1

Chem. Abstr. Name: 1(2H)-Phthalazinone hydrazone, monohydrochloride 

A. Evidence for carcinogenicity to humans (inadequate) 

Two studies suggest an association between exposure to hydralazine and cancer. One was confined 

to patients with and without signs of toxicity due to hydralazine, and potential confounding factors 

were not controlled for. The other involved a small number of subjects exposed to hydralazine, but 

the possibility of selection bias could not be excluded [ref: 1]. However, a study of 3988 participants 

in a hypertensive detection and follow-up programme suggested no increased risk for cancer at all 

sites from use of hydralazine. A logistic regression estimate of cancer risk after controlling for age, 

sex, race, smoking behaviour and concomitant drug therapy was 0.89 (95% confidence interval, 

0.45-1.8). It was noted that this estimate of no excess risk was restricted to a hypertensive 

population over 40 years of age, exposed to hydralazine for various periods (none longer than five 

years) [ref: 2]. Another study involving women with breast cancer also showed no increased risk 

with use of hydralazine (relative risk, 0.9; 0.5-1.7) [ref: 3]. 

B. Evidence for carcinogenicity to animals (limited) 

Hydralazine hydrochloride was tested in one experiment in mice by oral administration. A significant 

increase in the incidence of lung tumours was reported [ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of hydralazine in humans. 

In a single limited study, hydralazine did not induce DNA damage in animals treated in vivo. It 

induced sister chromatid exchanges in human lymphocytes in vitro, whereas assays for 

chromosomal aberrations in rodent cells in vitro were inconclusive. Hydralazine induced unscheduled 

DNA synthesis in rat and rabbit hepatocytes in vitro and induced mutation and DNA damage in 

bacteria [ref: 4]. 

Overall evaluation

Hydralazine is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 24 (1980)

References
1. IARC Monographs, 24, 85-100, 1980 

2. Rogers, A.S. (1984) Hydralazine: an estimate of cancer risk in a hypertensive program 

(Abstract). Diss. Abstr. int., 44, 2123 

3. Kaufman, D.W., Kelly, J.P., Rosenberg, L., Stolley, P.D., Schottenfeld, D. & Shapiro, S. (1987) 

Hydralazine and breast cancer. J. natl Cancer Inst., 78, 243-246 

4. IARC Monographs, Suppl. 6, 338-340, 1987 

Synonyms for Hydralazine

● Hydralazin 

● Hydrallazine 

● 1-Hydrazinophthalazine 

Synonyms for Hydralazine hydrochloride

● Aiselazine 

● Appresinum 

● Aprelazine 

● Apresazide 

● Apresine 

● Apresolin 

● Apresoline 

● Apresoline-esidrix 

● Apresoline HCl 

● Apresoline hydrochloride 

● Apressin 

● Apressoline 

● Aprezolin 

● Ba 5968 

● C 5968 

● Ciba 5968 

● Dralzine 

● Hidralazin 

● Hipoftalin 

● 1-Hydrazinophthalazine hydrochloride 

● Hydralazine chloride 

● Hydralazine HCl 

● Hydrapress 

● 1-Hydrazinophthalazine monohydrochloride 

● Hyperazin 

● Hyperazine 

● Hypophthalin 

● Hypos 

● Ipolina 

● Lopres 

● Lopress 

● Nor-press 25 

● 1(2H)-Phthalazinone hydrazone hydrochloride 

● Praparat 5968 

● Rolazine 

● Serpasil apresoline No. 2 

Last updated: 9 March 1998 
IRON AND STEEL FOUNDING

(Group 1) 

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 224) 

A. Evidence for carcinogenicity to humans (sufficient)

Analytical cohort epidemiological studies of foundry workers conducted in a number of countries 

have typically noted risks of lung cancer elevated between 1.5 and 2.5 fold [ref: 1,2]. Proportionate 

mortality studies have also shown the proportion of deaths from lung cancer to be 1.5- to 1.8-fold 

greater than that in the general population. Associations between foundry work and lung cancer 

have similarly been observed in studies of mortality statistics [ref: 1]. 

In two studies in which site-specific cancer deaths among iron and steel foundry workers were 

compared with corresponding rates for the general population, significantly increased risks for 

cancer of the digestive system were observed; in one, the elevated risk was for cancers in the 

'digestive system', in the other, it was for 'stomach cancer' [ref: 1]. 

Results of studies of a single cohort of steel foundry workers in the USA showed a significantly 

elevated risk of cancer of the genito-urinary system when compared with the entire steel worker 

population under study, the risk being significantly elevated also for some specific sites (prostate 

and kidney) [ref: 1]. 

Elevated lung cancer risks have also been reported in a grey-iron foundry [ref: 2], in steel foundries 

[ref: 3], in iron and steel foundries [ref: 2] and among persons living near steel foundries [ref: 4]. 

No consistent excess of lung cancer, however, was reported among foundrymen employed in a 

nickel-chromium alloy foundry [ref: 5]. Other cancer excesses reported have included leukaemia, 

stomach cancer and urogenital cancer [ref: 2]. Despite the absence of information to specify 

definitely the carcinogenic substances in the work environment (e.g., polynuclear aromatic 

hydrocarbons, silica, metal fumes, formaldehyde), the consistency of the excess in studies from 

around the world shows that certain exposures in iron and steel founding can cause lung cancer in 

humans. Most studies lacked information on smoking, but, when it was available, it did not appear 

that tobacco use could explain the lung cancer excess. 

B. Other relevant data

Antigenicity against benzo[a]pyrene diol epoxide-DNA adducts has been demonstrated in peripheral 

lymphocytes of foundry workers [ref: 5]. 

Overall evaluation

Iron and steel founding entails exposures that are carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 34 (1984)

References

1. IARC Monographs, 34, 133-190, 1984 

2. IARC Monographs, 42, 39-143, 1987 
3. Fletcher, A.C. & Ades, A. (1984) Lung cancer mortality in a cohort of English foundry workers. 

Scand. J. Work Environ. Health, 10, 7-16 

4. Lloyd, O.L., Smith, G., Lloyd, M.M., Holland, Y. & Gailey, F. (1985) Raised mortality from lung 

cancer and high sex ratios of births associated with industrial pollution. Br. J. ind. med., 42, 475-

480 

5. Cornell, R.G. & Landris, J.R. (1984) Mortality patterns among nickel/chromium alloy foundry 

workers. In: Sunderman, F.W., Jr, ed., Nickel in the Human Environment (IARC Scientific 

Publications No. 53), Lyon, International Agency for Research on Cancer, pp. 87-93 

5. IARC Monographs, Suppl. 6, 344, 1987 

Last updated: 9 February 1998 
IRON DEXTRAN COMPLEX

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 226) 

CAS No.: 9004-66-4

A. Evidence for carcinogenicity to humans (inadequate)

An early report was made of a woman who had developed an undifferentiated soft-tissue sarcoma 

following multiple injections of iron-dextran complex [ref: 1]. In a report on 196 cases of sarcoma of 

the buttock, four of 90 for whom records on drug use were still available had been given 

intramuscular injections of iron. In three of the cases, an interval of at least two years had elapsed 

[ref: 2]. A selective tendency to report receiving iron injections may have introduced bias. A review 

of reports during the period 1960-1977 indicated that nine malignancies had been described in five 

reports. Two were thought to have been foreign-body reactions to fat necrosis; one was a 

metastatic carcinoma at the site of an iron-dextran injection; and one was a reticulum-cell sarcoma 

with fractures of the pelvis possibly only coincidentally related to iron injections six years before. 

Several of the remainder were of different histological type [ref: 3]. Only one, a poorly 

differentiated spindle-cell fibrosarcoma, was believed likely to be related to iron-dextran injections 

given 14 years previously [ref: 4]. No further case report or epidemiological study is known to the 

Working Group. It seems probable that the considerable publicity given to the initial case report 

[ref: 1] and the tendency to give parenteral iron therapy intravenously may have considerably 

reduced human exposure to intramuscularly administered iron-dextran complex. 

B. Evidence for carcinogenicity to animals (sufficient)

Iron-dextran complex has been tested in mice, rabbits and rats by repeated subcutaneous or 

intramuscular injections, producing local tumours at the injection site [ref: 1,5]. The Working Group 

noted that iron-dextran complex accumulates at the site of injection in rodents, in contrast to its 

rapid dispersal after injection in human beings. 

C. Other relevant data

No adequate data were available to the Working Group. 

Overall evaluation

Iron dextran complex is possibly carcinogenic to humans (Group 2B).

References

1. IARC Monographs, 2, 161-178, 1973

2. Greenberg, G. (1976) Sarcoma after intramuscular iron injection. Br. med. J., ii, 1508-1509

3. Fielding, J. (1977) Does sarcoma occur in man after intramuscular iron? Scand. J. Haematol., 

Suppl. 32, 100-104

4. Robertson, A.G. & Dick, W.C. (1977) Intramuscular iron and local oncogenesis. Br. med. J., i, 946

5. Hruby, M. & Damková, E. (1985) Induction and transplantability of ferridextran tumours in inbred 

strains of Rattus norvegicus (Czech.). Sbornik Lék., 87, 114-120
For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 2 (1973)

Synonyms

● Dextran iron complex 

● Iron dextran injection 

● Ironorm injection 

Last updated: 3 March 1998 
ISONICOTINIC ACID HYDRAZIDE (ISONIAZID)

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 227)

CAS No.: 54-85-3 

A. Evidence for carcinogenicity to humans (inadequate) 

Several early studies showed no significant excess of cancer among patients treated with isoniazid 

[ref: 1]. A study of 3842 tuberculosis patients followed for 16-24 years showed slight excesses of 

deaths from malignant neoplasms of the bronchus, lung and pleura in 2041 patients treated with 

isoniazid during 1953-1957 and followed through to 1973 (relative risk, 1.6 [95% confidence 

interval, 1.2-2.1], but none in 655 treated for tuberculosis in 1950-1952 when isoniazid was not 

generally available (0.7 [0.1-1.5]). An excess of all malignant neoplasms was also seen in patients 

treated in 1953-1957 (1.4 [1.2-1.7]), but also in 145 patients not treated with isoniazid over the 

same period (1.8 [0.7-2.9]). Again, no excess was observed in those treated for tuberculosis in 

1950-1952. No dose-response effect was seen either for total consumption or for maximum daily 

dose of isoniazid [ref: 2]. Additional studies of cancer incidence and mortality among patients 

treated with isoniazid have shown no excess of lung cancer, or of cancer as a whole, that could be 

attributed to treatment [ref: 3-6]. A cancer incidence study in patients with tuberculosis, involving 

heavy smokers, showed an excess of lung cancer among men exposed to isoniazid (3.4, based on 

88 cases observed, 26.2 expected) but also among those not exposed (2.6, based on 18 cases 

observed, 7.0 expected). The difference between the two ratios was not statistically significant. The 

corresponding figures for women were 4.6, based on 14 cases exposed, and 0.5, based on one case 

not exposed [ref: 7]. In a preliminary analysis of one-year case records, 72 (4.9%) cancer patients 

had healed tuberculosis compared with 26 (2%) noncancer patients [ref: 8]. Four case-control 

studies concerning bladder and kidney cancers [ref: 9], bladder cancer [ref: 10,11] and cancer in 

children [ref: 12] have provided no conclusive evidence of a risk associated with isoniazid therapy. A 

single case of mesothelioma has been reported in a nine-year-old child whose mother was treated 

with isoniazid for a positive tuberculin skin test in the second and third trimesters of pregnancy [ref: 

13]. 

B. Evidence for carcinogenicity to animals (limited) 

Isoniazid produced lung tumours in mice after its oral, intraperitoneal or subcutaneous 

administration [ref: 1,8,13-16]. Studies in rats were considered inadequate for evaluation [ref: 1]. 

No tumour was produced in hamsters after given oral administration of isoniazid [ref: 1]. 

C. Other relevant data

In the one available study, isoniazid did not induce chromosomal aberrations in lymphocytes of 

treated patients [ref: 17]. 

Isoniazid did not induce dominant lethal mutations in mice, or chromosomal aberrations, sister 

chromatid exchanges or DNA damage in rodents treated in vivo. Results for chromosomal 

aberrations and sister chromatid exchanges in human cells in vitro were inconclusive; it did not 

induce unscheduled DNA synthesis. In cultured rodent cells, it induced chromosomal aberrations 

and sister chromatid exchanges, but not DNA damage. It did not induce transformation of Syrian 

hamster embryo cells. It did not induce gene conversion in yeast. Isoniazid was mutagenic to 

Salmonella typhimurium but not, in a single study, to Escherichia coli [ref: 17]. 

Overall evaluation

Isonicotinic acid hydrazide (Isoniazid) is not classifiable as to its carcinogenicity to humans (Group 
3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 4 (1974)

References

1. IARC Monographs, 4, 159-172, 1974 

2. Stott, H., Peto, J., Stephens, R., Fox, W., Sutherland, I., Foster-Carter, A.F., Teare, H.D. & 

Fenning, J. (1976) An assessment of the carcinogenicity of isoniazid in patients with pulmonary 

tuberculosis. Tubercle, 57, 1-15 

3. Glassroth, J.L., White, M.C. & Snider, D.E., Jr (1977) An assessment of the possible association of 

isoniazid with human cancer deaths. Am. Rev. respir. Dis., 116, 1065-1074 

4. Howe, G.R., Lindsay, J., Coppock, E. & Miller, A.B. (1979) Isoniazid exposure in relation to cancer 

incidence and mortality in a cohort of tuberculosis patients. Int. J. Epidemiol., 8, 305-312 

5. Boice, J.D. & Fraumeni, J.F., Jr (1980) Late effects following isoniazid therapy. Am. J. publ. 

Health, 70, 987-989 

6. Costello, H.D. & Snider, D.E., Jr (1980) The incidence of cancer among participants in a 

controlled, randomized isoniazid preventive therapy trial. Am. J. Epidemiol., 111, 67-74 

7. Clemmesen, J. & Hjalgrim-Jensen, S. (1979) Is isonicotinic acid hydrazide (INH) carcinogenic to 

man? A 24-year follow-up of 3371 tuberculosis cases. Ecotoxicol. environ. Saf., 3, 439-450 

8. Bhide, S.V., Maru, G.B., Mate, N.B., Menon, M. & Gangadharan, P. (1981) Metabolic studies on 

the possible mode of action of isoniazid tumorigenicity. J. Cancer Res. clin. Oncol., 99, 153-166 

9. Glassroth, J.L., Snider, D.E. & Comstock, G.W. (1977) Urinary tract cancer and isoniazid. Am. 

Rev. respir. Dis., 116, 331-333 

10. Miller, C.T., Neutel, C.I., Nair, R.C., Marrett, L.D., Last, J.M. & Collins, W.E. (1978) Relative 

importance of risk factors in bladder carcinogenesis. J. chron. Dis., 31, 51-56 

11. Kantor, A.F., Hartge, P., Hoover, R.N. & Fraumeni, J.F., Jr (1985) Tuberculosis chemotherapy 

and risk of bladder cancer. Int. J. Epidemiol., 14, 182-184 

12. Sanders, B.M. & Draper, G.J. (1979) Childhood cancer and drugs in pregnancy. Br. med. J., i, 

717-718 

13. Tuman, K.J., Chilcote, R.R., Berkow, R.I. & Moohr, J.W. (1980) Mesothelioma in child with 

prenatal exposure to isoniazid. Lancet, ii, 362 

14. Maru, G.B., Sawai, M.M. & Bhide, S.V. (1980) Prevention of isoniazid tumorigenicity by 

antitoxicants of isoniazid in Swiss mice. J. Cancer Res. clin. Oncol., 97, 145-151 

15. Maru, G.B. & Bhide, S.V. (1982) Effect of antioxidants and antitoxicants of isoniazid on the 

formation of lung tumours in mice by isoniazid and hydrazine sulphate. Cancer Lett., 17, 75-80 

16. Menon, M.M. & Bhide, S.V. (1983) Perinatal carcinogenicity of isoniazid (INH) in Swiss mice. J. 
Cancer Res. clin. Oncol., 105, 258-261 

17. IARC Monographs, Suppl. 6, 347-350, 1987 

Synonyms

● Actobine 

● Actotibine 

● Aldoxal 

● Andrazida 

● Aneufos simple 

● Anteben 

● Antimicina 

● Antituberkulosum trogalen 

● Armazide 

● Azuren 

● Bacikoch 

● Bacillin 

● Banzid 

● Basidracida 

● Becazida 

● Buco-hidracid 

● Cedin 

● Cemidon 

● Chemiazid 

● Chemidon 

● Cin-vis 

● Cotinazin 

● Cotinizin 

● Dardex 

● Diazid 

● Dif-azidrin 

● Dinacrin 

● Dioforin 

● Ditubin 

● Dracotil 

● Ducun 

● Ebidene 

● Eralon 

● Ertuban 

● Eutizon 

● Evalon 

● Evigril 

● Fimalene 

● Fimazid 

● FSR-3 

● GINK 

● Hain 

● HIA 

● Hidraciber 

● Hidracida 

● Hidrafasa 

● Hidral-grey 

● Hidralter 

● Hidranic 

● Hidranizil 

● Hidra-Noxi 

● Hidraquimia 

● Hidrasegur 

● Hidrasix 

● Hidrasonil 

● Hidrassal 

● Hidrastol 
● Hidratorax 

● Hidrazida-I.N. 

● Hidrazinol 

● Hidrina 

● Hidrulta 

● Hidrun 

● Hiperazida 

● Hycozid 

● Hydra 

● Hydrazid polfa 

● Hydrazide horus 

● Hydrazide medial 

● Hydrazide otsuka 

● Hydrozin 

● Hyzyd 

● Idocobin 

● Ido-Tebin 

● Idrazil 

● INA 

● INAH 

● Inazid 

● INH 

● Inhizid 

● Inizid 

● Iscotin 

● Isidrina 

● Ismazide 

● Isobicina 

● Isocid 

● Isocidene 

● Isocotin 

● Iso-Dexter 

● Isolyn 

● Isomerina 

● Isonazida 

● Isonerit 

● Isonex 

● Isonhidrol 

● Isoniazid 

● Isoniazide 

● Isoniazone 

● Isonicazide 

● Isonicid 

● Isonico 

● Isonicol 

● Isonicotan 

● Isonicotil 

● Isonicotinoylhydrazine 

● Isonicotinylhydrazine 

● Isonide 

● Isonidrin 

● Isonikazid 

● Isonilex 

● Isonilyd 

● Isonin 

● Isonindon 

● Isoniton 

● Isonitrit 

● Isonizan 

● Isonizide 

● Iso-pentabine 

● Isopyrin astra 

● Isotebe 

● Isotebezid 

● Isotinyl 
● Isotubin 

● Isoxine 

● Isozid 

● Isozide 

● Isozin 

● Isozyd 

● Isonisin 

● Kemia 

● Kozidrina 

● Kridansimple 

● L 1945 

● Laniazid 

● Laniozid 

● Lefos 

● Leotubrin-wirkstoff 

● Lesviazida 

● Lubacida 

● Marsilid 

● Marvidrazida 

● Mesegacida 

● Micosan 

● Milazide 

● Mybasan 

● Mycoseptina 

● Neoplasina 

● Neoteben 

● Neoxin 

● Neoxon 

● Neumandin 

● Nevin 

● Niadrin 

● Niazid 

● Niazida 

● Nicazid 

● Nicazide 

● Nicetal 

● Nicizina 

● Niconyl 

● Nicosciorin 

● Nicotibina 

● Nicotibine 

● Nicotisan 

● Nicotubin 

● Nicozid 

● Nicozide 

● Nicozin 

● Nidaton 

● Nidrazid 

● Nieteban 

● Nikozid 

● Niplen 

● Nitadon 

● Nortibina 

● Nydrazid 

● Nyscozid 

● Pacrazid 

● Pelazid 

● Percin 

● Percitron 

● Peritracida 

● Phthisen 

● Pycazide 

● Pyreazid 

● Pyricidin 

● Pyridicin 
● 4-Pyridinecarboxylic acid hydrazide 

● Pyridine-4-carboxylic acid hydrazide 

● Pyridine-γ-carboxylic acid hydrazide 

● Pyrinal 

● Pyrizidin 

● Raumanon 

● Rebilon 

● Retozide 

● Rimicid 

● Rimifon 

● Rimitsid 

● Rinverfons 

● Roberazyd 

● Robisellin 

● Roxifen miquel 

● RU-EF-Tb 

● Sanohidrazina 

● Sauterazid 

● Stanozide 

● Sumifon 

● Tb-Phlogin 

● T.B. Razide 

● TB-Vis 

● Tebecid 

● Tebecin 

● Tebenic 

● Tebesium-wirkstoff 

● Tebetracin 

● Tebexin 

● Tebilon 

● Tebos 

● Teebaconin 

● Tekazin 

● Tibazide 

● Tibemid 

● Tibinid 

● Tibinide 

● Tibison 

● Tibitan 

● Tibivis 

● Tibizide 

● Tibusan 

● Tisin 

● Tisiodrazida 

● Tizide 

● Tizopan 

● Tubazid 

● Tubazide 

● Tubeco 

● Tubercid 

● Tuberian 

● Tuberon 

● Tubezin 

● Tubicon 

● Tubilysin 

● Tubomel 

● Tubriz 

● Tyvid 

● Unicozyde 

● Vazadrine 

● Vederon 

● Zidafimia 

● Zideluy 

● Zinadon 

● Zonazide 
Last updated: 9 March 1998 
LEAD AND LEAD COMPOUNDS:

LEAD AND INORGANIC LEAD COMPOUNDS

(Group 2B)

ORGANOLEAD COMPOUNDS

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 230) 

Lead

CAS No.: 7439-92-1 

Lead acetate

CAS No.: 301-04-2

Chem. Abstr. Name: Acetic acid, lead (2+) salt 

Lead acetate trihydrate

CAS No.: 6080-56-4

Chem. Abstr. Name: Acetic acid, lead (2+) salt, trihydrate 

Lead carbonate

CAS No.: 598-63-0

Chem. Abstr. Name: Carbonic acid, lead (2+) salt (1:1) 

Lead chloride

Chem. Abstr. Name: 7758-95-4

Chem. Abstr Name: Lead chloride [PbCl2] 

Lead naphthenate

CAS No.: 50825-29-1 

Lead nitrate

CAS No.: 10099-74-8

Chem. Abstr. Name: Nitric acid, lead (2+) salt 

Lead oxide

CAS No.: 1317-36-8

Chem. Abstr. Name: Lead oxide [Pb0] 

Lead phosphate

CAS No.: 7446-27-7

Chem. Abstr. Name: Phosphoric acid, lead (2+) salt (2:3) 

Lead subacetate

CAS No.: 1335-32-6

Chem. Abstr. Name: Lead, bis(acetato-O)tetrahydroxytriLead tetroxide

CAS No.: 1314-41-6

Chem. Abstr. Name: Lead oxide [Pb3O4] 

Tetraethyllead

CAS No.: 78-00-2

Chem. Abstr. Name: Plumbane, tetraethyl- 
Tetramethyllead

CAS No.: 75-74-1

Chem. Abstr. Name: Plumbane, tetramethylA. Evidence for carcinogenicity to humans (inadequate)

Three epidemiological studies of workers exposed to lead and lead compounds were reviewed 

previously [ref: 1]: one on smelters and battery workers in the USA, one on workers exposed to 

tetraethyllead in the USA, and one on copper smelters in the USA; data on the first of these 

populations have been updated [ref: 2]. A study on battery workers in the UK [ref: 3] is now 

available, and studies of a US lead smelter [ref: 4] and of a Swedish copper smelter [ref: 5] have 

also been reported. A statistically significant excess of cancers of the digestive system (21 observed, 

12.6 expected) was found in the study of battery workers in the UK, spanning 1925-1976, although 

the excess was confined to the years 1963-1966 [ref: 3]. Significant excesses of stomach cancer (34 

observed, 20.2 expected) and of respiratory cancers (116 observed, 93.5 expected) were seen in the 

study of US battery plant workers [ref: 2], although there was a downward trend in standardized 

mortality ratio by number of years of employment; in the lead production facilities, the excesses 

noted for stomach and respiratory cancers were not significant [ref: 2]. A nonsignificant excess of 

respiratory cancer (41 observed, 36.9 expected) was reported in one of the studies of smelters [ref: 

4], with 28 observed and 25.7 expected in the group with high exposure to lead. Excesses were also 

noted in this study for kidney cancer (6 observed, 2.9 expected) and bladder cancer (6 observed, 

4.2 expected) [ref: 4]. A small study of workers at a Swedish smelter [ref: 5] with long-term 

exposure to lead demonstrated a nonsignificant excess of lung cancers (8 observed, 5 expected). 

Two cases of kidney cancer in lead smelter workers have also been reported [ref: 6,7].

The excesses of respiratory cancer in these studies were relatively small, showed no clear-cut trend 

with length or degree of exposure, and could have been confounded by factors such as smoking or 

exposure to arsenic.

A study of workers manufacturing tetraethyllead revealed excesses of respiratory cancer (15 

observed, 11.2 expected) and brain cancer (3 observed, 1.6 expected) [ref: 8]. 

B. Evidence for carcinogenicity to animals (sufficient for inorganic lead compounds; inadequate

for organolead compounds)

Lead acetate and lead subacetate were tested for carcinogenicity by oral, subcutaneous and 

intraperitoneal administration in rats, lead phosphate was tested by subcutaneous and 

intraperitoneal administration in rats, and lead subacetate was tested by oral administration in mice. 

Renal tumours were produced in animals of each species by each route of administration. Rats given 

lead acetate or lead subacetate orally developed gliomas. Lead subacetate also produced an 

increased incidence of lung adenomas in mice after intraperitoneal administration [ref: 1]. Oral 

administration of lead dimethyldithiocarbamate (ledate) increased the incidence of reticulum-cell 

sarcomas in male mice of one strain [ref: 9] but was not carcinogenic to mice or rats in another 

experiment [ref: 10].

Synergistic effects were reported [ref: 1,11-14] in the kidneys of rats given lead acetate and Nnitroso-N-(hydroxyethyl)ethylamine, N-(4'-fluoro-4-biphenyl)acetamide or 2-

(nitrosoethylamine)ethanol orally and in the lungs of hamsters given lead oxide with benzo[a]pyrene 

intratracheally. Lead subacetate given in the diet increased the incidences of liver and kidney 

tumours induced in rats by 2-acetylaminofluorene given in the diet [ref: 1].

The lead compounds tested for carcinogenicity in animals are almost all soluble salts that were 

selected on the basis of ease of administration. Metallic lead, lead oxide and lead tetraalkyls have 

not been tested adequately. 

C. Other relevant data

Studies of chromosomal aberrations in people exposed to lead have given conflicting results: positive 

reports have been published concerning workers in lead-battery industries and lead smelters, but 
other studies of workers under comparable conditions have given negative results. Increased 

incidences of sister chromatid exchanges have been reported in the peripheral blood lymphocytes of 

workers exposed to lead but not in those of children exposed to high levels of lead in the 

environment. An increased incidence of sperm abnormalities was seen in men exposed 

occupationally to lead [ref: 15].

Although a few studies in rodents treated with lead salts in vivo have shown small (but significant) 

increases in the frequency of chromosomal aberrations and micronuclei in bone-marrow cells, most 

studies showed no increase. Lead salts caused morphological sperm abnormalities in mice but not in 

rabbits. Sister chromatid exchanges and unscheduled DNA synthesis were not induced in cells of 

animals treated with lead salts in vivo. Lead salts did not induce chromosomal aberrations in human 

lymphocytes in vitro. Conflicting results have been obtained in assays for transformation in cultured 

rodent cells. Lead salts did not cause aneuploidy in Drosophila, mutation or gene conversion in yeast 

or mutation or DNA damage in bacteria [ref: 15].

Tetraethyl- and tetramethyllead did not induce mutation in bacteria [ref: 15]. 

References

1. IARC Monographs, 23, 39-141, 325-415, 1980

2. Cooper, W.C., Wong, O. & Kheifets, L. (1985) Mortality among employees of lead battery plants 

and lead producing plants, 1947-1980. Scand. J. Work Environ. Health, 11, 331-345

3. Malcolm, D. & Barnett, H.A.R. (1982) A mortality study of lead workers 1925-76. Br. J. ind. Med., 

39, 404-410

4. Selevan, S.G., Landrigan, P.J., Stern, F.B. & Jones, J.H. (1985) Mortality of lead smelter workers. 

Am. J. Epidemiol., 122, 673-783

5. Gerhardsson, L., Lundström, N.-G., Nordberg, G. & Wall, S. (1986) Mortality and lead exposures: 

a retrospective cohort study of Swedish smelter workers. Br. J. ind. Med., 43, 707-712

6. Baker, E.L., Jr, Goyer, R.A., Fowler, B.A., Khettry, U., Bernard, D.B., Adler, S., White, R. de V., 

Babayan, R. & Feldman, R.G. (1980) Occupational lead exposure, nephropathy, and renal cancer. 

Am. J. ind. Med., 1, 139-148

7. Lilis, R. (1981) Long term occupational lead exposure, chronic nephropathy, and renal cancer: a 

case report. Am. J. ind. Med., 2, 293-297

8. Sweeney, M.H., Beaumont, J.J., Waxweiler, R.J. & Halperin, W.E. (1986) An investigation of 

mortality from cancer and other causes of death among workers employed at an East Texas chemical 

plant. Arch. environ. Health, 41, 23-28

9. IARC Monographs, 12, 131-135, 1976

10. National Cancer Institute (1979) Bioassay of Lead Dimethyldithiocarbamate for Possible 

Carcinogenicity (Tech. Rep. Ser. No. 151; DHEW Publ. No. (NIH) 79-1707), Washington DC, US 

Department of Health, Education and Welfare

11. Hinton, D.E., Lipsky, M.M., Heatfield, B.M. & Trump, B.F. (1979) Opposite effects of lead on 

chemical carcinogenesis in kidney and liver of rats. Bull. environ. Contam. Toxicol., 23, 464-469

12. Tanner, D.C. & Lipsky, M.M. (1984) Effect of lead acetate on N-(4'-fluoro-4-biphenyl)acetamideinduced renal carcinogenesis in the rat. Carcinogenesis, 5, 1109-1113
13. Shirai, T., Ohshima, M., Masuda, A., Tamano, S. & Ito, N. (1984) Promotion of 2-

(ethylnitrosamine)ethanol-induced renal carcinogenesis in rats by nephrotoxic compounds: positive 

responses with folic acid, basic lead acetate, and N-(3,5-dichlorophenyl)succinimide but not with 2,3-

dibromo-1-propanol phosphate. J. natl Cancer Inst., 72, 477-482

14. Hiasa, Y., Ohshima, M., Kitahori, Y., Fujita, T., Yuasa, T. & Miyashiro, A. (1983) Basic lead 

acetate: promoting effect on the development of renal tubular cell tumors in rats treated with Nethyl-N-hydroxyethylnitrosamine. J. natl Cancer Inst., 70, 761-765

15. IARC Monographs, Suppl. 6, 351-354, 1987 

Overall evaluation

Lead and inorganic lead compounds are possibly carcinogenic to humans (Group 2B).

Organolead compounds are not classifiable as to their carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 1 (1972); Vol. 2 (1973) ; Vol. 12 (1976) ; Vol. 23 (1980) 

Synonyms for Lead

● KS-4 

● Lead flake 

● Lead S2 

● Pigment Metal 4 

● SO 

● SI 

Synonyms for Lead acetate

● Dibasic lead acetate 

● Lead[II] acetate 

● Lead (2+) acetate 

● Lead diacetate 

● Lead dibasic acetate 

● Plumbous acetate 

● Salt of Saturn 

● Sugar of Lead 

Synonym for Lead acetate trihydrate

● Lead diacetate trihydrate 

Synonyms for Lead carbonate

● Dibasic lead carbonate 

● Lead (2+) carbonate 

● White lead 

Synonyms for Lead chloride

● Lead[II] chloride 

● Lead (2+) chloride 
● Lead dichloride 

● Plumbous chloride 

Synonyms for Lead nitrate

● Lead dinitrate 

● Lead[II] nitrate 

● Lead (2+) nitrate 

Synonyms for Lead oxide

● Lead monoxide 

● Lead oxide yellow 

● Lead[II] oxide 

● Lead protoxide 

● Plumbous oxide 

● Litharge 

● Litharge pure 

● Litharge Yellow L-28 

● Massicot 

● Massicotite 

● Pigment Yellow 46 

● Yellow lead ocher 

Synonyms for Lead phosphate

● Lead orthophosphate 

● Lead phosphate (3:2) 

● Lead (2+) phosphate 

● Perlex Paste 500 

● Perlex Paste 600A 

● Trilead phosphate 

Synonyms for Lead subacetate

● Basic lead acetate 

● Bis(aceto)dihydroxytrilead 

● Bis(acetato)tetrahydroxytrilead 

● Lead acetate, basic 

● Monobasic lead acetate 

● Subacetate lead 

Synonyms for Lead tetroxide

● Lead orthoplumbate 

● Lead oxide, red 

● Lead tetraoxide 

● Orange lead 

● Saturn red 

● Pigment Red 105 

● Plumboplumbic oxide 

● Red lead 

● Red lead oxide 

● Trilead tetroxide 

● Mineral Orange 

● Minium 

● Minium red 

● Paris red 
Synonyms for Tetraethyllead

● TEL 

● Tetraethylplumbane 

Synonyms for Tetramethyllead

● Tetramethylplumbane 

● TML 

Last updated: 3 March 1998 
LEATHER GOODS MANUFACTURE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 235)

Evidence for carcinogenicity to humans (inadequate) 

A few cases of leukaemia have been reported following exposure to benzene (a known human 

carcinogen [ref: 1]) during the manufacture of leather goods other than boots and shoes. The 

number of cases of nasal cancer reported is insufficient to make an association with employment in 

the manufacture of leather goods (other than boots and shoes) [ref: 2]. A positive association 

between bladder cancer and employment in the leather products industry is suggested by a number 

of studies. A case-control study in West Yorkshire, UK, showed a statistically nonsignificant risk of 

bladder cancer associated with employment in leather goods production (as well as tanning, and 

boot and shoe repairing) [ref: 3]. Indications of an association with dusty leather occupations (not 

only shoemaking) came from a similar study in London [ref: 4]. In two of three areas in which a 

collaborative study of environmental risk factors for bladder cancer was conducted, a significant 

association with employment in 'leather' was found. The term 'leather' comprised the manufacture 

of leather goods, the leather or tanning industry or shoemaking [ref: 5]. Leather goods manufacture 

was most probably included in the leather exposure found to be statistically significantly associated 

with bladder cancer in another study in the USA [ref: 6]. None of the studies provides sufficient 

grounds to evaluate the specific role of the production of leather goods in the established 

association of leather work and cancer risk to humans. 

Overall evaluation

Leather goods manufacture entails exposures that are not classifiable as to their carcinogenicity to 

humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 25 (1981)

References

1. IARC Monographs, 29, 93-148, 391-397, 1982 

2. IARC Monographs, 25, 279-292, 1981 

3. Cartwright, R.A. & Boyko, R.W. (1984) Kidney cancer among leather workers. Lancet, i, 850-851 

4. Baxter, P.J. & McDowall, M.E. (1986) Occupation and cancer in London: an investigation into 

nasal and bladder cancer using the Cancer Atlas. Br. J. ind. Med., 43, 44-49 

5. Morrison, A.S., Ahlbom, A., Verhoek, W.G., Aoki, K., Leck, I., Ohno, Y. & Obata, K. (1985) 

Occupation and bladder cancer in Boston, USA, Manchester, UK, and Nagoya, Japan. J. Epidemiol. 

Commun. Health, 39, 294-300 

6. Marrett, L.D., Hartge, P. & Meigs, J.W. (1986) Bladder cancer and occupational exposure to 

leather. Br. J. ind. Med., 43, 96-100 
Last updated: 9 March 1998 
LEATHER TANNING AND PROCESSING

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 236) 

Evidence for carcinogenicity to humans (inadequate) 

Early studies of cancer risks possibly associated with leather industries provide little information 

specifically related to workers in tanneries. There was no evidence to suggest an association 

between leather tanning and nasal cancer [ref: 1]. Following the observation of an increased risk of 

nasal cancer among boot and shoe manufacturers, possibly associated with exposure to dust from 

leather tanned by a particular process [ref: 2], a study was designed to examine the possible cancer 

risk carried by different methods of leather tanning. The mortality experience of two groups of men 

working in tanneries in 1939 was compared to that of the population of England and Wales, and for 

no cause of death was a statistically significant increase above expectation found. Among the 573 

men employed in tanneries using a process with vegetable extracts, one death from nasal cancer 

was observed (0.21 expected); among 260 employees using a tanning process with chrome salts 

(tri- and hexavalent), one death from soft-tissue tumour (0.07 expected) was reported [ref: 3]. 

In a Swedish study, a slight increase in mortality from stomach cancer and a three-fold, significantly 

increased risk for cancer of the pancreas were found to be associated with the occupational titles 

'tanners' and 'tannery workers' as recorded in the registry of deaths and burials of a parish where a 

tannery had been in operation from 1873 to 1960. Tannery work involved exposure to chromium 

and, probably, to chlorophenols; smoking was an unlikely explanation for the findings, but the 

contribution of various dietary habits could not be ruled out [ref: 4]. Suggestions of increased risks 

for intestinal cancer and lung cancer and for cancer of the tonsils were imputed by a mortality study 

of workers employed in a tannery plant using chromium salts and synthetic tannins [ref: 5]. An 

association between lung cancer and tanning was also suggested by a study of incident cases in the 

UK [ref: 6] and by a study of cancer deaths among shoe and leather workers in the USA, in which 

the estimated risk for tannery workers relative to a group of workers classified as nonexposed was 

4.2, which was statistically significant. Chromium and arsenicals were mentioned as possibly 

contributing to the excess of lung cancer [ref: 7]. Significantly increased lung cancer mortality was 

also found among a group of fur tanners in the USA, who had probably been exposed to chrome 

(hexavalent) tanning agents [ref: 8]. 

In a study of bladder cancer and occupation, a relative risk of 1.5 was found for leather tanners , 

which is not statistically significant [ref: 1]. No significant excess of bladder cancer was found in 

another study in tanners in the UK [ref; 9]. In two of three areas in which a collaborative study of 

environmental risk factors for bladder cancer was conducted, a significant association with 

employment in 'leather' was found; the term 'leather' comprised the leather or tanning industry, the 

manufacture of leather goods or shoemaking [ref: 10]. 

In a cohort of 1629 leather tanners in Sweden, eight cases of kidney cancer were observed, while 

3.4 would have been expected from regional rates [ref: 11]. The hypothesis of this association was 

not supported by another study [ref: 12]. 

Overall evaluation

Leather tanning and processing entail exposures that are not classifiable as to their carcinogenicity 

to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 25 (1981)
References

1. IARC Monographs, 25, 201-247, 1981 

2. Acheson, E.D., Pippard, E.C. & Winter, P.D. (1982) Nasal cancer in the Northamptonshire boot 

and shoe industry: is it declining ? Br. J. Cancer, 46, 940-946 

3. Pippard, E.C., Acheson, E.D. & Winter, P.D. (1985) Mortality of tanners. Br. J. ind. Med., 42, 285-

287 

4. Edling, C., Kling, H., Flodin, U. & Axelson, O. (1986) Cancer mortality among leather tanners. Br. 

J. ind. Med., 43, 494-496 

5. Puntoni, R., Valerio, A., Cresta, E., Filiberti, R., Bonassi, S. & Vercelli, M. (1984) Mortality study 

in a tannery (Ital.). Med. Lav., 75, 471-477 

6. Coggon, D., Pannett, B., Osmond, C. & Acheson, E.D. (1986) A survey of cancer and occupation 

in young and middle aged men. I. Cancers of the respiratory tract. Br. J. ind Med., 43, 332-338 

7. Garabrant, D.H. & Wegman, D.H. (1984) Cancer mortality among shoe and leather workers in 

Massachusetts. Am. J. 

8. Sweeney, M.H., Walrath, J. & Waxweiler, R.J. (1985) Mortality among retired fur workers. Dyers, 

dressers (tanners) and service workers. Scand. J. Work Environ. Health, 11, 257-264 

9. Cartwright, R.A. & Boyko, R.W. (1984) Kidney cancer among leather workers. Lancet, i, 850-851 

10. Morrison, A.S., Ahlbom, A., Verhoek, W.G., Aoki, K., Leck, I., Ohno, Y. & Obata, K. (1985) 

Occupation and bladder cancer in Boston, USA, Manchester, UK, and Nagoya, Japan. J. Epidemiol. 

commun. Health, 39, 294-300 

11. Malker, H.R., Malker, B.K., McLaughlin, J.K. & Blot, W.J. (1984) Kidney cancer among leather 

workers. Lancet, i, 56 

12. Acheson, E.D. & Pippard, E.C. (1984) Kidney cancer among leather workers. Lancet, i, 563 

Last updated: 11 March 1998 
LUMBER AND SAWMILL INDUSTRIES (INCLUDING LOGGING)

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 383) 

A. Evidence for carcinogenicity to humans (inadequate)

Information on the occurrence of cancer in lumber and sawmill workers is limited. The available 

epidemiological data come primarily from surveys of statements of occupation on death certificates. 

Nasal tumours, malignant lymphomas and leukaemias and soft-tissue sarcomas have been linked 

with work in the lumber and sawmill industries, but the results are not consistent [ref: 1]. 

In a case-control study based on an analysis of occupational data in the hospital records of 121 men 

seen for nasal cancer in British Columbia, Canada, between 1939 and 1977, a relative risk of 2.5 

(adjusted for smoking and ethnic origin) was found to be associated with exposure to wood. There 

was increased risk for most histological types of epithelial tumour, except for transitional tumours. 

Of the 28 wood workers with nasal cancer, 16 had worked in the forestry industry, seven had been 

carpenters, four had been construction workers and one had been a cabinet-maker [ref: 2]. 

In a case-control study based on 167 cases of nasal or sinonasal cancer and 167 controls from 

Denmark, Finland and Sweden, exposure mainly to softwood dust (pine and spruce, but also some 

birch) was associated with epidermoid and anaplastic carcinomas, but not with adenocarcinomas. 

There were 13 cases with exposure only to softwood versus four controls (odds ratio, 3.3; 95% 

confidence interval, 1.1-9.4). Of these, four cases (all with epidermoid carcinoma) and two controls 

had been sawmill workers. Only two of the four cases had had potential exposure to chlorophenols 

[ref: 3]. 

In a Norwegian study based on 70 cases of various forms of sinonasal cancer (4 cases observed, 0.4 

expected in saw- and planingmill workers; 3 observed, 1.8 expected in forestry workers), three 

cases of non-Hodgkin's lymphoma were associated with employment in saw- and planingmill firms. 

The comparison was made beween the number of cases observed in different occupations and the 

expected number of cases according to the 1946 census data of workers in these occupations [ref: 

4]. 

A case-control study of Hodgkin's disease [ref: 5], using death certificates from North Carolina, USA, 

counties with a 'significant proportion' of the population employed in the furniture industry and in 

lumbering, showed an excess risk only among occupational groups with exposure to wood or paper. 

Carpenters and lumberers had a relative risk of 4.2 for Hodgkin's disease (95% confidence interval, 

1.4-12.5). In Oregon, USA, a case-control study on leukaemia (ICD-9 codes 204-208) [ref: 6] 

showed a three-fold increase in risk for patients who had worked for ten years or more in the 

sawmill industry (p = 0.017), based on nine exposed cases. 

In a proportionate mortality study of the causes of death of 375 union-affiliated Swedish 

lumberjacks who had died between 1968 and 1977, there were fewer deaths from cancer than 

expected (PMR, 88; 69-111). A marked deficiency of deaths from lung cancer (SMR, 33) and 

excesses of deaths from kidney cancer (SMR, 193; 92-407) and from cancers of the lymphatic and 

haematopoietic systems (SMR, 191; 105-349) were found. No information was given about the 

histology of these two groups of tumours. The mortality experience of Swedish males during that 

period was used as the standard for comparison [ref: 7]. 

A cohort study comparing the mortality experience of 10 322 men employed in the wood working 

industries with that of 406 798 non-wood workers showed no excess risk for all cancers combined. 

In the subcohort of lumber and sawmill workers, there was no statistically significantly increase in 

the incidence of cancer at any site. No case of nasal cancer was reported [ref: 8]. 

A nested case-control study [ref: 9], based on an average of 25 years' follow-up of 3805 men 
working in the Finnish particle-board, plywood, sawmill or formaldehyde glue industries between 

1944 and 1965, showed no clear connection between respiratory cancer incidence and most of the 

exposures studied, although some odds ratios were statistically significantly increased. For example, 

exposure to pesticides (in wood dust) and phenol was associated with elevated odds ratios, which 

became more marked among workers with more than ten years' exposure to pesticides. The raised 

odds ratios for exposure to phenol were partly explained by smoking and exposure to pesticides. 

Because of the mixed exposure, no single pesticide could be linked with respiratory cancer. Exposure 

to terpenes and other products of coniferous wood was also significantly associated with respiratory 

cancer when the duration of exposure exceeded five years. None of the odds ratios for exposure to 

wood dust and chlorophenols was statistically significant. 

A proportionate mortality study showed an elevated risk for death from all cancers (proportionate 

mortality ratio [PMR], 112; p < 0.01), stomach cancer (PMR, 128; p < 0.01) and non-Hodgkin's 

lymphoma (PMR, 139; p < 0.05) among woodworkers (including carpenters, cabinet and furniture 

workers, lumber graders and scalers, sawyers in sawmills and woodworkers not classified 

elsewhere). In this mixed category, there was no death from sinonasal cancer [ref: 10]. 

The epidemiological data reported here and previously [ref: 1] are not sufficient to make a definite 

assessment of the carcinogenic risks of employment in the lumber and sawmill industries. It should 

also be noted that these two industries differ greatly with regard to exposures other than wood dust. 

Some studies suggest that the incidences of nasal cancers, lung cancer and Hodgkin's and nonHodgkin's lymphoma may be increased. The patterns are not consistent, the results are based on 

few cases and, in some studies, work in furniture manufacture has not been excluded sufficiently 

well. The hypothesis of a link with Hodgkin's disease is not adequately supported. Soft-tissue 

sarcomas and histiocytic lymphomas have been reported following exposure to chlorophenols and 

phenoxyacetic acid herbicides, but the risk to sawmill and lumber workers was not quantified 

directly. Stomach cancer incidence was slightly elevated in these occupational groups in six mortality 

series; however, this might be related to nonoccupational factors. 

Overall evaluation

Lumber and sawmill industries (including logging) entail exposures that are not classifiable as to 

their carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 25 (1981) 

References

1. IARC Monographs, 25, 49-97, 1981 

2. Elwood, J.M. (1981) Wood exposure and smoking: association with cancer of the nasal cavity and 

paranasal sinuses in British Columbia. Can. med. Assoc. J., 15, 1573-1577 

3. Hernberg, S., Westerholm, P., Schultz-Larsen, K., Degerth, R., Kuosma, E., Englund, A., Engzell, 

U., Sand Hansen, H. & Mutanen, P. (1983) Nasal and sinonasal cancer. Connection with occupational 

exposures in Denmark, Finland and Sweden. Scand. J. Work Environ. Health, 9, 315-326 

4. Voss, R., Stenersen, T., Oppedal, B.R. & Boysen, M. (1985) Sinonasal cancer and exposure to 

softwood. Acta otolaryngol., 99, 172-178 

5. Greene, M.H., Brinton, L.A., Fraumeni, J.F., Jr & D'Amico, R. (1978) Familial and sporadic 

Hodgkin's disease associated with occupational wood exposure. Lancet, ii, 626-627 

6. Burkart, J.A. (1982) Leukemia in hospital patients with occupational exposure to the sawmill 

industry. West J. Med., 137, 440-441 
7. Edling, C. & Granstam, S. (1980) Causes of death among lumberjacks - a pilot study. J. occup. 

Med., 22, 403-406 

8. Stellman, S. & Garfinkel, L. (1984) Cancer mortality among woodworkers. Am. J. ind. Med., 5, 

343-357 

9. Kauppinen, T.P., Partanen, T.J., Nurminen, M.M., Nickels, J.I., Hernberg, S.G., Hakulinen, T.R., 

Pukkala, E.I. & Savonen, E.T. (1986) Respiratory cancers and chemical exposures in the wood 

industry: A nested case-control study. Br. J. ind. Med., 43, 84-90 

10. Gallagher, R.P., Threlfall, W.J., Band, P.R. & Spinelli, J.J. (1987) Cancer mortality experience of 

woodworkers, loggers, fishermen, farmers, and miners in British Columbia. Natl Cancer Inst. 

Monogr., 69, 163-167 

Last updated: 11 March 1998 
MEDROXYPROGESTERONE ACETATE

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 289) 

CAS No.: 71-58-9

Chem. Abstr. Name: (6α)-17-(Acetyloxy)-6-methylpregn-4-ene-3,20-dione 

A. Evidence for carcinogenicity to humans (inadequate)

The results of one cross-sectional study of the development of breast nodules in women given 

medroxyprogesterone acetate was difficult to interpret because of methodological considerations 

[ref: 1]. Two small cohort studies in the USA showed relative risks (and 95% confidence limits) of 

breast cancer in women exposed to medroxyprogesterone acetate of 0.69 (0.3-1.4) [ref: 2] and 1.1 

(0.5-2.4) [ref: 3], but both included only women with short-term exposure and limited duration of 

follow-up. A case-control study of 30 women with breast cancer and 179 controls [ref: 4] yielded a 

relative risk of 1.0 (no confidence limits given) for use of medroxyprogesterone acetate at some 

time. Preliminary analyses of a collaborative case-control study in Thailand, Kenya and Mexico 

sponsored by the World Health Organization [ref: 5], based on 427 cases (39 'ever' users) and 5951 

controls (557 'ever' users), provided estimates of relative risk (and 95% confidence limits) for breast 

cancer of 1.0 (0.7-1.5) in women who 'ever' used medroxyprogesterone acetate, 1.1 (0.7-1.9) for 

users for 1-12 months, 1.2 (0.7-2.2) for users for 13-36 months and 0.8 (0.4-1.7) for users for 37 

months or more.

Medroxyprogesterone acetate causes reversible changes in the endometrium, from proliferative to 

secretory or suppressed [ref: 4]. In one small cohort study, one case of uterine leiomyosarcoma was 

found, with 0.83 cancers of the uterine corpus expected, giving a relative risk of 1.2 [0.03-6.7] [ref: 

2]. In the collaborative study [ref: 5], the estimated relative risk for endometrial cancer in 'ever' 

users of medroxyprogesterone acetate was 0.3 (0.04-2.4), based on 57 cases, only one of which 

was exposed, and 316 matched controls (30 exposed).

In the small cohort study [ref: 2], one ovarian cancer case occurred in a medroxyprogesterone 

acetate user, with 1.16 expected, giving a relative risk of 0.86 [0.02-4.6]. Preliminary analysis of 

data from the collaborative study [ref: 5], based on 105 cases (seven exposed) and 637 matched 

controls (74 exposed) yielded a relative risk for ovarian cancer of 0.7 (0.3-1.7) in 'ever' users of 

medroxyprogesterone acetate.

The results of two cohort studies of dysplasia and of carcinoma in situ of the uterine cervix in women 

given medroxyprogesterone acetate were conflicting and difficult to interpret because of 

methodological problems [ref: 1]. Preliminary results from the collaborative study [ref: 5], based on 

920 cases of invasive cervical carcinoma (126 exposed to medroxyprogesterone acetate) and 5833 

controls (545 exposed) yielded estimated relative risks of 1.2 (0.9-1.5) in 'ever' users, after 

controlling for parity, history of vaginal discharge, age at first sexual relationship, number of sexual 

partners, number of prior Pap smears and use of an intrauterine device and oral contraceptives. 

Relative risks in users for 1-12, 13-24, 25-60 and 61 months or more were estimated to be 1.4 (1.0-

2.0), 1.2 (0.7-2.0), 0.6 (0.4-1.1) and 1.4 (0.9-2.2), respectively.

Preliminary analyses of data from the collaborative study [ref: 5] showed the relative risk for 

primary liver cancer (all histological types combined) in women who had ever used 

medroxyprogesterone acetate to be 1.0 (0.4-2.8), based on 57 cases (seven exposed) and 290 

controls (34 exposed). 

B. Evidence for carcinogenicity to animals (sufficient)

Medroxyprogesterone acetate was tested by intramuscular injection in dogs and by subcutaneous 

implantation in mice. It induced adenocarcinomas of the mammary gland in one study in female 
mice [ref: 6], and produced malignant mammary tumours in dogs [ref: 1]. After four years of 

intramuscular treatment of dogs with a human contraceptive dose, a dose-related increase in the 

incidence of mammary nodules was seen; the incidence of mammary-gland nodules at that time was 

comparable with that seen in dogs given progesterone at 25 times the canine luteal level [ref: 7]. 

Female dogs treated with medroxyprogesterone acetate for at least one year had a significant 

increase in the incidence of large and small mammary nodules as compared with control animals in 

one study [ref: 8], and a dose-related increase in the incidence of large mammary nodules was 

found in another after intramuscular administration [ref: 9]. 

C. Other relevant data

No data were available on the genetic and related effects of medroxyprogesterone acetate alone in 

humans. See, however, the summary of data for combined oral contraceptives. 

Medroxyprogesterone acetate induced sister chromatid exchanges in mouse cells in vitro. 

Overall evaluation

Medroxyprogesterone acetate is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 6 (1974) ; Vol. 21 (1979)

References

1. IARC Monographs, 21, 417-429, 1979

2. Liang, A.P., Levenson, A.G., Layde, P.M., Shelton, J.D., Hatcher, R.A., Potts, M. & Michelson, M.J. 

(1983) Risk of breast, uterine corpus, and ovarian cancer in women receiving medroxyprogesterone 

injections. J. Am. med. Assoc., 249, 2909-2912

3. Danielson, D.A., Jick, H., Hunter, J.R., Stergachis, A. & Madsen, S. (1982) Nonestrogenic drugs 

and breast cancer. Am. J. Epidemiol., 116, 329-332

4. Greenspan, A.R., Hatcher, R.A., Moore, A., Rosenberg, M.J. & Ory, H.W. (1980) The association of 

depo-medroxyprogesterone acetate and breast cancer. Contraception, 21, 563-569

5. Special Programme of Research, Development and Research Training in Human Reproduction 

(1986) Depot-medroxyprogesterone acetate DMPA and cancer. Memorandum from a WHO meeting. 

WHO Bull., 64, 375-382

6. Lanari, C., Molinolo, A.A. & Pasqualini, C.D. (1986) Induction of mammary adenocarcinomas by 

medroxyprogesterone acetate in BALB/c female mice. Cancer Lett., 33, 215-223

7. Frank, D.W., Kirton, K.T., Murchison, T.E., Quinlan, W.J., Coleman, M.E., Gilbertson, T.J., 

Feenstra, E.S. & Kimball, F.A. (1979) Mammary tumors and serum hormones in the bitch treated 

with medroxyprogesterone acetate or progesterone for four years. Fertil. Steril., 31, 340-346

8. van Os, J.L., van Laar, P.H., Oldenkamp, E.P. & Verschoor, J.S.C. (1981) Oestrus control and the 

incidence of mammary nodules in bitches, a clinical study with two progestogens. Vet. Q., 3, 46-56

9. Concannon, P.W., Spraker, T.R., Casey, H.W. & Hansel, W. (1981) Gross and histopathologic 

effects of medroxyprogesterone acetate and progesterone on the mammary glands of adult beagle 

bitches. Fertil. Steril., 36, 373-387
10. IARC Monographs, Suppl. 6, 359-360, 1987 

Synonyms for Medroxyprogesterone acetate

● 17α-Acetoxy-6α-methylprogesterone 

● Amen 

● Clinovir 

● Depcorlutin 

● Depo-clinovir 

● Depomedroxyprogesterone acetate 

● Depo-provera 

● Deporone 

● Farlutal 

● Farlutin 

● Gesinal 

● Gestapuran 

● Gestapuron 

● 17-Hydroxy-6α-methylpregn-4-ene-3,20-dione acetate 

● 17α-Hydroxy-6α-methylprogesterone acetate 

● Luteocrin 

● Lutopolar 

● Lutoral 

● MAP 

● Metigestrona 

● Metilgestene 

● Metipregnone 

● 6α-Methyl-17-acetoxyprogesterone 

● 6α-Methyl-17α-hydroxyprogesterone acetate 

● MPA 

● Nogest 

● Oragest 

● Perlutex 

● Prodasone 

● Progestalfa 

● Progevera 

● Promone-E 

● Provera 

● Proverone 

● Provest 

● Repromix 

● Sirprogen 

● Sodelut G 

● U 8839 

● Veramix 

Last updated: 3 March 1998 
MELPHALAN

(Group 1) 

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 239) 

CAS No.: 148-82-3

Chem. Abstr. Name: 4-[Bis(2-chloroethyl)amino]-L-phenylalanine 

A. Evidence for carcinogenicity to humans (sufficient)

Epidemiological studies of patients with ovarian carcinoma [ref: 1-3], multiple myeloma [ref: 4,5] or 

breast cancer [ref: 6] have consistently shown very large excesses of acute nonlymphocytic 

leukaemia in the decade following therapy with melphalan. The relative risk was consistently 

estimated to be in excess of 100, to increase with increasing dose, and to be roughly the same with 

and without radiotherapy [ref: 7]. 

B. Evidence for carcinogenicity to animals (sufficient)

Melphalan has been tested in mice and rats by intraperitoneal injection, producing lymphosarcomas 

and a dose-related increase in the incidence of lung tumours in mice and peritoneal sarcomas in rats 

[ref: 8]. 

C. Other relevant data

Melphalan is a bifunctional alkylating agent. Patients treated therapeutically with melphalan had 

increased frequencies of chromosomal aberrations and sister chromatid exchanges in their 

peripheral lymphocytes [ref: 9]. 

Melphalan induced chromosomal aberrations in bone-marrow cells of rats treated in vivo. The 

compound induced chromosomal aberrations, sister chromatid exchanges and DNA damage in 

human cells in vitro. It induced transformation of C3H 10T1/2 cells. In cultured rodent cells, it 

induced chromosomal aberrations, sister chromatid exchanges, mutation and DNA damage. It 

induced aneuploidy and sex-linked recessive lethal mutations in Drosophila and mutation in bacteria 

[ref: 9]. 

Overall evaluation

Melphalan is carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 9 (1975)

References

1. Einhorn, N., Eklund, G., Franzén, S., Lambert, B., Lindsten, J., & Söderhall, S. (1982) Late side 

effects of chemotherapy in ovarian carcinoma. A cytogenetic, hematologic, and statistical study. 

Cancer, 49, 2234-2241 

2. Reimer, R.R., Hoover, R., Fraumeni, J.F., Jr & Young, R.C. (1977) Acute leukemia after alkylatingagent therapy of ovarian cancer. New Engl. J. Med., 297, 177-181 
3. Greene, M.H., Boice, J.D., Jr, Greer, B.E., Blessing, J.A. & Dembo, A.J. (1982) Acute 

nonlymphocytic leukemia after therapy with alkylating agents for ovarian cancer. A study of five 

randomized clinical trials. New Engl. J. Med., 307, 1416-1421 

4. Law, I.P. & Blom, J. (1977) Second malignancies in patients with multiple myeloma. Oncology, 

34, 20-24 

5. Gonzalez, F., Trujillo, J.M. & Alexanian, R. (1977) Acute leukemia in multiple myeloma. Ann. 

intern. Med., 86, 440-443 

6. Greene, M.H., Harris, E.L., Gershenson, D.M., Malkasian, G.D., Jr, Melton, L.J., III, Dembo, A.J., 

Bennett, J.M., Moloney, W.C. & Boice, J.D., Jr (1986) Melphalan may be a more potent leukemogen 

than cyclophosphamide. Ann. intern. Med., 105, 360-367 

7. Fisher, B., Rockette, H., Fisher, E.R., Wickerham, D.L., Redmond, C. & Brown, A. (1985) 

Leukemia in breast cancer patients following adjuvant chemotherapy or postoperative radiotherapy: 

the NSABP experience. J. clin. Oncol., 3, 1640-1658 

8. IARC Monographs, 9, 167-180, 1975 

9. IARC Monographs, Suppl. 6, 363-365, 1987 

Synonyms

● Alkeran 

● L-3-[para-[Bis(2-chloroethyl)amino]phenyl]alanine 

● CB 3025 

● para-Di(2-chloroethyl)amino-L-phenylalanine 

● para-Di(2-chloroethyl)aminophenylalanine 

● Melfalan 

● NSC 88-6 

● Phenylalanine mustard 

● L-Phenylalanine mustard 

● Phenylalanine nitrogen mustard 

● Sarcolysin 

● L-Sarcolysin 

● Sarcolysine 

● L-Sarcolysine 

● L-Sarkolysin 

● SK 15673 

Last updated: 9 February 1998 
6-MERCAPTOPURINE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 240) 

CAS No.: 50-44-2

Chem. Abstr. Name: 6H-Purine-6-thione,1,7-dihydroA. Evidence for carcinogenicity to humans (inadequate) 

No epidemiological study of 6-mercaptopurine as a single agent was available to the Working Group. 

Occasional case reports of exposure to 6-mercaptopurine, especially in the presence of concurrent 

therapy with other putative carcinogens, such as ionizing radiation, alkylating agents and other 

potent oncotherapeutic drugs, do not constitute evidence of carcinogenesis [ref: 1]. 

B. Evidence for carcinogenicity to animals (inadequate) 

6-Mercaptopurine was tested by intraperitoneal administration and by skin painting (followed by 

croton oil) in mice and by intraperitoneal, subcutaneous and intravenous injection in rats. 

Limitations to the data in all the reports precluded evaluation of the possible carcinogenicity of this 

compound [ref: 1]. 

C. Other relevant data

6-Mercaptopurine induced chromosomal aberrations and sister chromatid exchanges in lymphocytes 

of treated patients in single studies [ref: 2]. 

In rodents treated in vivo, 6-mercaptopurine induced dominant lethal mutations, chromosomal 

aberrations and micronuclei, but not aneuploidy. The compound induced chromosomal aberrations 

in human lymphocytes in vitro. It induced mutation in cultured rodent cells and chromosomal 

aberrations and sister chromatid exchanges but not aneuploidy in Chinese hamster cells in vitro. It 

did not transform mouse C3H 10T1/2 cells. 6-Mercaptopurine was mutagenic to and caused DNA 

damage in bacteria [ref: 2]. 

Overall evaluation

6-Mercaptopurine is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 26 (1981)

References

1. IARC Monographs, 26, 249-266, 1981 

2. IARC Monographs, Suppl. 6, 366-368, 1987

Synonyms

● IND 1226 
● Ismipur 

● Leukerin 

● Leupurin 

● Mercaleukin 

● Mercapurin 

● Mern 

● 6-Mercaptopurin 

● Mercaptopurine 

● Mercapto-6-purine 

● 6-Mercapto-1H-purine 

● Mercaptopurinum 

● 7-Mercapto-1,3,4,6-tetrazaindene 

● 6-MP 

● NSC 755 

● Purine-6-thiol 

● Purinethiol 

● 6-Purinethiol 

● 3H-Purine-6-thiol 

● Purinethol 

● Thiohypoxanthine 

● 6-Thiopurine 

● 6-Thioxopurine 

Last updated: 11 March 1998 
METHOTREXATE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 241) 

CAS No.: 59-05-2

Chem. Abstr. Name: L-Glutamic acid, N-(4-[[(2,4-diamino-6-pteridinyl]methyl]-

methylamino]benzoylA. Evidence for carcinogenicity to humans (inadequate) 

The relationship between methotrexate treatment and subsequent malignancy has been investigated 

in one cohort of 457 patients (3522 person-years) treated for trophoblastic tumours (2 observed, 3.5 

expected) [ref: 1] and in a cohort of 248 patients treated for psoriasis (10 observed, 22 expected) 

[ref: 2]. A case control study of treatment for psoriasis has also been performed, in which 26 cases 

of noncutaneous cancer (104 matched controls) and 80 cases of nonmelanoma skin cancer (297 

matched controls) were studied; relative risks were 1.0 and 1.2, respectively [ref: 3]. In each 

comparison, no excess (significant or otherwise) or subsequent malignancy was observed. 

B. Evidence for carcinogenicity to animals (inadequate) 

Methotrexate was tested by oral administration in mice and hamsters, by intraperitoneal injection in 

mice and rats, and by intravenous injection in rats. One study in mice by oral administration showed 

a high incidence of lung carcinomas, but the study design did not include matched controls. No other 

study revealed a carcinogenic effect, but the significance of several was limited because of 

deficiencies in experimental design or reporting of data [ref: 4]. A study in which methotrexate was 

given intraperitoneally in combination with cyclophosphamide and 5-fluorouracil to rats resulted in 

induction of tumours in the nervous system, haematopoietic and lymphatic tissues, the urinary 

bladder and adrenal glands; however, because of lack of matched controls, it could not be concluded 

whether tumour induction was due to a combined effect of the three chemicals or to any one of them 

[ref: 5]. 

C. Other relevant data

In patients treated with methotrexate, chromosomal aberrations were observed in bone-marrow 

cells, and, in one of two studies, sister chromatid exchanges were induced in lymphocytes [ref: 6]. 

Methotrexate induced micronuclei in mice, but neither aneuploidy in mouse oocytes nor DNA strand 

breaks in granuloma cells of rats treated in vivo. It induced chromosomal aberrations in human and 

rodent cells in vitro and sister chromatid exchanges in rodent but not in human cells in vitro. It did 

not induce unscheduled DNA synthesis in human cells in vitro. It caused transformation of C3H 

10T1/2 cells but not of Syrian hamster embryo cells and was mutagenic to mouse lymphoma cells 

but not to Chinese hamster cells in vitro. Methotrexate induced genetic crossing-over but not sexlinked recessive lethal mutations in Drosophila. It was not mutagenic to Salmonella typhimurium but 

gave conflicting results in Escherichia coli and was mutagenic to Bacillus subtilis. It did not induce 

DNA damage in bacteria [ref: 6]. 

Overall evaluation

Methotrexate is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 26 (1981)
References

1. Rustin, G.J.S., Rustin, F., Dent, J., Booth, M., Salt, S. & Bagshawe, K.D. (1983) No increase in 

second tumors after cytotoxic chemotheraphy for gestational trophoblastic tumors. New Engl. J. 

Med., 308, 473-476 

2. Nyfors, A. & Jensen, H. (1983) Frequency of malignant neoplasms in 248 long-term methotrexatetreated psoriatics. A preliminary study. Dermatologica, 167, 260-261 

3. Stern, R.S., Zierler, S. & Parrish, J.A. (1982) Methotrexate used for psoriasis and the risk of 

noncutaneous or cutaneous malignancy. Cancer, 50, 869-872 

4. IARC Monographs, 26, 267-292, 1981 

5. Habs, M., Schmähl, D. & Lin, P.Z. (1981) Carcinogenic activity in rats of combined treatment with 

cyclophosphamide, methotrexate and 5-fluorouracil. Int. J. Cancer, 28, 91-96 

6. IARC Monographs, Suppl. 6, 372-374, 1987 

Synonyms

● Amethopterin 

● 4-Amino-10-methylfolic acid 

● 4-Amino-N10-methylpteroylglutamic acid 

● Antifolan 

● CL-14377 

● N-[p-[(2,4-Diamino-6-pteridinyl)methyl]methylamino]-benzoyl L-(+)-glutamic acid 

● N-(4-[[(2,4-Diamino-6-pteridinyl)methyl]methylamino]-benzoyl)-L-glutamic acid 

● N-[p-[(2,4-Diaminopteridin-6-yl-methyl)methylamino]benzoyl]-L-glutamic acid 

● L-(+)-N-(p-[[(2,4-Diamino-6-pteridinyl)methyl]methyl-amino]benzoyl)glutamic acid 

● Ledertrexate 

● α-Methopterin 

● A-Methopterin 

● Methotrexate specia 

● Methotrexatum 

● Methylaminopterin 

● MEXATE 

● MTX 

● NSC 740 

● R 9985 

Last updated: 11 March 1998 
5-METHOXYPSORALEN

(Group 2A)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 242)

CAS No.: 484-20-8

Chem. Abstr. Name: 4-Methoxy-7H-furo[3,2-g][1]benzopyran-7-one 

A. Evidence for carcinogenicity to humans (inadequate)

In a survey of 87 persons employed in the production of bergamot oil (of which 5-methoxypsoralen 

is a constituent), 19% of 79 exposed workers and 16% of a comparison group of 31 people resident 

in the same area were observed to have 'keratomas' or 'epitheliomas' of the skin. Possible 

confounding effects of age, sex and outdoor employment were not considered in this analysis [ref: 

1]. 

B. Evidence for carcinogenicity to animals (sufficient)

5-Methoxypsoralen was tested in by skin application in combination with ultraviolet A radiation or 

solar-simulated radiation, producing skin papillomas and carcinomas; in these studies, no or few 

skin tumours were observed with ultraviolet A radiation or solar-simulated radiation alone. The 

studies were inadequate to evaluate the local and systemic carcinogenic effects of the compound 

itself [ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of 5-methoxypsoralen in humans.

In the presence of ultra-violet A radiation, 5-methoxypsoralen induced chromosomal aberrations, 

sister chromatid exchanges and unscheduled DNA synthesis in human cells in vitro; sister chromatid 

exchanges, mutation and DNA cross-links in rodent cells in vitro; mutation, gene conversion and 

DNA cross-links in yeast; and mutation and prophage in bacteria [ref: 2].

5-Methoxypsoralen, tested in the absence of ultraviolet A radiation, was reported to be weakly 

mutagenic to bacteria [ref: 2]. 

Overall evaluation

5-Methoxypsoralen is probably carcinogenic to humans (Group 2A).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 40 (1986)

References

1. IARC Monographs, 40, 327-347, 1986

2. IARC Monographs, Suppl. 6, 377-379, 1987 

Synonyms
● Bergaptan 

● Bergapten 

● Bergaptene 

● Heraclin 

● 6-Hydroxy-4-methoxy-5-benzofuranacrylic acid, delta-latone 

● Majudin 

● 5-Methoxy-6,7-furanocoumarin 

● 5-MOP 

Last updated: 11 February 1998 
8-METHOXYPSORALEN (METHOXSALEN) 

PLUS ULTRAVIOLET RADIATION

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 261) 

8-Methoxypsoralen

CAS No.: 298-81-7

Chem. Abstr. Name: 7H-Furo[3,2-g][1]benzopyran-7-one, 9-methoxyA. Evidence for carcinogenicity to humans (sufficient)

The development of nonmelanocytic skin cancer (basal- and squamous-cell skin cancers) has been 

reported in patients treated with 8-methoxypsoralen and long-wave ultraviolet light (UVA) (PUVA) 

for psoriasis or mycosis fungoides [ref: 1-5]. Three cases of malignant melanomas of the skin have 

been reported in patients with psoriasis treated with PUVA [ref: 6,7]. The strongest evidence for a 

causal association between PUVA treatment and nonmelanocytic skin cancer comes from the followup of 1380 psoriatic patients treated in the USA. The standardized incidence ratio (SIR) for 

squamous-cell carcinoma increased from 4.1 (95% confidence interval, 2.3-6.8) at low doses to 22.3 

(13.5-34.1) at medium doses and 56.8 (42.7-74.2) at high doses; this effect was independent of 

possible confounding effects of therapy with ionizing radiation and topical tar. The effect on basalcell cancer was much weaker (high doses: SIR, 4.5; 2.8-6.9) [ref: 8]. One cohort study of 525 

psoriatic patients treated with PUVA did not suggest an increase in the incidence of skin cancer 

(mean follow-up period, 2.1 years) [ref: 9]. This 'negative' result could have been due to lack of 

statistical power and to the low doses used in the study. Another study with a five-year follow up 

showed no skin tumour in 94 patients treated with PUVA for psoriasis or mycosis fungoides [ref: 10]. 

8-Methoxypsoralen alone did not alter the incidence of new skin cancer over two years in two small 

controlled trials of its use as a putative prophylactic for skin cancer [ref: 1]. 

B. Evidence for carcinogenicity to animals (sufficient)

8-Methoxypsoralen was tested by oral and intraperitoneal administration and by skin application in 

combination with ultraviolet A radiation in mice, producing epidermal and dermal tumours [ref: 1,11-

15]. When it was tested alone in mice by intraperitoneal administration [ref: 13] or by skin 

application [ref: 12,13], it did not induce skin tumours. The studies were inadequate to evaluate the 

systemic carcinogenicity of 8-methoxypsoralen. 

C. Other relevant data

In patients treated with PUVA, neither chromosomal aberrations (one study) nor sister chromatid 

exchanges were observed [ref: 16]. 

8-Methoxypsoralen in combination with ultraviolet A radiation induced sister chromatid exchanges in 

epithelial cells of cheek pouches of hamsters treated in vivo. In a large number of studies, it induced 

chromosomal aberrations, sister chromatid exchanges, mutation, DNA damage and DNA cross-links 

in human cells in vitro. It transformed mouse C3H 10T1/2 cells. In rodent cells in culture, it induced 

chromosomal aberrations, micronuclei, sister chromatid exchanges, mutation, unscheduled DNA 

synthesis and DNA cross-links. It induced mitotic recombination and mutation in fungi and mutation 

and DNA damage in bacteria [ref: 16]. 

8-Methoxypsoralen in the absence of ultra-violet A radiation induced mutation in bacteria, but 

inconclusive results were obtained with respect to chromosomal aberrations and sister chromatid 

exchanges in human cells in vitro, gene mutation and DNA damage in rodent cells in vitro and 

mutation in yeast [ref: 16]. 
Overall evaluation

8-Methoxypsoralen (methoxsalen) plus ultraviolet radiation is carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 24 (1980)

References

1. IARC Monographs, 24, 101-124, 1980 

2. Roenigk, H.H., Jr & Caro, W.A. (1981) Skin cancer in the PUVA-48 cooperative study. J. Am. 

Acad. Dermatol., 4, 319-324 

3. Stüttgen, G., Kentsch, V., Schalla, W. & Schneider, L. (1981) The risks of photochemotherapy 

(Ger.). Z. Hautkr., 56, 1379-1399 

4. Abel, E.A., Deneau, D.G., Farber, E.M., Price, N.M. & Hoppe, R.T. (1981) PUVA treatment of 

erythrodermic and plaque type mycosis fungoides. J. Am. Acad. Dermatol., 4, 423-429 

5. Stern, R., Zierler, S. & Parrish, J.A. (1982) Psoriasis and the risk of cancer. J. invest. Dermatol., 

78, 147-149 

6. Frenk, E. (1983) Malignant melanoma in a patient with severe psoriasis treated by oral 

methoxsalen photochemotherapy. Dermatologica, 167, 152-154 

7. Marx, J.L., Auerbach, R., Possick, P., Myrow, R., Gladstein, A.H. & Kopf, A.W. (1983) Malignant 

melanoma in situ in two patients treated with psoralens and ultraviolet A. J. Am. Acad. Dermatol., 9, 

904-911 

8. Stern, R.S., Laird, N., Melski, J., Parrish, J.A., Fitzpatrick, T.B. & Bleich, H.L. (1984) Cutaneous 

squamous-cell carcinoma in patients treated with PUVA. New Engl. J. Med., 310, 1156-1161 

9. Lassus, A., Reunala, T., Idanpää-Heikkilä, J., Juvakoski, T. & Salo, O. (1981) PUVA treatment and 

skin cancer: a follow-up study. Acta dermatol. venereol., 61, 141-145 

10. Fitzsimons, C.P., Long, J. & MacKie, R.M. (1983) Synergistic carcinogenic potential of 

methotrexate and PUVA in psoriasis. Lancet, i, 235-236 

11. Kripke, M.L., Morison, W.L. & Parrish, J.A. (1982) Induction and transplantation of murine skin 

cancers induced by methoxsalen plus ultraviolet (320-400 nm) radiation. J. natl Cancer Inst., 68, 

685-690 

12. Nagayo, K., Way, B.H., Tran, R.M. & Song, P.S. (1983) Photocarcinogenicity of 8-

methoxypsoralen and aflatoxin B1 with longwave ultraviolet light. Cancer Lett., 18, 191-198 

13. Young, A.R., Magnus, I.A., Davies, A.C. & Smith, N.P. (1983) A comparison of the 

phototumorigenic potential of 8-MOP and 5-MOP in hairless albino mice exposed to solar simulated 

radiation. Br. J. Dermatol., 108, 507-518 

14. Gibbs, N.K., Young, A.R. & Magnus, I.A. (1985) A strain of hairless mouse susceptible to 

tumorigenesis by TPA alone: studies with 8-methoxypsoralen and solar simulated radiation. 

Carcinogenesis, 6, 797-799 
15. Hannuksela, M., Stenbäck, F. & Lahti, A. (1986) The carcinogenic properties of topical PUVA. A 

lifelong study in mice. Arch. Dermatol. Res., 278, 347-351 

16. IARC Monographs, Suppl. 6, 380-385, 1987 

Synonyms for 8-Methoxypsoralen

● Ammoidin 

● Meladinin [VAN] 

● Meladinine 

● Meladoxen 

● Meloxine 

● Methoxa-Dome 

● 9-Methoxy-7H-furo[3,2-g]benzopyran-7-one 

● 6-Hydroxy-7-methoxy-5-benzofuranacrylic acid δ-lactone 

● Methoxsalen 

● 8-Methoxy-(furano-3',2':6,7-coumarin) 

● 8-Methoxy-4'-5':6,7-furocoumarin 

● 8-Methoxypsoralen 

● 9-Methoxypsoralen 

● 8-Methoxypsoralene 

● 8-MOP 

● Mopsoralen 

● 8-MP 

● Oxypsoralen 

● Oxsoralen 

● Soloxsalen 

● Trioxun 

● Xanthotoxin 

● Xanthotoxine 

Last updated 12/23/1997 
4,4'-METHYLENE BIS(2-METHYLANILINE)

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 248) 

CAS No.: 838-88-0

A. Evidence for carcinogenicity to humans (inadequate)

A study of an Italian cohort of 906 dyestuffs workers employed between 1922 and 1970 revealed an 

impressive excess of deaths from bladder cancer (36 observed, 1.2 expected). Workers were 

classified into ten exposure categories. Among 53 workers employed in the manufacture of new 

fuchsin ('new' magenta) and safranine T, five died from bladder cancer, whereas 0.08 would have 

been expected. Their minimum length of employment was 12 years. Three of the five deaths 

occurred among workers engaged in the synthesis of ortho-toluidine and 4,4'-methylenebis(2-

methylaniline), used as precursors in the production of fuchsin and safranine T, which was carried 

out in a separate building within the plant [ref: 1]. 

B. Evidence for carcinogenicity to animals (sufficient)

4,4'-Methylene bis(2-methylaniline) was tested for carcinogenicity by oral administration in rats and 

dogs, inducing high incidences of hepatocellular carcinomas in animals of each species; neoplasms 

of the lung, mammary gland and skin in rats and of the lung in dogs were also reported [ref: 2-4]. 

C. Other relevant data

No data were available to the Working Group. 

Overall evaluation

4,4'-Methylene bis(2-methylaniline) is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 4 (1974)

References

1. Rubino, G.F., Scansetti, G., Piolatto, G. & Pira, E. (1982) The carcinogenic effect of aromatic 

amines: an epidemiological study on the role of o-toluidine and 4,4'-methylene bis(2-methylaniline) 

in inducing bladder cancer in man. Environ. Res., 27, 241-254

2. IARC Monographs, 4, 73-77, 1974

3. Stula, E.F., Sherman, H., Zapp, J.A., Jr & Clayton, J.W., Jr (1975) Experimental neoplasia in rats 

from oral administration of 3,3'-dichlorobenzidine, 4,4'-methylene-bis(2-chloroaniline), and 4,4'-

methylene-bis(2-methylaniline). Toxicol. appl. Pharmacol., 31, 159-176

4. Stula, E.F., Barnes, J.R., Sherman, H., Reinhardt, C.F. & Zapp, J.A., Jr (1978) Liver and lung 

tumors in dogs from 4,4'-methylene-bis(2-methylaniline). J. environ. Pathol. Toxicol., 1, 339-356 
Synonyms

● 4,4'-Diamino-3,3'-dimethyldiphenylmethane 

● 3,3'-Dimethyl-4,4'-diaminodiphenylmethane 

● 3,3'-Dimethyldiphenylmethane-4,4'-diamine 

● 2,2'-Dimethyl-4,4'-methylenedianiline 

● Methylenebis(3-methylphenylene-4-amine) 

● Methylenebis(o-methylaniline) 

● Methylenebis(o-toluidine) 

● Methylenebis(2-toluidine) 

● 4,4'-Methylenedi-o-toluidine 

Last updated: 3 March 1998 
N-METHYL-N'-NITRO-N-NITROSOGUANIDINE (MNNG)

(Group 2A)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p.248) 

CAS No.: 70-25-7

A. Evidence for carcinogenicity to humans (inadequate)

Three cases of brain tumour (gliomas) and one of colon cancer have been reported from a genetics 

laboratory over a 13-year period. All the subjects were likely to have been exposed to MNNG for at 

least six to 15 years prior to death, but other carcinogens had been used in the laboratory [ref: 1,2]. 

B. Evidence for carcinogenicity to animals (sufficient)

MNNG has been tested for carcinogenicity in mice, rats, hamsters, rabbits and dogs, producing 

tumours at many sites. It has a predominantly local carcinogenic effect and is carcinogenic in singledose experiments. Following its oral administration, papillomas and squamous-cell carcinomas of the 

oesophagus and forestomach, adenocarcinomas of the stomach, small intestine and large bowel, and 

sarcomas of the gastrointestinal tract were reported [ref: 3]. These findings have been extended in 

more recent studies after oral administration to rats [ref: 4-7], hamsters [ref: 8,9] and dogs [ref: 

10,11]. After subcutaneous injection in mice, it produced lung and liver tumours and 

haemangioendotheliomas [ref: 12]; after intrarectal instillation in rats and guinea-pigs [ref: 13-15] 

and after intrauterine and intravaginal application to rats, it produced local tumours [ref: 16]. 

C. Other relevant data

MNNG is an alkylating agent [ref: 17]. No data were available to evaluate the genetic and related 

effects of this compound in humans.

MNNG induced DNA strand breaks in various organs of rats treated in vivo. It did not cause dominant 

lethal mutations in mice, but it gave positive results for mutation in the mouse spot test; it induced 

chromosomal aberrations and micronuclei in bone-marrow cells of mice and sister chromatid 

exchanges in bone-marrow cells of mice and Chinese hamsters treated in vivo. It induced 

chromosomal aberrations, sister chromatid exchanges, DNA strand breaks and unscheduled DNA 

synthesis in human and rodent cells in vitro and induced mutation in cultured rodent cells. It gave 

positive results in several assays for cell transformation. MNNG induced somatic and sex-linked 

recessive lethal mutations in Drosophila. It caused chromosomal aberrations, sister chromatid 

exchanges and mutation in plants and recombination and mutation in fungi. It was mutagenic to and 

caused DNA damage in bacteria, and gave positive results in host-mediated assays using bacteria or 

yeast as indicators and mice as hosts [ref: 17]. 

Overall evaluation

N-Methyl-N'-Nitro-N-Nitrosoguanidine (MNNG) is probably carcinogenic to humans (Group 2A).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 4 (1974)

References

1. Pleven, C., Audran, R., Falcy, M., Efthymiou, M.-L. & Philbert, M. (1983) Glioblastomas and 
chemical mutagenesis in biology laboratories. Report of 3 deaths in the same institute (Fr.). Arch. 

Mal. prof., 44, 411-418

2. Pleven, C., Falcy, M., Audran, R., Philbert, M. & Efthymiou, M.L. (1984) Occurrence of 

glioblastomas in people working in research laboratories using nitroso compounds (Fr.). J. Toxicol. 

med., 4, 249-257

3. IARC Monographs, 4, 183-195, 1974

4. Martin, M.S., Martin, F., Justrabo, E., Michiels, R., Bastien, H. & Knobel, S. (1974) Susceptibility of 

inbred rats to gastric and duodenal carcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine. J. 

natl Cancer Inst., 53, 837-840

5. Kartasheva, L.A. & Bykorez, A.J. (1975) Induction of adenocarcinomas of the stomach in rats by Nmethyl-N'-nitroso-N-nitroguanidine (Russ.). Vopr. Onkol., 21, 50-55

6. Habs, M., Deutsch-Wenzel, R., Preussmann, R. & Schmahl, D. (1978) Induction of gastric tumors 

in BD-IV rats by single application of N-methyl-N'-nitro-N-nitrosoguanidine. Z. Krebsforsch., 91, 183-

188

7. Sherenesheva, N.I. (1979) Induction of gastrointestinal tumours in rats by N-methyl-N'-nitro-Nnitrosoguanidine (MNNG) (Russ.). Vopr. Onkol., 25, 72-74

8. Kogura, K., Sasadaira, H., Kawachi, T., Shimosato, Y., Tokunaga, A., Fujimura, S. & Sugimura, T. 

(1974) Further studies on induction of stomach cancer in hamsters by N-methyl-N'-nitro-Nnitrosoguanidine. Br. J. Cancer, 29, 132-142

9. Ketkar, M., Reznik, G. & Green, U. (1978) Carcinogenic effect of N-methyl-N'-nitro-Nnitrosoguanidine (MNNG) in European hamsters. Cancer Lett., 4, 241-244

10. Fujita, M., Taguchi, T., Takami, M., Usugane, M., Takahashi, A. & Shiba, S. (1974) Carcinoma 

and related lesion in dog stomach induced by oral administration of N-methyl-N'-nitro-Nnitrosoguanidine. Gann, 65, 207-214

11. Koyama, Y., Omori, K., Hirota, T., Sano, R. & Ishihara, K. (1976) Leiomyosarcomas of the small 

intestine induced in dogs by N-methyl-N'-nitro-N-nitrosoguanidine. Gann, 67, 241-251

12. Fujii, K. & Nakadate, M. (1977) Tumor induction by a single subcutaneous injection of N-methylN'-nitro-N-nitrosoguanidine and its derivatives in newborn mice. Z. Krebsforsch., 90, 313-319

13. Nakano, H. (1973) Histopathological studies on rat colo-rectal carcinoma induced by N-methyl-N'-

nitro-N-nitrosoguanidine. Tokohu J. exp. Med., 110, 7-21

14. Chlap, Z. & Przewlocki, F. (1979) A study of colon cancer in rats after rectal administration of Nmethyl-N'-nitro-N-nitrosoguanidine (Pol.). Pat. Pol., 30, 475-488

15. Narisawa, T., Wong, C.Q. & Weisburger, J.H. (1976) Large bowel carcinoma in strain-2 guinea 

pigs by intrarectal instillation of N-methyl-N'-nitro-N-nitrosoguanidine. Gann, 67, 41-46

16. Tanaka, T. & Mori, H. (1983) Experimental induction of uterine cancer in rats by N-methyl-N'-

nitro-N-nitrosoguanidine. Pathol. Res. Pract., 178, 20-26

17. IARC Monographs, Suppl. 6, 394-398, 1987 

Synonyms
● 1-Methyl-3-nitro-l-nitrosoguanidine 

● N-Methyl-N-nitroso-N'-nitroguanidine 

● MNG 

● MNNG 

● NG 

Last updated: 11 February 1998 
METHYL PARATHION

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 392)

CAS No.: 298-00-0

Chem. Abstr. Name: Phosphorothioic acid, O,O-dimethyl O-(4-nitrophenyl) ester

A. Evidence for carcinogenicity to animals (evidence suggesting lack of carcinogenicity) 

Methyl parathion was tested adequately by oral administration in the diet of mice and rats. There 

was no increase in tumour incidence over that in controls [ref: 1]. 

B. Other relevant data

The incidences of chromosomal aberrations and of dominant lethal mutations were not increased in 

mice treated in vivo with methyl parathion. In mammalian cells, sister chromatid exchange and 

presumed gene mutations were induced, but neither chromosomal aberration nor unscheduled DNA 

synthesis was elicited. Methyl parathion was weakly or nonmutagenic in Drosophila melanogaster

and in bacterial systems, but it was mutagenic in yeasts [ref: 1]. 

Overall evaluation

Methyl parathion is not classifiable as to its carcinogenicity to humans (Group 3). 

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 30 (1983)

Reference

1. IARC Monographs, 30, 131-152, 1983 

Synonyms

● A-Gro 

● Azofos 

● Azophos 

● Bay 11405 

● Bladan M 

● Cekumethion 

● Dalf 

● Demethylfenitrothion 

● Dimethyl 4-nitrophenyl phosphorothionate 

● Dimethyl para-nitrophenyl monothiophosphate 

● Dimethyl para-nitrophenyl phosphorothionate 

● Dimethyl para-nitrophenyl thiophosphate 

● Dimethyl parathion 

● Drexel methyl parathion 4E 

● Drexel methyl parathion 601 

● Dygun 

● Dypar 

● E 601 
● Ekatox 

● ENT 17292 

● Folidol 80 

● Folidol M 

● Folidol M40 

● Fosferno M50 

● Gearphos 

● M-Parathion 

● Mepaton 

● Meptox 

● Metacid 50 

● Metacide 

● Metafos 

● Metaphor 

● Metaphos 

● Methyl fosferno 

● Methyl-E 605 

● Methylthiophos 

● Metron 

● MPT 

● NCI C02971 

● Niletar 

● Niran M-4 

● Nitran 

● Nitrox 

● Nitrox 80 

● O,O-dimethyl O-(para-nitrophenyl) phosphorothioate 

● O,O-dimethyl O-(para-nitrophenyl) thionophosphate 

● O,O-dimethyl O-(para-nitrophenyl) thiophosphate 

● O,O-Dimethyl O-4-nitrophenyl phosphorothioate 

● Oleovofotox 

● Parapest M-50 

● Parataf 

● Parathion methyl homolog 

● Parathion-methyl 

● Paratox 

● Paridol 

● Partron M 

● Penncap M 

● Penncap MLS 

● Phosphorothioic acid O,O-dimethyl O-(para-nitrophenyl) ester 

● Sinafid M-48 

● Tekwaisa 

● Thiophenit 

● Thylpar M-50 

● Toll 

● Unidol 

● Vertac methyl parathion technisch 80% 

● Vofatox 

● Wofatox 

● Wofotox 

Last updated: 11 March 1998 
METRONIDAZOLE

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 250) 

CAS No.: 443-48-1 

Chem. Abstr. Name: 2-Methyl-5-nitro-1H-imidazole-1-ethanol 

A. Evidence for carcinogenicity to humans (inadequate)

Two epidemiological studies [ref: 1,2] of women treated with metronidazole showed some excesses 

of cancers of the uterine cervix, a neoplasm that has risk factors in common with vaginal 

trichomoniasis, the main indication in women for treatment with this drug. In one study [ref: 1], a 

greater excess of cervical cancer was observed in women with trichomoniasis who were not exposed 

to metronidazole than in those who were (relative risk, 2.1 versus 1.7). An excess of lung cancer (4 

observed, 0.6 expected) seen in one of these studies [ref: 1] was not found in the other (2 

observed, 2.6 expected) [ref: 3]. In the former, the excess was mainly of adenocarcinoma (3/4 

cases) and was concentrated after at least ten years from first use of metronidazole (3 observed, 

0.3 expected) [ref: 4]. Further follow-up and analysis of these data have suggested that the excess 

could be explained entirely by confounding with smoking [ref: 5]. Another study in which 12 280 

users of metronidazole were followed up for two and one-half years gave a relative risk of 0.89 

(95% confidence interval, 0.45-1.9) for all cancers [ref: 6]. 

B. Evidence for carcinogenicity to animals (sufficient)

Metronidazole has been tested for carcinogenicity by oral administration in mice and rats. It 

significantly increased the incidences of lung tumours in mice of each sex, of lymphomas in female 

mice [ref: 7,8] and of mammary, pituitary, testicular and liver tumours in rats [ref: 7,9,10]. It 

increased the incidence of colonic tumours induced in rats by subcutaneous administration of 1,2-

dimethylhydrazine [ref: 11,12]. 

C. Other relevant data

Studies on bone-marrow cells and lymphocytes from a series of patients treated with metronidazole 

showed no increase in the incidence of chromosomal damage. Metronidazole was active in body fluid 

assays using sweat, faeces and urine from humans exposed in vivo and urine from rodents exposed 

in vivo [ref: 13].

Metronidazole did not induce micronuclei in bone-marrow cells of mice or rats, sister chromatid 

exchanges in bone-marrow cells of Chinese hamsters or unscheduled DNA synthesis in germ cells of 

male rabbits treated in vivo. Human cells exposed to metronidazole in vitro did not show increased 

incidences of chromosomal aberrations, whereas results with respect to sister chromatid exchanges 

were inconclusive. Metronidazole did not induce sister chromatid exchanges in cultured hamster 

cells; conflicting results were reported for the induction of mutation and DNA damage in rodent cells 

in vitro. It did not induce sex-linked recessive lethal mutations in Drosophila or recombination in 

yeast. It induced mutation in fungi and bacteria and induced prophage in bacteria [ref: 13]. 

Overall evaluation

Metronidazole is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 13 (1977)
References

1. Beard, C.M., Noller, K.L., O'Fallon, W.M., Kurland, L.T. & Dockerty, M.B. (1979) Lack of evidence 

for cancer due to use of metronidazole. New Engl. J. Med., 301, 519-522

2. Friedman, G.D. & Ury, H.K. (1980) Initial screening for carcinogenicity of commonly used drugs. 

J. natl Cancer Inst., 65, 723-733

3. Friedman, G.D. (1980) Cancer after metronidazole. New Engl. J. Med., 302, 519

4. Beard, C.M. (1980) Cancer after metronidazole. New Engl. J. Med., 302, 520

5. Beard, C., Noller, K. & O'Fallon, W.M. (1985) Metronidazole and subsequent malignant neoplasms 

(Abstract). Am. J. Epidemiol., 122, 529

6. Danielson, D.A., Hannan, M.T. & Jick, H. (1982) Metronidazole and cancer. J. Am. med. Assoc., 

247, 2498-2499

7. IARC Monographs, 13, 113-122, 1977

8. Cavaliere, A., Bacci, M., Amorosi, A., Del Gaudio, M. & Vitali, R. (1983) Induction of lung tumors 

and lymphomas in BALB/c mice by metronidazole. Tumori, 69, 379-382

9. Rustia, M. & Shubik, P. (1979) Experimental induction of hepatomas, mammary tumors, and 

other tumors with metronidazole in noninbred Sas:MRC(WI)BR rats. J. natl Cancer Inst., 63, 863-

868

10. Cavaliere, A., Bacci, M. & Vitali, R. (1984) Induction of mammary tumors with metronidazole in 

female Sprague-Dawley rats. Tumori, 70, 307-311

11. Sloan, D.A., Fleiszer, D.M., Richards, G.K., Murray, D. & Brown, R.A. (1983) Increased incidence 

of experimental colon cancer associated with long-term metronidazole therapy. Am. J. Surg., 145, 

66-70

12. A-Kareem, A.M., Fleiszer, D.M., Richards, G.K., Senterman, M.K. & Brown, R.A. (1984) Effect of 

long-term metronidazole (MTZ) therapy on experimental colon cancer in rats. J. surg. Res., 36, 547-

552

13. IARC Monographs, Suppl. 6, 399-402, 1987 

Synonyms

● Acromona 

● Anagiardil 

● Atrivyl 

● Bayer 5360 

● Bexon 

● Clont 

● Cont 

● Danizol 

● Deflamon-wirkstoff 

● Efloran 

● Elyzol 

● Entizol 

● 1-(β-Ethylol)-2-methyl-5-nitro-3-azapyrrole 
● Eumin 

● Flagemona 

● Flagesol 

● Flagil 

● Flagyl 

● Flegyl 

● Giatricol 

● Gineflavir 

● 1-Hydroxyethyl-2-methyl-5-nitroimidazole 

● 1-(2-Hydroxyethyl)-2-methyl-5-nitroimidazole 

● 1-(β-Hydroxyethyl)-2-methyl-5-nitroimidazole 

● Klion 

● Maxibol silanes 

● Meronidal 

● 2-Methyl-5-nitro-1-imidazoleethanol 

● 2-Methyl-5-nitroimidazole-1-ethanol 

● Metronidaz 

● Metronidazol 

● Monagyl 

● Nalox 

● Neo-Tric 

● Nida 

● Novonidazol 

● Orvagil 

● RP 8823 

● Sanatrichom 

● SC 10295 

● Takimetol 

● Trichazol 

● Trichex 

● Trichocide 

● Trichomol 

● Trichomonacid pharmachim 

● Trichopal 

● Trichopol 

● Tricocet 

● Tricom 

● Tricowas B 

● Trikacide 

● Trikamon 

● Trikojol 

● Trikozol 

● Trimeks 

● Trivazol 

● Vagilen 

● Vagimid 

● Vertisal 

Last updated: 3 March 1998 
MINERAL OILS:

UNTREATED AND MILDLY-TREATED OILS

(Group 1)

HIGHLY-REFINED OILS 

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 252) 

Mineral oil

CAS No.: 8002-05-9

Chem. Abstr. Name: Petroleum 

A. Evidence for carcinogenicity to humans (sufficient for untreated and mildly-treated oils; 

inadequate for highly-refined oils)

Exposure to mineral oils that have been used in a variety of occupations, including mulespinning, 

metal machining and jute processing, has been associated strongly and consistently with the 

occurrence of squamous-cell cancers of the skin, and especially of the scrotum [ref: 1]. Production 

processes for these oils have changed over time, and with more recent manufacturing methods 

highly-refined products are produced that contain smaller amounts of contaminants, such as 

polycyclic aromatic hydrocarbons. 

Excess mortality or morbidity from gastrointestinal malignancies was seen in two out of three cohort 

studies of metal workers (stomach cancer in two studies, large-bowel cancer in one): however, the 

only significant excess was for the sum of stomach cancer plus large-bowel cancer in one study. 

Four cases of scrotal cancer were detected in one relatively small cohort study of metal industry 

workers [ref: 1]. Among 682 turners with five or more years of exposure to mineral oils, five cases 

of squamous-cell carcinoma of the skin (four of the scrotum) occurred, with 0.3 expected [ref: 2]. 

In a case-control study, a relative risk of 4.9 was reported for the association of scrotal cancer with 

potential exposure of metal workers to mineral oils. Neither the actual levels of exposure nor the 

classification of the mineral oil to which the machine workers were potentially exposed was available 

in the reports of the epidemiological studies [ref: 1]. 

In a case-control study, an excess of sinonasal cancers was seen in toolsetters, set-up men and 

toolmakers [ref: 1]. In a series of 344 cases of scrotal cancer from 1936 to 1976, 62% had held 

occupations in which exposure to mineral oils was likely to have occurred. The median latent period 

was 34 years [ref. 3]. 

An examination of the incidence of second primary cancers among men with scrotal cancer 

demonstrated excess of respiratory, upper alimentary tract and skin cancers; when the occupations 

were grouped, the excess was largely confined to those with exposure to oil [ref: 1]. 

Excesses of bladder cancer have been reported in case-control studies in several countries among 

machinists and engineers, who were possibly exposed to cutting oils containing aromatic amines 

and additives [ref: 1]. 

With regard to printing pressmen, one of two cohort studies addressing lung cancer showed an 

excess and one of two proportionate mortality studies showed a small, statistically nonsignificant 

excess of lung cancer among newspaper pressmen but no excess among non-newspaper pressmen; 

the other study did not address lung cancer. One of three proportionate mortality studies on manual 

workers in the printing industry, not specifically addressing printing pressmen, did not show an 

increased lung cancer risk, whereas the other two studies found a statistically significant excess. 

One of two proportionate mortality studies of printing pressmen indicated a statistically significant 
increase of deaths from rectal cancer, and the other showed a statistically nonsignificant increase of 

deaths from colon cancer; the cohort study considering colorectal cancers did not show an increased 

occurrence. One proportionate mortality study among newspaper and other commercial printing 

pressmen showed a statistically significant excess of mortality from cancers of the buccal cavity and 

pharynx, whereas no such excess was observed in a cohort study. One case-control study indicated 

a statistically significant excess of cancers of the buccal cavity and pharynx. The findings regarding 

other malignancies were inconsistent; scrotal cancers were not mentioned. The type and amount of 

exposure were usually not described; exposure to both mineral oils and carbon blacks (see p. 142) 

would probably have been involved [ref: 1]. 

In mortality statistics from the UK and from Washington State, USA, excesses of lung and skin 

cancer have been registered for jobs entailing exposure to mineral oils [ref: 1]. 

B. Evidence for carcinogenicity to animals (sufficient for untreated and mildly-treated oils; 

inadequate for highly-refined oils)

Vacuum-distillate fractions, acid-treated oils, mildly-treated solvent-refined oils, mildly-treated 

hydrotreated oils, solvent extracts (aromatic oils) and some cutting oils produced skin tumour after 

repeated skin applications to mice. Similar treatment with high-boiling catalytically-cracked oils 

produced skin tumours in rabbits and rhesus monkeys. Some severely solvent-refined oils did not 

produce skin tumours in mice. Highly-refined food-grade mineral oils did not produce skin tumours 

when applied to the skin of mice, although after intraperitoneal injection they produced plasma-cell 

neoplasms and reticulum-cell sarcomas in certain strains of mice [ref: 1]. It was agreed that, in 

accordance with the previous evaluation, 'the significant latter finding is difficult to interpret' [ref: 

1]. 

C. Other relevant data

An increase in the frequency of chromosomal aberrations was observed in the peripheral blood 

lymphocytes of glass workers exposed to mineral oil mists. Urine from workers in a cold-rolling steel 

plant exposed to oil mists of solvent-refined oils was mutagenic to Salmonella typhimurium in the 

present of an exogenous metabolic system [ref: 4]. 

Special test protocols may be necessary to evaluate mineral oils adequately in short-term tests. 

Vacuum distillates from oil refining were reported to be mutagenic to S. typhimurium in the 

presence of an exogenous metabolic system. Positive findings were obtained when the concentration 

of the exogenous metabolic system was five to ten fold that used generally. Acid-treated oils were 

not mutagenic to S. typhimurium in the presence of an exogenous metabolic system; solventrefined oils were reported to be mutagenic in the presence of an exogenous metabolic system. 

Hydrotreated oil was reported to be mutagenic to S. typhimurium in the presence of an exogenous 

metabolic system, while white oils, highly-refined steel-hardening oil and solvent-refined steelrolling oils were not. Unused crankcase oil was mutagenic to S. typhimurium in the presence of an 

exogenous metabolic system, while in other studies no mutagenic activity was found. Used 

crankcase oil from both gasoline and diesel engines was mutagenic to S. typhimurium both in the 

presence and absence of a metabolic system [ref: 4]. 

Two insulation oils from highly-refined mineral-base oils induced transformation of Syrian hamster 

embryo cells and enhanced transformation of mouse C3H 10T1/2 cells. Unused new, re-refined and 

used crankcase oils induced transformation in Syrian hamster embryo cells [ref: 4]. 

Overall evaluation

Untreated and mildly-treated oils are carcinogenic to humans (Group 1).

Highly-refined oils are not classifiable as to their carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.
Previous evaluation: Vol. 33 (1984)

References

1. IARC Monograph, 33, 87-168, 1984 

2. Järvholm, B., Fast, K., Lavenius, B. & Tomsic, P. (1985) Exposure to cutting oils and its 

relationship to skin tumors and premalignant skin lesions on the hands and forearms. Scand. J. 

Work Environ. Health, 11, 365-369 

3. Waldron, H.A., Waterhouse, J.A.H. & Tessema, N. (1984) Scrotal cancer in the West Midlands, 

1936-76. Br. J. ind. Med., 41, 437-444 

4. IARC Monographs, Suppl. 6, 403, 1987 

Synonym for Mineral oil

● Petroleum distillate 

Last updated: 9 February 1998 
MOPP AND OTHER COMBINED CHEMOTHERAPY 

INCLUDING ALKYLATING AGENTS 

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 254) 

A. Evidence for carcinogenicity to humans (sufficient)

In 1972, roughly five years after the introduction of intensive combined chemotherapy for Hodgkin's 

disease, the first report of subsequent acute nonlymphocytic leukaemia (ANLL) appeared [ref: 1]. 

Since then, investigators in more than 15 clinical centres and collaborative treatment groups in 

Europe and North America have performed a series of studies leading to the conclusion that the 

association is probably causal. 

These studies are not easily compared with one another. The groups and subgroups of study 

subjects differ in distribution by age, stage at diagnosis, timing of initial therapy (both radiological 

and chemotherapeutic), interval between diagnosis and intensive chemotherapy, composition of the 

chemotherapeutic regimen and length of follow-up. Further, the methods of counting and allocating 

patients or person-years at risk, the criteria for diagnosis, the method of validating the separate 

identity of a second malignancy, the 'unexposed' group used as a reference standard, the method of 

statistical analysis, and the index used to summarize risk differences vary greatly from study to 

study. Finally, the extent to which such specific details are clearly described in the published reports 

is also variable. 

Nonetheless, these reports are consistent in describing a strongly increased risk of ANLL after 

intensive treatment with combined chemotherapeutic regimens, particularly those containing 

alkylating agents. The most recent reports [ref: 2-18] describe a total of over 11 000 patients, 

reported roughly a decade after diagnosis, among whom more than 170 cases of ANLL have thus far 

occurred. About a quarter of these patients had received no intensive combined chemotherapy, yet 

all but a few leukaemia cases have occurred among those patients who did. Summary estimates of 

the relative risk of ANLL after intensive chemotherapy (relative to reasonably appropriate healthy 

populations) have been calculated to vary from 9 [ref: 11] through 40 [ref: 4,10] to well over 100 

[ref: 6,9,16], precluding meaningful comparisons between studies, and estimates of the absolute 

(actuarial) risk observed in the first ten years range from 2-3% [ref: 3,4,10,14] through 5-6% [ref: 

5,7-9,12] to 9-10% [ref: 2,13], again precluding direct comparisons between estimates. Observed 

variations in both relative risk and actuarial risk are probably due to differences in both 

methodology and exposure. 

Although cases of leukaemia have been observed after radiotherapy in the absence of 

chemotherapy for Hodgkin's disease, the magnitude of the risk ratio is much lower, and may not 

even be elevated [ref: 6,19]. In contrast, the risk for ANLL is consistently high after chemotherapy 

even in the absence of radiation [ref: 7-9]. Although few untreated patient-years have been 

analysed recently, the relative absence of ANLL as an observed sequela of Hodgkin's disease prior to 

the era of intensive combined regimens [ref: 20,21], the absence of any relationship to histological 

subtype [ref: 13], and the appearance of ANLL during complete remission [ref: 5] emphasize the 

etiological role of chemotherapy, although interactions with stage of disease, with radiation or with 

factors important in the pathogenesis of Hodgkin's disease itself cannot be ruled out completely. 

The only specific drug combination that has been used with sufficient frequency that it can be clearly 

linked to ANLL is MOPP (nitrogen mustard, vincristine, procarbazine and prednisone), although 

several reports describe excess cases not attributable to MOPP [ref: 9,11,14,16], and excesses of 

ANLL have appeared after treatment with other alkylating agent-containing combinations. The 

predominance of combined chemotherapy also precludes the identification of risk from individual 

constituents. Preliminary experience does indicate that risk for ANLL may be lower with some 

specific combinations, such as ABVD (adriamycin, bleomycin, vinblastine and dacarbazine) [ref: 

14,22,23]. 
Solid tumours, especially non-Hodgkin's lymphomas [ref: 10,24-27] and lung cancer [ref: 

3,6,12,28,29], but including sarcomas, melanoma, malignancies of the central nervous system and 

carcinomas of the thyroid and gastrointestinal system, have also been reported in abundance after 

combined chemotherapy for Hodgkin's disease [ref: 3,6,7,10,12,29-32], but comparisons of 

observed to expected frequencies have not yielded consistent results. In contrast to leukaemia, solid 

tumours are more common in the general population, increase rapidly in frequency with age (and 

therefore the passage of time after treatment), are more diverse in known etiology, and are 

considered to appear with greater frequency after intensive radiotherapy [ref: 6]. Moreover, they 

are observed to appear with increasing frequency only after longer average duration of follow-up 

[ref: 32]. Some reports have shown increased risk after intensive chemotherapy [ref: 10], and the 

plausibility of a relationship is further suggested by multiple case reports of second malignancies 

that are unusual because of their rarity, either at an age [ref: 33] or on an absolute basis [ref: 

9,24,31]. At present, it would appear that solid tumours occur among survivors of Hodgkin's disease 

in excess of the expected frequency; but, because too few patients have been followed into the 

second decade after treatment, it is too early to determine whether the increase can be better 

attributed to chance or to factors other than chemotherapy [ref: 32]. 

Combined chemotherapy containing alkylating agents for non-Hodgkin's lymphoma may also lead to 

ANLL [ref: 34-37], although the reports are not consistent and the documentation is less complete. 

Treatment of nonhaematological malignancies may also cause second tumours, but most reported 

cases have occurred after the use of single agents [ref: 38], and combination regimens are less 

commonly used. Intensive combination therapy including alkylating agents for small-cell carcinoma 

of the lung [ref: 39,40], and possibly for cancer of the testis [ref: 41], may increase the risk for 

ANLL. 

B. Evidence for carcinogenicity to animals (inadequate)

No data on MOPP were available to the Working Group. Combined treatment with 

cyclophosphamide, methotrexate and 5-fluorouracil induced carcinogenic responses in several 

organs in rats [ref: 42]. See also the summaries of data on individual compounds: adriamycin, 

bleomycins, chlorambucil, cyclophosphamide, 5-fluorouracil, methotrexate, nitrogen mustard, 

prednisone, procarbazine hydrochloride, vinblastine sulphate and vincristine sulphate. 

C. Other relevant data

For data on genetic and related effects, see the summaries on individual compounds, listed above. 

Overall evaluation

MOPP and other combined chemotherapy including alkylating agents are carcinogenic to humans 

(Group 1).

For definition of the italicized terms, see Preamble Evaluation.

References

1. Arseneau, J.C., Sponzo, R.W., Levin, D.L., Schnipper, L.E., Bonner, H., Young, R.C., Canellos, 

G.P., Johnson, R.E. & DeVita, V.T. (1972) Nonlymphomatous malignant tumours complicating 

Hodgkin's disease. Possible association with intensive therapy. New Engl. J. Med., 287, 1119-1122 

2. Aisenberg, A.C. (1983) Acute nonlymphocytic leukemia after treatment for Hodgkin's disease. 

Am. J. Med., 75, 449-454 

3. Baccarani, M., Bosi, A., Papa, G. (1980) Second malignancy in patients treated for Hodgkin's 

disease. Cancer, 46, 1735-1740 
4. Bergsagel, D.E., Alison, R.E., Bean, H.A., Brown, T.C., Bush, R.S., Clark, R.M., Chera, T., Dalley, 

D., DeBoer, G., Gospadarowicz, M., Hasselback, R., Perrault, D. & Rideout, D.F. (1982) Results of 

treating Hodgkin's disease without a policy of laparotomy staging. Cancer Treat. Rep., 66, 717-731 

5. Brusamolino, E., Lazzarino, M., Salvaneschi, L., Canevari, A., Morra, E., Castelli, G., Pagnucco, 

G., Isernia, P. & Bernasconi, C. (1982) Risk of leukemia in patients treated for Hodgkin's disease. 

Eur. J. Cancer clin. Oncol., 18, 237-242 

6. Boivin, J.F., Hutchison, G.B., Lyden, M., Godbold, J., Chorosh, J. & Schottenfeld, D. (1984) 

Second primary cancers following treatment of Hodgkin's disease. J. natl Cancer Inst., 72, 233-241 

7. Coleman, C.N., Kaplan, H.S., Cox, R., Varghese, A., Butterfield, P. & Rosenburg, S.A. (1982) 

Leukaemias, non-Hodgkin's lymphomas and solid tumours in patients treated for Hodgkin's disease. 

Cancer Surv., 1, 733-744 

8. Coltman, C.A., Jr & Dixon, D.O. (1982) Second malignancies complicating Hodgkin's disease. A 

Southwest Oncology Group 10-year follow-up. Cancer Treat. Rep., 66, 1023-1033 

9. Glicksman, A.S., Pajak, T.F., Gottlieb, A., Nissen, N., Stutzman, L. & Cooper, M.R. (1982) Second 

malignant neoplasms in patients successfully treated for Hodgkin's disease: a Cancer and Leukemia 

Group B study. Cancer Treat Rep., 66, 1035-1044 

10. Henry-Amar, M. (1983) Second cancers after radiotherapy and chemotherapy for early stages of 

Hodgkin's disease. J. natl Cancer Inst., 71, 911-916 

11. Jacquillat, C., Auclerc, G., Weil, M., Auclerc, M.F. & Maral, J. (1983) Acute leukaemias and solid 

tumours in the course of Hodgkin's disease (Fr.). Bull. Cancer, 70, 61-66 

12. Tester, W.J., Kinsella, T.J., Waller, B., Makuch, R.W., Kelley, P.A., Glatstein, E. & DeVita, V.T. 

(1984) Second malignant neoplasms complicating Hodgkin's disease: the National Cancer Institute 

experience. J. clin. Oncol., 2, 762-769 

13. Pedersen-Bjergaard, J. & Larsen, S.O. (1982) Incidence of acute nonlymphocytic leukemia, 

preleukemia, and acute myeloproliferative syndrome up to 10 years after treatment of Hodgkin's 

disease. New Engl. J. Med., 307, 965-971 

14. Valagussa, P., Santoro, A., Fossati Bellani, F., Franchi, F., Banfi, A. & Bonadonna, G. (1982) 

Absence of treatment-induced second neoplasms after ABVD in Hodgkin's disease. Blood, 59, 488-

494 

15. Prosnitz, L.R., Farber, L.R., Kapp, D.S., Bertino, J.R., Nordlund, M. & Lawrence, R. (1982) 

Combined modality therapy for advanced Hodgkin's disease: long-term follow-up data. Cancer 

Treat. Rep., 66, 871-879 

16. Bartolucci, A.A., Liu, C., Durant, J.R. & Gams, R.A. (1983) Acute myelogenous leukemia as a 

second malignant neoplasm following the successful treatment of advanced Hodgkin's disease. 

Cancer, 52, 2209-2213 

17. Andrieu, J.M., Montagnon, B., Asselain, B., Bayle-Weisgerber, C., Chastang, C., Teillet, F. & 

Bernard, J. (1980) Chemotherapy-radiotherapy association in Hodgkin's disease, clinical stages IA, 

II2A: results of a prospective clinical trial with 166 patients. Cancer, 46, 2126-2130 

18. Shishkin, I.P. (1984) Secondary tumours in patients with Hodgkin's disease following treatment 

(Russ.). Med. Radiol. (Moscow), 29, 24-28 

19. Selby, P. & Horwich, A. (1986) Secondary leukaemia in Hodgkin's disease. Lancet, i, 1027-1028 
20. Berg, J.W. (1967) The incidence of multiple primary cancers. 1. Development of further cancers 

in patients with lymphomas, leukemias, and myeloma. J. natl Cancer Inst., 38, 741-752 

21. Newman, D.R., Maldonado, J.E., Harrison, E.G., Jr, Kiely, J.M. & Linman, J.W. (1970) 

Myelomonocytic leukemia in Hodgkin's disease. Cancer, 25, 128-134 

22. Amadori, S., Papa, G., Anselmo, A.P., Fidani, P. & Mandelli, F. (1983) Acute promyelocytic 

leukemia following ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and radiotherapy 

for Hodgkin's disease. Cancer Treat. Rep., 67, 603-604 

23. Valagussa, P., Santoro, A., Fossati-Bellani, F., Banfi, A., Bonadonna, G. & Veronesi, U. (1985) 

Second neoplasms in Hodgkin's disease (HD): progress report (Abstract No. 720). Proc. Am. Assoc. 

Cancer Res., 26, 182 

24. Armitage, J.O., Dick, F.R., Goeken, J.A., Foucar, M.K. & Gingrich, R.D. (1983) Second lymphoid 

malignant neoplasms occurring in patients treated for Hodgkin's disease. Arch. intern. Med., 143, 

445-450 

25. Krikorian, J.G., Burke, J.S., Rosenberg, S.A. & Kaplan, H.S. (1979) Occurrence of non-Hodgkin's 

lymphoma after therapy for Hodgkin's disease. New Engl. J. Med., 300, 452-458 

26. Jacquillat, C., Khayat, D., Desprez-Corely, J.P., Weil, M., Brocheriou, C., Auclerc, G., 

Chamseddine, N. & Bernard, J. (1984) Non-Hodgkin's lymphoma occurring after Hodgkin's disease. 

Four new cases and a review of the literature. Cancer, 53, 459-462 

27. Miettinen, M., Franssila, K.O. & Saxén, E. (1983) Hodgkin's disease, lymphocytic predominance 

nodular. Increased risk for subsequent non-Hodgkin's lymphomas. Cancer, 51, 2293-2300 

28. Kaldor, J.M., Day, N.E., Band, P., Choi, N.W., Clarke, E.A., Coleman, M.P., Hakama, M., Koch, 

M., Langmark, F., Neal, F.E., Pettersson, F., Pompe-Kirn, V., Prior, P. & Storm, H.H. (1987) Second 

malignancies following testicular cancer, ovarian cancer and Hodgkin's disease: an international 

collaborative study among cancer registries. Int. J. Cancer, 39, 571-585 

29. Valagussa, P., Santora, A., Kenda, R., Bellani, F.F., Franchi, F., Banfi, A., Rilke, F. & Bonadonna, 

G. (1980) Second malignancies in Hodgkin's disease: a complication of certain forms of treatment. 

Br. med. J., i, 216-219 

30. Nelson, D.F., Cooper, S., Weston, M.G. & Rubin, P. (1981) Second malignant neoplasms in 

patients treated for Hodgkin's disease with radiotherapy or radiotherapy and chemotherapy. Cancer, 

48, 2386-2393 

31. Tucker, M.A., Misfeldt, D., Coleman, C.N., Clark, W.H., Jr & Rosenberg, S.A. (1985) Cutaneous 

maligneant melanoma after Hodgkin's disease. Ann. intern. Med., 102, 37-41 

32. Boivin, J.-F. & O'Brien, K. (1987) Solid cancer risk after treatment of Hodgkin's disease. Cancer 

(in press) 

33. Brumbach, R.A., Gerber, J.E., Hicks, D.G. & Strauchen, J.A. (1984) Adenocarcinoma of the 

stomach following irradiation and chemotherapy for lymphoma in young patients. Cancer, 54, 994-

998 

34. Greene, M.H., Young, R.C., Merrill, J.M. & DeVita, V.T. (1983) Evidence of a treatment dose 

response in acute nonlymphocytic leukemia which occur after therapy of non-Hodgkin's lymphoma. 

Cancer Res., 43, 1891-1898 
35. Gomez, G.A., Aggarwal, K.K. & Han, T. (1983) Post-therapeutic acute malignant 

myeloproliferative syndrome and acute nonlymphocytic leukemia in non-Hodgkin's lymphoma. 

Correlation with intensity of treatment. Cancer, 50, 2285-2288 

36. Harousseau, J.L., Andrieu, J.M., Dumont, J., Montagnon, B. Asselain, B., Daniel, M.T. & Flandrin, 

G. (1980) Acute myeloblastic leukaemia during the course of malignant non-Hodgkin's lymphomas 

(Fr.). Nouv. Presse med., 9, 3513-3516 

37. Pedersen-Bjergaard, J., Ersboll, J., Sørensen, H.M., Keiding, N., Larsen, S.O., Philip, P., Larsen, 

M.S., Schultz, H. & Nissen, N.I. (1985) Risk of acute nonlymphocytic leukemia and preleukemia in 

patients treated with cyclophosphamide for non-Hodgkin's lymphoma. Comparison with results 

obtained in patients treated for Hodgkin's disease and ovarian carcinoma with other alkylating 

agents. Ann. intern. Med., 103, 195-200 

38. Kyle, R.A. (1982) Second malignancies associated with chemotherapeutic agents. Semin. 

Oncol., 9, 131-142 

39. Markman, M., Pavy, M.D. & Abeloff, M.D. (1982) Acute leukemia following intensive therapy for 

small-cell carcinoma of the lung. Cancer, 50, 672-675 

40. May, J.T., Hsu, S.D. & Costanzi, J.J. (1981) Acute leukemia following combination chemotherapy 

for cancer of the lung. Oncology, 38, 134-137 

41. van Imhoff, G.W., Steijfer, D.T., Breuning, M.H., Anders, G.J.P.A., Mulder, N.H. & Halie, M.R. 

(1986) Acute nonlymphocytic leukemia 5 years after treatment with cisplatin, vinblastine, and 

bleomycin for disseminated testicular cancer. Cancer, 57, 984-987 

42. Habs, M., Schmähl, D. & Lin, P.Z. (1981) Carcinogenic activity in rats of combined treatment 

with cyclophosphamide, methotrexate and 5-fluorouracil. Int. J. Cancer, 28, 91-96 

Last updated: 9 February 1998 
MUSTARD GAS (SULPHUR MUSTARD)

(Group 1) 

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 259) 

CAS No.: 505-60-2

Chem. Abstr. Name: 1,1'-Thiobis(2-chloroethane) 

A. Evidence for carcinogenicity to humans (sufficient)

The mortality of British and American veterans who were exposed to mustard gas during the First 

World War has been compared with that of other veterans who experienced respiratory infections; 

the effect of smoking could not be directly controlled for in either group. Cumulative lung cancer risk 

was not affected in UK veterans and was only modestly elevated (relative risk, 1.5, compared with 

the effect of cigarette smoking, roughly 10) in US veterans [ref: 1]. 

In contrast, mustard gas production workers in Japan during the Second World War have been 

found to have experienced an increase in the proportion of deaths attributed to lung cancer (three 

fold) compared to the local population [ref: 1,2], and especially in respiratory cancer (40 fold) in 

comparison with the general population [ref: 1]. Although sophisticated analytical methods were not 

used, the prevalence of smoking appeared to be comparable in the exposed and unexposed groups, 

and there was increased risk with increased duration of exposure [ref: 3]. British workers engaged 

in mustard gas production during the Second World War have also been followed up. Among 511 

individuals, 11 cases of cancer (nine of the larynx and two of the pharynx) were identified, whereas 

one would have been expected [ref: 4]. 

B. Evidence for carcinogenicity to animals (limited)

Mustard gas was tested for carcinogenicity in mice, producing lung tumours after its inhalation or 

intravenous injection and local sarcomas after its subcutaneous injection [ref: 1]. 

C. Other relevant data

Mustard gas is a bifunctional alkylating agent [ref: 5]. No data were available on its genetic and 

related effects in humans. 

Evidence of covalent binding to cellular DNA, RNA and protein in vivo was obtained in mice injected 

intraperitoneally with 35S-labelled mustard gas. It induced chromosomal aberrations and DNA 

damage in rodent cells in vitro and mutation in mouse lymphoma cells in vitro and in a hostmediated assay. It induced aneuploidy, heritable translocations, dominant lethal mutations and sexlinked recessive lethal mutations in Drosophila. It was mutagenic to fungi and induced DNA damage 

in bacteria [ref: 5]. 

Overall evaluation

Mustard gas (sulphur mustard) is carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 9 (1975)

References
1. IARC Monographs, 9, 181-192, 1975 

2. Shigenobu, T. (1980) Occupational cancer of the lungs - cancer of the respiratory tract among 

workers manufacturing poisonous gases (Jpn.). Jpn. J. thorac. Dis., 18, 880-885 

3. Nishimoto, Y., Yamakido, M., Shigenobu, T., Onari, K. & Yukutake, M. (1983) Long term 

observation of poison gas workers with special reference to respiratory cancers. J. Univ. occup. 

environ. Health, 5 (Suppl.), 89-94 

4. Manning, K.P., Skegg, D.C.G., Stell, P.M. & Doll, R. (1981) Cancer of the larynx and other 

occupational hazards of mustard gas workers. Clin. Otolaryngol., 6, 165-170 

5. IARC Monographs, Suppl. 6, 403-405, 1987 

Synonyms

● Bis(2-chloroethyl)sulphide 

● Bis( β-chloroethyl)sulphide 

● 1-Chloro-2-( β-chloroethylthio)ethane 

● 2,2'-Dichlorodiethyl sulphide 

● Di-2-chloroethyl sulphide 

● β,β'-Dichloroethyl sulphide 

● Schwefel-lost 

● S-Lost 

● S-Mustard 

● Sulphur mustard 

● Sulphur mustard gas 

● Yellow cross liquid 

● Yperite 

Last updated: 9 February 1998 
1-NAPHTHYLAMINE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 260)

CAS No.: 134-32-7 

A. Evidence for carcinogenicity to humans (inadequate) 

An excess occurrence of bladder cancer was observed in workers who had been exposed to 

commercial 1-naphthylamine for five or more years who had not also been engaged in the 

production of 2-naphthylamine or benzidine. However, commercial 1-naphthylamine made at that 

time may have contained 4-10% 2-naphthylamine [ref: 1]. Among a cohort of 906 men employed 

for at least one year between 1922 and 1970 in a dyestuffs plant in Italy, a considerable excess of 

bladder cancer deaths (27 observed, 0.19 expected) was observed among 151 workers involved in 

the manufacture of 1- and 2-naphthylamine and benzidine [ref: 2]. A case-control study of bladder 

cancer in the UK showed a significant, exposure-related increased risk for dyestuffs workers. 1-

Naphthylamine was plausibly concerned, but it was not possible to single out any compound from 

the combined exposure to arylamines [ref: 3]. 

In view of the contamination of the commercial product and the mixed nature of the exposures 

investigated, it is not possible to assess the carcinogenicity of 1-naphthylamine alone. 

B. Evidence for carcinogenicity to animals (inadequate) 

1-Naphthylamine was tested for carcinogenicity mice, hamsters and dogs by oral administration and 

in newborn mice by subcutaneous injection. No carcinogenic effect was observed following oral 

administration to hamsters [ref: 1] or dogs [ref: 1,4,5] or in a lung adenoma bioassay in mice [ref: 

6]. Inconclusive results were obtained after oral administration to adult mice and subcutaneous 

injection of newborn mice [ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of 1-naphthylamine in humans. 

1-Naphthylamine did not induce micronuclei in bone-marrow cells of mice treated in vivo; it induced 

DNA strand breaks in mice, but not in rats. 1-Naphthylamine increased the incidence of 

chromosomal aberrations in cultured rodent cells, but the results for sister chromatid exchanges, 

mutation and DNA damage were inconclusive; no cell transformation was induced in Syrian hamster 

embryo cells. It did not induce sex-linked recessive lethal mutations in Drosophila. It induced 

aneuploidy but not mutation in yeast; results for mitotic recombination were conflicting. It was 

mutagenic to bacteria [ref: 7]. 

Overall evaluation

1-Naphthylamine is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 4 (1974)

References
1. IARC Monographs, 4, 87-96, 1974 

2. Decarli, A., Peto, J., Piolatto, G. & La Vecchia, C. (1985) Bladder cancer mortality of workers 

exposed to aromatic amines: analysis of models of carcinogenesis. Br. J. Cancer, 51, 707-712 

3. Boyko, R.W., Cartwright, R.A. & Glashan, R.W. (1985) Bladder cancer in dye manufacturing 

workers. J. occup. Med., 27, 799-803 

4. Radomski, J.L., Deichmann, W.B., Altman, N.H. & Radmonski, T. (1980) Failure of pure 1-

naphthylamine to induce bladder tumors in dogs. Cancer Res., 40, 3537-3539 

5. Purchase, I.F.H., Kalinowski, A.E., Ishmael, J., Wilson, J., Gore, C.W. & Chart, I.S. (1981) 

Lifetime carcinogenicity study of 1- and 2-naphthylamine in dogs. Br. J. Cancer, 44, 892-901 

6. Theiss, J.C., Shimkin, M.B. & Weisburger, E.K. (1981) Pulmonary adenoma response of strain A 

mice to sulfonic acid derivatives of 1- and 2-naphthylamines. J. natl Cancer Inst., 67, 1299-1302 

7. IARC Monographs, Suppl. 6, 406-409, 1987 

Synonyms

● 1-Aminonaphthalene 

● Azoic diazo component 114 

● Fast garnet B base 

● Fast garnet base B 

● Naphthalidam 

● Naphthalidine 

● α-Naphthylamine 

Last updated: 11 March 1998 
2-NAPHTHYLAMINE

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 261) 

CAS No.: 91-59-8

A. Evidence for carcinogenicity to humans (sufficient)

Case reports and epidemiological studies conducted independently in the 1950s and 1960s showed 

that occupational exposure to 2-naphthylamine, either alone or as an impurity in other compounds, 

is causally associated with the occurrence of bladder cancer [ref: 1].

Two studies in the USA examined cancer incidence and mortality in a group of chemical workers 

exposed mainly to 2-naphthylamine. In one, a remarkable and significantly increased incidence of 

bladder cancer was found (13 observed, 3.3 expected), which was not explained by smoking habits 

[ref: 2]. Investigation of mortality failed to pinpoint this increased risk and suggested an excess of 

oesophageal cancer, which, however, was not considered to be associated with the occupational 

exposure [ref: 3]. Two reports on one occupational population at a dyestuffs plant in Italy 

documented a very high bladder cancer risk linked specifically to 2-naphthylamine production (6 

deaths observed, 0.04 expected) and a clear exposure-response relationship of the risk to 

exposures in the plant [ref: 4,5]. Incidence studies from Japan dealing with exposure to both 2-

naphthylamine and benzidine showed apparently increased risks of cancer of the urinary tract and 

bladder and, possibly, an increased occurrence of second primary cancers at several sites, including 

the liver [ref: 6-8]. Case reports and ecological studies also documented the relationship between 

exposure to 2-naphthylamine, as well as to benzidine, and bladder cancer risk [ref: 9,10]. 2-

Naphthylamine was most probably involved in the exposure to aryl amines reported in a UK study 

as producing a significantly increased bladder cancer risk, which was not accounted for by smoking 

habits [ref: 11]. 

B. Evidence for carcinogenicity to animals (sufficient)

2-Naphthylamine was tested for carcinogenicity by oral administration in many animal species and 

by the mouse-lung adenoma bioassay. Following its oral administration, it induced bladder 

neoplasms in hamsters [ref: 1], dogs [ref: 1,12-14] and nonhuman primates [ref: 1], and liver 

tumours in mice [ref: 1]. A low incidence of bladder carcinomas was observed in rats after its oral 

administration [ref: 15]. In a lung adenoma bioassay in mice, 2-naphthylamine produced positive 

results [ref: 16]. 

C. Other relevant data

No data were available on the genetic and related effects of 2-naphthylamine in humans.

Mice and rabbits treated with 2-naphthylamine had increased incidences of sister chromatid 

exchanges; micronuclei were not induced in bone-marrow cells of mice treated in vivo. 2-

Naphthylamine was mutagenic in the mouse spot test and induced DNA strand breaks in 

hepatocytes of treated rats. It formed DNA adducts in bladder and liver cells of dogs in vivo. It 

induced unscheduled DNA synthesis in human cells in vitro and chromosomal aberrations, sister 

chromatid exchanges, DNA strand breaks and unscheduled DNA synthesis in rodent cells in vitro. 

Equivocal results were obtained for mutation, but it caused morphological transformation in Syrian 

hamster embryo and virus-infected rat cells. 2-Naphthylamine induced aneuploidy in Drosophila, but 

equivocal results were found for sex-linked recessive lethal mutations. It caused aneuploidy, 

mutation and mitotic recombination in yeast and was mutagenic to plants and bacteria [ref: 17]. 

Overall evaluation
2-Naphthylamine is carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 4 (1974)

References

1. IARC Monographs, 4, 97-111, 1974

2. Schulte, P.A., Ringen, K., Hemstreet, G.P., Altekruse, E.B., Gullen, W.H., Patton, M.G., Allsbrook, 

W.C., Jr, Crosby, J.H., West, S.S., Witherington, R., Koss, L., Bales, C.E., Tillet, D., Rooks, S.C.F., 

Stern, F., Stringer, W., Schmidt, V.A. & Brubaker, M.M. (1985) Risk assessment of a cohort exposed 

to aromatic amines. Initial results. J. occup. Med., 27, 115-121

3. Stern, F.B., Murthy, L.I., Beaumont, J.J., Schulte, P.A. & Halperin, W.E. (1985) Notification and 

risk assessment for bladder cancer of a cohort exposed to aromatic amines. III. Mortality among 

workers exposed to aromatic amines in the last beta-naphthylamine manufacturing facility in the 

United States. J. occup. Med., 27, 495-500 

4. Rubino, G.F., Scansetti, G., Piolatto, G. & Pira, E. (1982) The carcinogenic effect of aromatic 

amines: an epidemiological study on the role of o-toluidine and 4,4'-methylene bis(2-methylaniline) 

in inducing bladder cancer in man. Environ. Res., 27, 241-254 

5. Decarli, A., Peto, J., Piolatto, G. & La Vecchia, C. (1985) Bladder cancer mortality of workers 

exposed to aromatic amines: analysis of models of carcinogenesis. Br. J. Cancer, 51, 707-712 

6. Tsuchiya, K., Okubo, T. & Ishizu, S. (1975) An epidemiological study of occupational bladder 

tumours in the dye industry of Japan. Br. J. ind. Med., 32, 203-209 

7. Nakamura, J., Takamatsu, M., Doi, J., Ohkawa, T., Fujinaga, T., Ebisuno, S. & Sone, M. (1980) 

Clinical study on the occupational urinary tract tumor in Wakayama. Jpn. J. Urol., 71, 945-951 

8. Morinaga, K., Oshima, A. & Hara, I. (1982) Multiple primary cancers following exposure to 

benzidine and beta-naphthylamine. Am. J. ind. Med., 3, 243-246 

9. Budnick, L.D., Sokal, D.C., Falk, H., Logue, J.N. & Fox, J.M. (1984) Cancer and birth defects near 

the Drake Superfund site, Pennsylvania. Arch. environ. Health, 39, 409-413 

10. Segnan, N. & Tanturri, G. (1976) A study on the geographical pathology of laryngeal, bladder 

and children cancer in the Province of Turin (Ital.). Tumori, 62, 377-386 

11. Boyko, R.W., Cartwright, R.A., Chir, B. & Glashan, R.W. (1985) Bladder cancer in dye 

manufacturing workers. J. occup. Med., 27, 799-803 

12. Romanenko, A.M. & Martynenko, A.G. (1972) Morphological peculiarities of vesical tumours 

induced by beta-naphthylamine in dogs (Russ.). Vopr. Onkol., 18, 70-75 

13. Radomski, J.L., Krischer, C. & Krischer, K.N. (1978) Histologic and histochemical preneoplastic 

changes in the bladder mucosae of dogs given 2-naphthylamine. J. natl Cancer Inst., 60, 327-333 

14. Purchase, I.F.H., Kalinowski, A.E., Ishmael, J., Wilson, J., Gore, C.W. & Chart, I.S. (1981) 

Lifetime carcinogenicity study of 1- and 2-naphthylamine in dogs. Br. J. Cancer, 44, 892-901 
15. Hicks, R.M., Wright, R. & Wakefield, J.St J. (1982) The induction of rat bladder cancer by 2-

naphthylamine. Br. J. Cancer, 46, 646-661 

16. Theiss, J.C., Shimkin, M.B. & Weisburger, E.K. (1981) Pulmonary adenoma response of strain A 

mice to sulfonic acid derivaties of 1- and 2-naphthylamines. J. natl Cancer Inst., 67, 1299-1302 

17. IARC Monographs, Suppl. 6, 410-414, 1987 

Synonyms

● 2-Aminonaphthalene 

● BNA 

● Fast scarlet base B 

● β-Naphthylamine 

Last updated: 9 February 1998 
1-NAPHTHYLTHIOUREA (ANTU) 

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 263) 

CAS No.: 86-88-4

Chem. Abstr. Name: Thiourea, 1-naphthalenylA. Evidence for carcinogenicity to humans (inadequate) 

Cases of bladder tumours have been reported among rat catchers exposed to 1-naphthylthiourea 

(containing up to 0.2% 2-naphthylamine) [ref: 1]. 

B. Evidence for carcinogenicity to animals (inadequate) 

1-Naphthylthiourea was tested for carcinogenicity in mice and rats by administration in the diet. The 

studies were considered to be inadequate for evaluation [ref: 2]. 

C. Other relevant data

No data were available on the genetic and related effects of ANTU in humans. It did not induce 

unscheduled DNA synthesis in rat hepatocytes in vitro. It was mutagenic to bacteria [ref: 3]. 

Overall evaluation

1-Naphthylthiourea (ANTU) is not classifiable as to its carcinogenicity to humans (Group 3).

Also see previous evaluation: Vol. 30 (1983)

References

1. Davies, J.M., Thomas, H.F. & Manson, D. (1982) Bladder tumours among rodent operatives 

handling ANTU. Br. med. J., 285, 927-931 

2. IARC Monographs, 30, 347-357, 1983 

3. IARC Monographs, Suppl. 6, 415-416, 1987 

Synonyms

● Alrato 

● ANTU 

● Anturat 

● Bantu 

● Chemical 109 

● Dirax 

● Kill kantz 

● Kripid 

● Krysid PI 

● Krysidaptan 

● α-Naphthylthiocarbamide 

● α-Naphthothiourea 
● N-(1-Naphthyl)-2-thiourea 

● N-1-Naphthylthiourea 

● 1-(1-Naphthyl)-2-thiourea 

● 1-(1-Naphthyl)thiourea 

● α-Naphthylthiourea 

● Naphtox 

● Rat-tu 

● Rattrack 

● Smeesana 

● U 5227 

Last updated: 9 March 1998 
NITROGEN MUSTARD

(Group 2A)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 269)

CAS No.: 51-75-2

Chem. Abstr. Name: 2-Chloro-N-(2-chloroethyl)-N-methylethanamine

A. Evidence for carcinogenicity to humans (limited)

No epidemiological study of nitrogen mustard as a single agent was available to the Working Group. 

However, it is the principal alkylating agent in leukaemogenic combination chemotherapy given for 

Hodgkin's disease, and other alkylating agents are clearly leukaemogenic. The many case reports of 

cancer following topical application of nitrogen mustard cannot be interpreted with certainty because 

concurrent treatment with radiation and other potent drugs has been the rule rather than the 

exception, and occasionally such associations would be expected by chance.

Squamous-cell carcinomas of the skin following long-term topical application of nitrogen mustard 

alone or in combination with systemic therapy for mycosis fungoides [ref: 1-4] and psoriasis [ref: 5-

7] have been observed to appear on skin surfaces not exposed to the sun. 

B. Evidence for carcinogenicity to animals (sufficient)

Nitrogen mustard, administered mainly as the hydrochloride, has been tested for carcinogenicity in 

mice and rats by subcutaneous, intravenous and intraperitoneal administration and by skin painting. 

It produced mainly lung tumours and lymphomas in mice after subcutaneous, intravenous and 

intraperitoneal administration. Intravenous injection of nitrogen mustard to rats induced tumours in 

different organs [ref: 8]. Application by skin painting produced local tumours in mice in a dosedependent manner [ref: 9,10]. 

C. Other relevant data

Nitrogen mustard is a bifunctional alkylating agent. In one study, it induced chromosomal 

aberrations in lymphocytes of treated patients [ref: 11]. 

Nitrogen mustard induced dominant lethal mutations and micronuclei in bone-marrow cells of mice 

exposed in vivo and alkylated DNA of ascites cells in experimental animals treated in vivo. It 

induced chromosomal aberrations, sister chromatid exchanges and unscheduled DNA synthesis in 

human cells in vitro. In rodent cells in vitro, it induced sister chromatid exchanges, chromosomal 

aberrations and DNA damage; studies on the induction of mutation were inconclusive. It 

transformed mouse C3H 10T1/2 cells. Nitrogen mustard induced aneuploidy and somatic mutation 

and recombination in Drosophila, chromosomal aberrations in plants, mitotic recombination and 

mutation in fungi, and mutation and DNA damage in fungi [ref: 11]. 

Overall evaluation

Nitrogen mustard is probably carcinogenic to humans (Group 2A).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 9 (1975)

References
1. Du Vivier, A, Vonderheid, E.C., Van Scott, E.J., Urbach, F. (1978) Mycosis fungoides, nitrogen 

mustard and skin cancer. Br. J. Dermatol., 99, 61-63

2. Kravitz, P.H. & McDonald, C.J. (1978) Topical nitrogen mustard induced carcinogenesis. Acta 

dermatol. venereol., 58, 421-425

3. Lee, L.A., Fritz, K.A., Golitz, L., Fritz, T.J. & Weston, W.L. (1982) Second cutaneous malignancies 

in patients with mycosis fungoides treated with topical nitrogen mustard. J. Am. Acad. Dermatol., 7, 

590-598

4. Abel, E.A., Sendagorta, E. & Hoppe, R.T. (1986) Cutaneous malignancies and metastatic 

squamous cell carcinoma following topical therapies for mycosis fungoides. J. Am. Acad. Dermatol., 

14, 1029-1038

5. Halprin, K.M., Comerford, M. & Taylor, J.R. (1982) Cancer in patients with psoriasis. J. Am. Acad. 

Dermatol, 7, 633-638

6. Ganor, S. (1983) Skin cancer in psoriatics treated with nitrogen mustard. J. Am. Acad. Dermatol., 

8, 164

7. Halprin, K.M., Comerford, M. & Taylor, J.R. (1982) Skin cancer in psoriatics treated with nitrogen 

mustard. J. Am. Acad. Dermatol., 8, 164-165

8. IARC Monographs, 9, 193-207, 1975

9. Zackheim, H.S. & Smuckler, E.A. (1980) Tumorigenic effect of topical mechlorethamine, BCNU 

and CCNU in mice. Experientia, 36, 1211-1212

10. Epstein, J.H. (1984) Nitrogen mustard (mechlorethamine) and UVB photocarcinogenesis: a dose 

response effect. J. invest. Dermatol., 83, 320-322

11. IARC Monographs, Suppl. 6, 421-424, 1987 

Synonyms

● N,N'-Bis(2-chloroethyl)-N-methylamine 

● N,N-Bis(2-chloroethyl)methylamine 

● Bis(2-chloroethyl)methylamine 

● Bis(β-chloroethyl)methylamine 

● Caryolysin 

● Chloramine 

● Chlormethine 

● Cloramin 

● β,β'-Dichlorodiethyl-N-methylamine 

● Di(2-chloroethyl)methylamine 

● 2,2'-Dichloro-N-methyl-diethylamine 

● Embichin 

● HN2 

● MBA 

● Mechlorethamine 

● N-Methyl-bis(2-chloroethyl)amine 

● N-Methyl-bis(β-chloroethyl)amine 

● Methylbis(beta-chloroethyl)amine 

● Methylbis(chloroethylamine) 

● N-Methyl-2,2'-dichlorodiethylamine 

● Methyldi(2-chloroethyl)amine 

● Mustargen 
● Mustine 

● Mutagen 

Last updated: 11 February 1998 
OESTROGENS, NONSTEROIDAL

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 273) 

Diethylstilboestrol

CAS No.: 56-53-1

Chem. Abstr. Name: (E)-4,4'-(1,2-Diethyl-1,2-ethenediyl)bisphenol

Diethylstilboestrol dipropionate

CAS No.:130-80-3

Chem. Abstr. Name: (E)-4,4'-(1,2-Diethyl-1,2-ethenediyl)bisphenol dipropionate

Dienoestrol

CAS No.:84-17-3

Chem. Abstr. Name: 4,4'-(1,2-Diethylidene-1,2-ethanediyl)bisphenol

Hexoestrol

CAS No.: 84-16-2 

Chlorotrianisene

CAS No.: 569-57-3

Chem. Abstr. Name:1,1',l"-(1-Chloro-1-ethenyl-2-ylidene)-tris(4-methoxybenzene)

Diethylstilboestrol

A. Evidence for carcinogenicity to humans (sufficient)

Diethylstilboestrol (DES) causes clear-cell adenocarcinoma of the vagina and cervix in women 

exposed in utero. There is sufficient evidence that administration of oestrogens for the control of 

symptoms of the climacteric is causally related to an increased incidence of endometrial carcinoma; 

DES is no different from other oestrogens in this respect [ref: 1]. 

There is also clear evidence that administration of DES in large doses during pregnancy increases 

the subsequent risk of breast cancer and that DES increases the risk of testicular cancer in males 

exposed in utero. 

In four follow-up studies [ref: 2-5] of exposed and nonexposed groups of women, the possible 

effects of DES exposure during pregnancy on subsequent breast cancer risk have been evaluated. All 

have shown an increased risk in exposed women; two were randomized trials [ref: 2,3]. In one [ref: 

2], there were 32 (4.6%) breast cancers among 693 women exposed to an average total dose of 12 

g DES, and 21 (3.1%) breast cancers among 668 control (placebo) women. In the other [ref: 3], 

there were four (5.0%) breast cancers among 80 women exposed to an average total dose DES of 

16 g (plus ethisterone, average total dose, 14 g), compared to none of 76 controls; all 156 women 

were diabetic. In two studies, an exposed group and a 'matched' unexposed group were followed-up 

[ref: 4,5]. One [ref: 4] found 118 (4.4%) breast cancer cases in 2680 women exposed to a mean 

DES dose of 5 g, and 80 (3.1%) among 2566 control women. The other [ref: 5] similarly showed 38 

(2.5%) breast cancer cases among 1531 women exposed to a mean DES dose of 2 g, and 24 (1.7%) 

cases among the 1404 control women. The overall relative risk from these four studies is 1.5 (p = 

0.001). 

A further group of 408 DES-exposed women (median dose, 1.5 g) was followed up and the eight 

breast cancer cases found were contrasted to the 8.1 cases expected on the basis of local breast 

cancer incidence rates [ref: 6]. If this study is considered together with the four studies described 

above, the overall relative risk is 1.4 (p = 0.0016). 
In all five papers [ref: 2-6], the possibility is discussed that there may be a long (15-20 years) 

'latent' period before the first 'DES-induced' breast cancer would be seen. Clear evidence was found 

in a study [ref: 4] in which there was no difference in the breast cancer rates of exposed and 

unexposed women until 22 years after exposure, but an increasing difference thereafter. Similarly, 

in another study [ref: 3], there was no case in the exposed group in the first 18 years after 

exposure. In a further study [ref: 5], the relative risk was 1.3 before age 50 and 1.7 thereafter, and 

in another [ref: 6], three cases were reported with 5.1 expected before age 50 and five cases versus

3.0 expected thereafter. In contrast, however, a randomized study [ref: 2] showed 11 exposed 

cases and five nonexposed cases during the first 15 years of follow-up, compared to 21 exposed 

cases and 16 nonexposed cases thereafter. Further data are required to settle this issue. 

The four follow-up studies [ref: 2-5] of exposed and nonexposed women also included information 

on other possibly 'hormone-related' cancers. The occurrence of endometrial cancer was not 

increased in any study. The study [ref: 2] of 693 women exposed to DES and 668 controls showed 

increases in the occurrence of cancer of the ovary (4 exposed, 1 nonexposed), cancer of the cervix 

(7 exposed, 3 non-exposed) and cancer of the colon-rectum (2 exposed, 1 nonexposed); there was 

also a risk for cancer at these sites in the study of 1531 women exposed to DES and 1404 controls 

[ref: 5] (6 exposed, 2 nonexposed; 9 exposed, 6 nonexposed; 11 exposed, 7 nonexposed for the 

three sites, respectively). A third study [ref: 4] showed, in contrast, no elevation of rates for cancer 

at any other site, and there were seven deaths from cervical cancer in the control group and none in 

the exposed group, suggesting that matching in the control group was 'inadequate'; the authors 

could not identify the matching problem, and, in particular, they found that the two groups were well 

matched on educational level. The data are too few to draw any firm conclusions. 

A greater frequency of abnormalities of the reproductive tract has been found in males exposed 

prenatally to DES in comparison with nonexposed controls, although the data are few. 

Cryptorchidism, a major risk factor for testicular cancer, is one of the associated lesions [ref: 1]. 

Cancer of the testis has been investigated in five case-control studies of fetal exposure to DES [ref: 

7-11]. One [ref: 7] showed that 5.1% (4/78) of cases and 1% of controls had been exposed to 

hormones (in all likelihood DES) for bleeding; the second [ref: 8] similarly found that 5.8% (11/190) 

versus 2.3% (7/304) had had such exposure; the third [ref: 9] found 1.9% (2/108) versus 0 

(0/108) exposed to DES; the fourth [ref: 10] found 1.0% (2/202) versus 1.0% (2/206) exposed to 

DES; and the fifth [ref: 11] found 1.9% (4/211) versus 0.9% (2/214) exposed to DES. The 

combined relative risk is 2.5 (p = 0.014). 

A number of unusual tumours have been reported in women exposed to DES in utero: a fatal 

adenocarcinoma of the endometrium at age 26 [ref: 12]; a pituitary adenoma at age 18 [ref: 13]; 

an invasive squamous-cell carcinoma of the cervix at age 21 [ref: 14]; an invasive adenosquamouscell carcinoma of the cervix at age 27 [ref: 15]; and an ovarian teratoma at age 12 [ref: 16]. 

There has been no further report to add to the six cases of primary breast cancer in males with 

prostatic cancer treated with DES [ref: 1]. A case has been reported of a Leydig-cell tumour 

developing in such a man treated with DES at 1 mg per day for 2.5 years [ref 17]. There has been a 

second case report of hepatic angiosarcoma in a man treated over a long period with DES for 

prostatic cancer [ref: 1,18], and a second case report of a hepatoma in a prostatic cancer patient 

treated with DES at 3 mg per day for 4.5 years (to diagnosis of hepatoma) [ref: 1,19]. Three renal 

carcinomas have been reported after exposure to DES for prostatic cancer [ref: 20,21]. 

B. Evidence for carcinogenicity to animals (sufficient)

DES has been tested in mice, rats, hamsters, frogs and squirrel monkeys, producing tumours 

principally in oestrogen-responsive tissues [ref: 1]. Female newborn mice injected with DES 

developed epidermoid carcinomas and granular-cell myoblastomas of the cervix and squamous 

carcinomas of the vagina [ref: 22]. Mice treated prenatally with DES developed adenocarcinomas of 

the uterus, cervix and vagina, epidermoid carcinomas of the uterine cervix and vagina and ovarian 

and mammary tumours [ref: 23-28]. Female mice fed diets containing DES developed cervical and 

endometrial adenocarcinomas, mammary adenocarcinomas, osteosarcomas and mesotheliomas [ref: 

29-33]. Mice treated subcutaneously with DES had a slightly increased incidence of lymphomas and 

subcutaneous fibrosarcomas [ref: 34,35]. Prenatal exposure to DES potentiated mammary 

tumorigenesis in rats given 7,12-dimethylbenz[a]anthracene at about 50 days of age [ref: 36]. Rats 

given DES by subcutaneous pellet developed mammary and pituitary tumours. When these animals 
wee also treated with X-rays or neutrons, they developed a higher incidence of mammary tumours 

[ref: 37-39]. In other studies (subcutaneous, transplacental, oral), rats treated with DES developed 

mammary, hepatic and pituitary tumours [ref: 40-44]. When hamsters were treated prenatally with 

DES, females developed endometrial adenocarcinoma, squamous-cell papillomas of the cervix and 

vagina, and a mixed Mullerian tumour of the cervix (myosarcoma); in males, a leiomysarcoma of the 

seminal vesicles and a Cowper's gland adenoma were found [ref: 45]. Male hamsters castrated as 

adults and given DES subcutaneously developed renal tumours [ref: 46,47]. 

C. Other relevant data

No data were available on the genetic and related effects of DES in humans. 

DES induced chromosomal aberrations in bone-marrow cells of mice treated in vivo, but data on 

induction of sister chromatid exchanges and micronuclei were equivocal; it induced sister chromatid 

exchanges in one study in rats. Unusual nucleotides were found in kidney DNA following chronic 

treatment of hamsters with DES. Aneuploidy was induced in human cells in vitro, but data on 

induction of sister chromatid exchanges. chromosomal aberrations and mutation were inconclusive; 

it induced DNA strand breaks, but not unscheduled DNA synthesis, except in a single study. Tests for 

transformation in rat and Syrian hamster embryo cells gave positive results, while results for mouse 

cells were negative. Aneuploidy and DNA strand breaks were induced in rodent cells in vitro, but 

results for chromosomal aberrations and sister chromatid exchanges were equivocal; DES did not 

induce mutation or unscheduled DNA synthesis, except in a single study in Syrian hamster embryo 

cells. It did not inhibit intercellular communication of Chinese hamster V79 cells. It induced 

aneuploidy in fungi, but, in most studies, it did not induce mutation, recombination or gene 

conversion. It did not induce mutation in a variety of bacterial and insect systems, but it was 

mutagenic in plants. DNA damage was not induced in fungi or bacteria. DES induced single-strand 

breaks in bacteriophage DNA in the presence of a horseradish peroxidase activation system [ref: 

48]. 

References

1. IARC Monographs, 21, 131-134, 173-231, 1979 

2. Bibbo, M., Haenszel, W.M., Wied, G.L., Hubby, M. & Herbst, A.L. (1978) A twenty-five-year followup of women exposed to diethylstilbestrol during pregnancy. New Engl. J. Med., 298, 763-767 

3. Beral, V. & Colwell, L. (1980) Randomised trial of high doses of stilboestrol and ethisterone in 

pregnancy: Long-term follow-up of mothers. Br. med. J., 281, 1098-1101 

4. Greenberg, E.R., Barnes, A.B., Resseguie, L., Barrett, J.A., Burnside, S., Lanza, L.L., Neff, R.K., 

Stevens, M., Young, R.H. & Colton, T. (1984) Breast cancer in mothers given diethylstilbestrol in 

pregnancy. New Engl. J. Med., 311, 1393-1398 

5. Hadjimichael, O.C., Meigs, J.W., Falcier, F.W., Thompson, W.D. & Flannery, J.T. (1984) Cancer 

risk among women exposed to exogenous estrogens during pregnancy. J. natl Cancer Inst., 73, 831-

834 

6. Brian, D.D., Tilley, B.C., Labarthe, D.R., O'Fallon, W.M., Noller, K.L. & Kurland, L.T. (1980) Breast 

cancer in DES-exposed mothers. Absence of association. Mayo Clin. Proc., 55, 89-93 

7. Henderson, B.E., Benton, B., Jing, J., Yu, M.C. & Pike, M.C. (1979) Risk factors for cancer of the 

testis in young men. Int. J. Cancer, 23, 598-602 

8. Schottenfeld, D., Warshauer, M.E., Sherlock, S., Zauber, A.G., Leder, M. & Payne, R. (1980) The 

epidemiology of testicular cancer in young adults. Am. J. Epidemiol., 112, 232-246 

9. Depue, R.H., Pike, M.C. & Henderson, B.E. (1983) Estrogen exposure during gestation and risk of 

testicular cancer. J. natl Cancer Inst., 71, 1151-1155 
10. Brown, L.M., Pottern, L.M. & Hoover, R.N. (1986) Prenatal and perinatal risk factors for testicular 

cancer. Cancer Res., 46, 4812-4816 

11. Moss, A.R., Osmond, D., Bacchetti, P., Torti, F.M. & Gurgin, V. (1986) Hormonal risk factors in 

testicular cancer. A case-control study. Am. J. Epidemiol., 124, 39-52 

12. Barter, J.F., Austin, J.M., Jr & Shingleton, H.M. (1986) Endometrial adenocarcinoma after in 

utero diethylstilbestrol exposure. Obstet. Gynecol., 67 (Suppl.), 84S-85S 

13. Cunningham, J.R., Gidwani, G.P., Gupta, M.S., Duchesneau, P.M. & Schumacher, O.P. (1982) 

Prolactin-secreting pituitary adenoma: occurrence following prenatal exposure to diethylstilbestrol. 

Cleveland Clin. Q., 49, 249-254 

14. Lamb, E.J. (1977) Invasive squamous cell carcinoma of the cervix in a diethylstilbestrol-exposed 

offspring. Am. J. Obstet. Gynecol., 129, 924-925 

15. Vandrie, D.M., Puri, S., Upton, R.T. & Demeester, L.J. (1983) Adenosquamous carcinoma of the 

cervix in a woman exposed to diethylstilbestrol in utero. Obstet. Gynecol., 61 (Suppl.), 84S-87S 

16. Lazarus, K.H. (1984) Maternal diethylstilboestrol and ovarian malignancy in offspring. Lancet, i, 

53 

17. Deshmukh, A.S. & Hartung, W.H. (1983) Leydig cell tumor in patient on estrogen therapy. 

Urology, 21, 538-539 

18. Ham, J.M., Pirola, R.C. & Crouch, R.L. (1980) Hemangioendothelial sarcoma of the liver 

associated with long-term estrogen therapy in a man. Dig. Dis. Sci., 25, 879-883 

19. Brooks, J.J. (1982) Hepatoma associated with diethylstilbestrol therapy for prostatic carcinoma. 

J. Urol., 128, 1044-1045 

20. Bellet, R.E. & Squitieri, A.P. (1974) Estrogen-induced hypernephroma. J. Urol., 112, 160-161 

21. Nissenkorn, I., Servadio, C. & Avidor, I. (1979) Oestrogen-induced renal carcinoma. Br. J. Urol., 

51, 6-9 

22. Dunn, T.B. (1979) Cancer and other lesions in mice receiving estrogens. Recent Results Cancer 

Res., 66, 175-192 

23. McLachlan, J.A. (1979) Transplacental effects of diethylstilbestrol in mice. Natl Cancer Inst. 

Monogr., 51, 67-72 

24. McLachlan, J.A., Newbold, R.R. & Bullock, B.C. (1980) Long-term effects on the female mouse 

genital tract associated with prenatal exposure to diethylstilbestrol. Cancer Res., 40, 3988-3999 

25. Lamb, J.C., IV, Newbold, R.R. & McLachlan, J.A. (1981) Visualization by light and scanning 

electron microscopy of reproductive tract lesions in female mice treated transplacentally with 

diethylstilbestrol. Cancer Res., 41, 4057-4062 

26. Newbold, R.R. & MacLachlan, J.A. (1982) Vaginal adenosis and adenocarcinoma in mice exposed 

prenatally or neonatally to diethylstilbestrol. Cancer Res., 42, 2003-2011 

27. Walker, B.E. (1983) Uterine tumors in old female mice exposed prenatally to diethylstilbestrol. J. 

natl Cancer Inst., 70, 477-484 
28. Nagasawa, H., Mori, T. & Nakajima, Y. (1980) Long-term effects of progesterone or 

diethylstilbestrol with or without estrogen after maturity on mammary tumorigenesis in mice. Eur. J. 

Cancer, 16, 1583-1589 

29. Highman, B., Greenman, D.L., Norvell, M.J., Farmer, J. & Shellenberger, T.E. (1980) Neoplastic 

and preneoplastic lesions induced in female C3H mice by diets containing diethylstilbestrol or 17βestradiol. J. environ. Pathol. Toxicol., 4, 81-95 

30. Highman, B., Roth, S.I. & Greenman, D.L. (1981) Osseous changes and oesteosarcomas in mice 

continuously fed diets containing diethylstilbestrol or 17β-estradiol. J. natl Cancer Inst., 67, 653-662 

31. Greenman, D.L., Highman, B., Kodell, R.L., Morgan, K.T. & and Norvell, M. (1984) Neoplastic 

and nonneoplastic responses to chronic feeding of diethylstilbestrol in C3H mice. J. Toxicol. environ. 

Health, 14, 551-567 

32. Greenman, D.L., Kodell, R.L., Highman, B., Schieferstein, G.J. & Norvell, M. (1984) Influence of 

strain and age on the induction of mammary tumours by diethylstilboestrol in C3H mice. Food chem. 

Toxicol., 22, 871-874 

33. Greenman, D.L., Highman, B., Chen, J.J., Schieferstein, G.J. & Norvell, M.J. (1986) Influence of 

age on induction of mammary tumors by diethylstilbestrol in C3H/HeN mice with low murine 

mammary tumor virus titer. J. natl Cancer Inst., 77, 891-898 

34. Boján, F., Rédai, I. & Gomba, S. (1979) Induction of lymphomas by urethane in combination 

with diethylstilboestrol in CFLP mice. Experientia, 35, 378-379 

35. Ways, S. (1982) Local induction of fibrosarcomas by diethylstilbestrol. Int. Res. Commun. 

System med. Sci., 10, 796-797 

36. Boylan, E.S. & Calhoon, R.E. (1979) Mammary tumorigenesis in the rat following prenatal 

exposure to diethylstilbestrol and postnatal treatment with 7,12-dimethylbenz(a)anthracene. J. 

Toxicol. environ. Health, 5, 1059-1071 

37. Holtzman, S., Stone, J.P. & Shellabarger, C.J. (1979) Synergism of diethylstilbestrol and 

radiation in mammary carcinogenesis in female F344 rats. J. natl Cancer Inst., 63, 1071-1074 

38. Holtzman, S., Stone, J.P. & Shellabarger, C.J. (1981) Synergism of estrogens and X-rays in 

mammary carcinogenesis in female ACI rats. J. natl Cancer Inst., 67, 455-459 

39. Shellabarger, C.J., Chmelevsky, D., Kellerer, A.M., Stone, J.P. & Holtzman, S. (1982) Induction 

of mammary neoplasms in the ACI rat by 430-keV neutrons, X-rays, and diethylstilbestrol. J. natl 

Cancer Inst., 69, 1135-1146 

40. Sumi, C., Yokoro, K. & Matsushima, R. (1983) Induction of hepatic tumors by diethylstilbestrol 

alone or in synergism with N-nitrosobutylurea in castrated male WF rats. J. natl Cancer Inst., 70, 

937-942 

41. Phelps, C. & Hymer, W.C. (1983) Characterization of estrogen-induced adenohypophyseal 

tumors in the Fischer 344 rat. Neuroendocrinology, 37, 23-31 

42. Rothschild, T.C., Calhoon, R.E. & Boylan, E.S. (1985) Transplacental carcinogenicity of 

diethylstilbestrol (DES) in female ACI rats (Abstract No. 770). Proc. Am. Assoc. Cancer Res., 26, 195 

43. Inoh, A., Kamiya, K., Fujii, Y. & Yokoro, K. (1985) Protective effects of progesterone and 

tamoxifen in estrogen-induced mammary carcinogenesis in ovariectomized W/FU rats. Jpn. J. Cancer 

Res. (Gann), 76, 699-704 
44. Wanless, I.R. & Medline, A. (1982) Role of estrogens as promoters of hepatic neoplasia. Lab. 

Invest., 46, 313-320 

45. Rustia, M. (1979) Role of hormone imbalance in transplacental carcinogenesis induced in Syrian 

golden hamsters by sex hormones. Natl Cancer Inst. Monogr., 51, 77-87 

46. Li, J.J., Li, S.A., Klicka, J.K., Parsons, J.A. & Lam, L.K.T. (1983) Relative carcinogenic activity of 

various synthetic and natural estrogens in the Syrian hamster kidney. Cancer Res., 43, 5200-5204 

47. Li, J.J. & Li, S.A. (1984) Estrogen-induced tumorigenesis in hamsters: roles for hormonal and 

carcinogenic activities. Arch. Toxicol., 55, 110-118 

48. IARC Monographs, Suppl. 6, 250-256, 1987 

Dienoestrol

A. Evidence for carcinogenicity to animals (limited)

Dienoestrol was tested in female guinea-pigs by subcutaneous injection and in female mice by 

intravaginal administration. Although these experiments indicated induction of 'uterine tumours' in 

guinea-pigs and of ovarian tumours in mice, they were regarded as inadequate [ref: 1]. Renal 

tumours were produced by administration of α-dienoestrol in male hamsters castrated as adults [ref: 

2,3]. In noninbred rats, dienoestrol given prenatally and neonatally did not increase tumour 

incidence [ref: 4]. 

B. Other relevant data

No data were available on the genetic and related effects of dienoestrol in humans. 

There are two stable stereoisomers of dienoestrol - Z,Z-dienoestrol (cis,cis-dienoestrol, βdienoestrol) and E,E-dienoestrol (trans,trans-dienoestrol, α-dienoestrol). E,E-Dienoestrol is the 

principal constituent of dienoestrol-containing medications, whereas Z,Z-dienoestrol is a metabolite 

of diethylstilboestrol. Z,Z-Dienoestrol induced sister chromatid exchanges in human fibroblasts in 

vitro. Z,Z-Dienoestrol, but not E,E-dienoestrol, transformed cultured hamster cells. Z,Z-Dienoestrol 

produced single-strand breaks in hamster cells in the absence of an exogenous metabolic system, 

whereas both Z,Z- and E,E-dienoestrol gave weakly positive results in tests for unscheduled DNA 

synthesis in hamster cells only in the presence of a metabolic system. Z,Z-Dienoestrol did not induce 

single-strand breaks in bacteriophage DNA in the presence of a horseradish peroxidase activation 

system. Z,Z-Dienoestrol and E,E-dienoestrol were not mutagenic to bacteria [ref: 5]. 

References

1. IARC Monographs, 21, 161-171, 1979

2. Li, J.J., Li, S.A., Klicka, J.K., Parsons, J.A. & Lam, L.K.T. (1983) Relative carcinogenic activity of 

various synthetic and natural estrogens in the Syrian hamster kidney. Cancer Res., 43, 5200-5204 

3. Li, J.J. & Li, S.A. (1984) Estrogen-induced tumorigenesis in hamsters: roles for hormonal and 

carcinogenic activities. Arch. Toxicol., 55, 110-118 

4. Ird (Y.A. (1983) Blastomogenesis induced in rats by transplacental treatment with strogens 

(Russ.). Vopr. Onkol., 29, 61-66

5. IARC Monographs, Suppl. 6, 336-337, 1987 
Hexoestrol

A. Evidence for carcinogenicity to animals (sufficient)

Hexoestrol was tested for carcinogenicity in intact male hamsters and in males castrated as adults 

by subcutaneous implantation as a pellet, producing renal tumours, some of which were described as 

renal carcinomas, in 85-100% of tested animals [ref: 1-3]. 

B. Other relevant data

No data were available on the genetic and related effects of hexoestrol in humans. Unusual 

nucleotides were found in kidney DNA of hamsters treated with hexoestrol in vivo. The compound 

was not mutagenic to bacteria [ref: 4]. 

References

1. Li, J.J., Li, S.A., Klicka, J.K., Parsons, J.A. & Lam, L.K.T. (1983) Relative carcinogenic activity of 

various synthetic and natural estrogens in the Syrian hamster kidney. Cancer Res., 43, 5200-5204 

2. Li, J.J. & Li, S.A. (1984) Estrogen-induced tumorigenesis in hamsters: roles for hormonal and 

carcinogenic activities. Arch. Toxicol., 55, 110-118 

3. Liehr, J.G., Ballatore, A.M., Dague, B.B. & Ulubelen, A.A. (1985) Carcinogenicity and metabolic 

activation of hexestrol. Chem.-biol. Interactions, 55, 157-176 

4. IARC Monographs, Suppl. 6, 336-337, 1987 

Chlorotrianisene

A. Evidence for carcinogenicity to animals (inadequate) 

Chlorotrianisene was tested in only one experiment in rats by oral administration. The data were 

insufficient to evaluate the carcinogenicity of this compound [ref: 1]. 

B. Other relevant data

No data were available to the Working Group. 

Reference

1. IARC Monographs, 21, 139-146, 1979 

Overall evaluation

Nonsteroidal oestrogens are carcinogenic to humans (Group 1).

N.B. - This evaluation applies to the group of chemicals as a whole and not necessarily to all 

individual chemicals within the group.

For definition of the italicized terms, see Preamble Evaluation.

Also previous evaluations: Vol. 6 (1974); Vol. 21 (1979)
Synonyms for Diethylstilboestrol

● Acnestrol 

● Antigestil 

● Bio-des 

● 3,4-Bis(para-hydroxyphenyl)-3-hexene 

● Bufon 

● Comestrol 

● Cyren 

● Cyren A 

● Dawe's destrol 

● DEB 

● DES 

● Desma 

● Destrol 

● DiBestrol '2' Premix 

● Dicorvin 

● DiEstryl 

● α,α'-Diethylstilbenediol 

● (E)-α,α'-Diethyl-4,4'-stilbenediol 

● trans-α,α'-Diethyl-4,4'-stilbenediol 

● trans-Diethylstilbesterol 

● Diethylstilbestrol 

● trans-Diethylstilbestrol 

● trans-Diethylstilboestrol 

● 4,4'-Dihydroxydiethylstilbene 

● 4,4'-Dihydroxy-α,β-diethylstilbene 

● Distilbene 

● Domestrol 

● Estilbin 'MCO' 

● Estrobene 

● Estromenin 

● Estrosyn 

● [Follidiene] 

● Fonatol 

● Grafestrol 

● Gynopharm 

● Hi-Bestrol 

● Idroestril 

● Iscovesco 

● Menostilbeen 

● Microest 

● Milestrol 

● Neo-Oestranol I 

● Oekolp 

● Oestrogen 

● Oestrogenine 

● Oestrol Vetag 

● Oestromenin 

● Oestromensyl 

● Oestromon 

● Pabestrol 

● Palestrol 

● Percutatrine Oestrogenique Iscovesco 

● Rumestrol 1 

● Rumestrol 2 

● Sedestran 

● Serral 

● Sexocretin 

● Sibol 

● Sintestrol 

● Stibilium 

● Stilbestrol 
● Stilbetin 

● Stilboefral 

● Stilboestrol 

● Stilboestroform 

● Stilbofollin 

● Stilbol 

● Stilkap 

● Stil-Rol 

● Synestrin 

● Synthoestrin 

● Synthofolin 

● Syntofolin 

● Tampovagan stilboestrol 

● Tylosterone 

● Vagestrol 

Synonyms for Diethylstilboestrol dipropionate

● Clinestrol 

● Cyren B 

● Dibestil 

● α,α,'-Diethyl-4,4'-stilbenediol dipropionate 

● (E)-α,α'-Diethyl-4,4'-stilbenediol dipropionate 

● α,α'-Diethyl-4,4'-stilbenediol trans-dipropionate 

● α,α'-Diethyl-4,4'-stilbenediol dipropionyl ester 

● Diethylstilbene dipropionate 

● Diethylstilbesterol dipropionate 

● Diethylstilbestrol dipropionate 

● Diethylstilbestrol propionate 

● Diethylstilboestrol dipropionate 

● Diethylstilboestrol propionate 

● Dihydroxydiethylstilbene dipropionate 

● para,para'-Dipropionoxy-trans-α,β-diethylstilbene 

● Estilben 

● Estilbin 

● Estrobene DF 

● Estrobene DP 

● Estrogenin 

● Estrostilben 

● Euvestin 

● Gynolett 

● Horfemine 

● Neo-Oestranol II 

● Neo-Oestronol II 

● New-Oestranol 11 

● Oestrogynaedron 

● Orestol 

● Pabestrol D 

● Sinciclan 

● Stilbestrol dipropionate 

● Stilbestrol propionate 

● Stilbestronate 

● Stilboestrol dipropionate 

● Stilboestrol DP 

● Stilbofax 

● Stilronate 

● Synoestron 

● Syntestrin 

● Syntestrine 

● Willestrol 

Synonyms for Dienoestrol
● Agaldog 

● 3,4-Bis(4-hydroxyphenyl)-2,4-hexadiene 

● 3,4-Bis(para-hydroxyphenyl)-2,4-hexadiene 

● Cycladiene 

● Dehydrostilbestrol 

● Dehydrostilboestrol 

● Dienol 

● 4,4'-(Diethylideneethylene)diphenol 

● para,para'-(Diethylideneethylene)diphenol 

● 4,4'-Dihydroxy-γ,δ-diphenyl-β,δ-hexadiene 

● Dinovex 

● Di(para-oxyphenyl)-2,4-hexadiene 

● DV 

● Estrodienol 

● Estraguard 

● Estroral 

● Follidiene 

● Follormon 

● Gynefollin 

● Hormofemin 

● Isodienestrol 

● Oestrasid 

● Oestrodiene 

● Oestrodienol 

● Oestroral 

● Oestrovis 

● Para-dien 

● Restrol 

● Retalon 

● Sexadien 

● Synestrol 

● Teserene 

● Willnestrol 

Synonyms for Chlorotrianisene

● Anisene 

● Chlorestrolo 

● Chlorotrianisine 

● Chlorotrianizen 

● Chlorotrisin 

● Chlorotris-(para-methoxyphenyl)ethylene 

● Chlortrianisen 

● Clorestrolo 

● Clorotrisin 

● Hormonisene 

● Khlortrianizen 

● Merbentul 

● Metace 

● NSC-10108 

● Rianil 

● Tace 

● TACE 

● Tace-FN 

● Tri-para-anisylchloroethylene 

● Tris(para-methoxyphenyl)chloroethylene 

Last updated: 9 February 1998 
OESTROGEN-PROGESTIN REPLACEMENT THERAPY

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 308)

A. Evidence for carcinogenicity to humans (inadequate) 

Progestins, when administered for at least ten days per 28-day oestrogen replacement therapy 

cycle, prevent adenomatous hyperplasia, a precursor of endometrial carcinoma, and cause 

regression of pre-existing adenomatous hyperplasia in some patients [ref: 1]. When administered 

alone, progestins are effective in the treatment of carcinoma in situ of the endometrium [ref: 2] and 

of more advanced disease [ref: 3,4]. 

Progestins increase the conversion of oestradiol-17β to oestrone, a biologically less active oestrogen 

[ref: 5], and they reduce the concentration of oestrogen receptors [ref: 6]. Maximal mitotic activity 

in the endometrium occurs during the follicular phase of the cycle; luteal-phase progesterone 

effectively stops mitotic activity and causes differentiation of endometrial cells to a secretory state 

[ref: 7]. 

Support for a protective effect of progestins against endometrial cancer risk is obtained from the 

results of studies of the effects of oral contraceptives on endometrial cancer risk. Case-control 

studies have consistently shown that, whereas ingestion of sequential oral contraceptives containing 

an oestrogen alone throughout most of the menstrual cycle increases risk, ingestion of combined 

oral contraceptives, in which each pill contains an oestrogen and a progestin, substantially 

decreases risk. 

The effect of progestins on the breast is markedly different from that on the endometrium. 

Endometrial cancer risk is considerably reduced with combined oral contraceptives, but there is no 

evidence of a reduced risk of breast cancer, even after long periods of combined oral contraceptive 

use [ref: 8]. Maximal mitotic activity in breast tissue occurs during the luteal phase of the normal 

menstrual cycle in the face of maximal progesterone levels [ref: 9]. These results concerning the 

effects of combined oral contraceptives suggest strongly that progestins do not have an 

antioestrogen, anticancer effect on the breast. A number of studies [ref: 10-12] have addressed the 

relationship between oestrogen-progestin replacement therapy and cancer, but in each instance 

either the small size of the study or apparently inadequate study design or data analysis prevent 

conclusions from being drawn. 

B. Other relevant data

No data were available to the Working Group. 

Overall evaluation

Oestrogen-progestin replacement therapy is not classifiable as to its carcinogenicity to humans 

(Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 6 (1974); Vol. 21 (1979)

Subsequent evaluation: Vol. 72 (1999)

References
1. Gambrell, R.D., Jr (1982) Clinical use of progestins in the menopausal patient. Dosage and 

duration. J. reprod. Med., 27, 531-538 

2. Kohorn, E.I. (1976) Gestagens and endometrial carcinoma. Gynecol. Oncol., 4, 398-411 

3. Thornton, J.G., Brown, L.A., Wells, M. & Scott, J.S. (1985) Primary treatment of endometrial 

cancer with progestogen alone. Lancet, ii, 207-208 

4. Mackillop, W.J. & Pringle, J.F. (1985) Stage III endometrial carcinoma: a review of 90 cases. 

Cancer, 56, 2519-2523 

5. Tseng, L. & Gurpide, E. (1975) Induction of human endometrial estradiol dehydrogenase by 

progestins. Endocrinology, 97, 825-833 

6. Hsueh, A.J.W., Peck, E.J., Jr & Clark, J.H. (1975) Progesterone antagonism of the oestrogen 

receptor and oestrogen-induced uterine growth. Nature, 254, 337-339 

7. Novak, E.R. & Woodruff, J.D. (1979) Novak's Gynaecologic and Obstetric Pathology with Clinical 

and Endocrine Relations, Philadelphia, PA, W.B. Saunders, pp. 171-184 

8. Kelsey, J.L. (1979) A review of the epidemiology of human breast cancer. Epidemiol. Rev., 1, 74-

109 

9. Anderson, T.J., Ferguson, D.J.P. & Raab, G.M. (1982) Cell turnover in the 'resting' human breast: 

influence of parity, contraceptive pill, age and laterality. Br. J. Cancer, 46, 376-382 

10. Gambrell, R.D., Jr, Massey, F.M., Castaneda, T.A., Ugenas, A.J. & Ricci, C.A. (1979) Reduced 

incidence of endometrial cancer among postmenopausal women treated with progestogens. J. Am. 

Geriatr. Soc., 27, 389-394 

11. Nachtigall, L.E., Nachtigall, R.H., Nachtigall, R.B. & Beckman, E.M. (1979) Estrogen replacement 

therapy. II. A prospective study in the relationship to carcinoma and cardiovascular and metabolic 

problems. Obstet. Gynecol., 54, 74-79 

12. Gambrell, R.D., Jr, Maier, R.C. & Sanders, B.I. (1983) Decreased incidence of breast cancer in 

postmenopausal estrogen-progestogen users. Obstet. Gynecol., 62, 435-443 

Last updated: 11 March 1998 
OESTROGEN REPLACEMENT THERAPY

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p.280) 

A. Evidence for carcinogenicity to humans (sufficient)

A number of studies, utilizing a variety of designs, have shown a consistent, strongly positive 

association between exposure to a number of oestrogenic substances and risk of endometrial 

cancer, with evidence of positive dose-response relationships both for strength of medication and 

duration of use [ref: 1]. Consistent findings have also been seen in more recent studies [ref: 2-16]. 

The rise and fall of incidence of endometrial cancer in several areas of the USA was compatible with 

trends in oestrogen use [ref: 1,15].

Of the 20 epidemiological studies of oestrogen replacement therapy and breast cancer risk [ref: 16-

35], nine show a positive relation between oestrogen use and breast cancer [ref: 17-20,22-

24,28,33]. The increased risks tend to be small; for example, a 50% increase was found with 20 

years of menopausal oestrogen replacement therapy use [ref: 24]. All except one [ref: 33] of the 

positive studies involved use of population controls (eight of the nine studies with population 

controls gave positive results), and most showed increased risk after prolonged use or after ten or 

more years since initial exposure. One study showed a positive association with current oestrogen 

use [ref: 28].

One possible reason that studies with hospital controls gave negative results and those with 

population controls positive results is that oestrogen replacement therapy may be used more 

frequently in hospitalized women than in the general population. However, in two studies involving 

use of both hospital and population control groups, one giving positive [ref: 29] and the other 

largely negative [ref: 25] results, similar results were obtained when hospital and population 

controls were used to estimate the relative risk. Three of the studies with negative results [ref: 

26,27,34] probably did not permit the authors to address satisfactorily the question of long-term 

use of oestrogen replacement therapy. The large hospital-based study that showed a positive 

finding used as controls subjects with a large spectrum of acute conditions unrelated to any of the 

known or suspected risk factors for breast cancer [ref: 33].

One cohort study of 1439 women initially treated for benign breast disease showed increased risk 

for women who took exogenous oestrogens after biopsy, but not for those who had taken them 

before biopsy. The increased risk in the former group appeared to be associated with epithelial 

hyperplasia or calcification in the initial lesion [ref: 35]. 

Overall evaluation

Oestrogen replacement therapy is carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also previous evaluations: Vol. 6 (1974); Vol. 21 (1979)

Subsequent evaluation: Vol. 72 (1999)

References

1. IARC Monographs, 21, 95-102, 147-159, 1979
2. Buring, J.E., Bain, C.J. & Ehrmann, R.L. (1986) Conjugated estrogen use and risk of endometrial 

cancer. Am. J. Epidemiol., 124, 434-441

3. Ewertz, M., Machado, S.G., Boice, J.D., Jr & Jensen, O.M. (1984) Endometrial cancer following 

treatment for breast cancer: A case-control study in Denmark. Br. J. Cancer, 50, 687-692

4. Henderson, B.E., Casagrande, J.T., Pike, M.C., Mack, T., Rosario, I. & Duke, A. (1983) The 

epidemiology of endometrial cancer in young women. Br. J. Cancer, 47, 749-756

5. Hulka, B.S., Fowler, W.C., Jr, Kaufman, D.G., Grimson, R.C., Greenberg, B.G., Hogue, C.J.R., 

Berger, G.S. & Pulliam, C.C. (1980) Estrogen and endometrial cancer: Cases and two control groups 

from North Carolina. Am. J. Obstet. Gynecol., 137, 92-101

6. Kelsey, J.L., LiVolsi, V.A., Holford, T.R., Fischer, D.B., Mostow, E.D., Schwartz, P.E., O'Connor, T. 

& White, C. (1982) A case-control study of cancer of the endometrium. Am. J. Epidemiol., 116, 333-

342

7. La Vecchia, C., Franceschi, S., Gallus, G., DeCarli, A., Colombo, E., Mangioni, C. & Tognoni, G. 

(1982) Oestrogens and obesity as risk factors for endometrial cancer in Italy. Int. J. Epidemiol., 11, 

120-126

8. La Vecchia, C., Franceschi, S., DeCarli, A., Gallus, G. & Tognoni, G. (1984) Risk factors for 

endometrial cancer at different ages. J. natl Cancer Inst., 73, 667-671

9. Öbrink, A., Bunne, G., Collén, J. & Tjernberg, B. (1981) Estrogen regimen of women with 

endometrial carcinoma. A retrospective case-control study at Radiumhemmet. Acta obstet. gynecol. 

scand., 60, 191-197

10. Shapiro, S., Kaufman, D.W., Slone, D., Rosenberg, L., Miettinen, O.S., Stolley, P.D., 

Rosenshein, N.B., Watring, W.G., Leavitt, T., Jr & Knapp, R.C. (1980) Recent and past use of 

conjugated estrogens in relation to adenocarcinoma of the endometrium. New Engl. J. Med., 303, 

485-489

11. Shapiro, S., Kelly, J.P., Rosenberg, L., Kaufman, D.W., Helmrich, S.P., Rosenshein, N.B., Lewis, 

J.L., Jr, Knapp, R.C., Stolley, P.D. & Schottenfeld, D. (1985) Risk of localized and widespread 

endometrial cancer in relation to recent and discontinued use of conjugated estrogens. New Engl. J. 

Med., 313, 969-972

12. Spengler, R.F., Clarke, E.A., Woolever, C.A., Newman, A.M. & Osborn, R.W. (1981) Exogenous 

estrogens and endometrial cancer: a case-control study and assessment of potential biases. Am. J. 

Epidemiol., 114, 497-506

13. Stavraky, K.M., Collins, J.A., Donner, A. & Wells, G.A. (1981) A comparison of estrogen use by 

women with endometrial cancer, gynecologic disorders, and other illnesses. Am. J. Obstet. Gynecol., 

141, 547-555

14. Weiss, N.S., Farewell, V.T., Szekely, D.R., English, D.R. & Kiviat, N. (1980) Oestrogens and 

endometrial cancer: effect of other risk factors on the association. Maturitas, 2, 185-190

15. Marrett, L.D., Meigs, J.W. & Flannery, J.T. (1982) Trends in the incidence of cancer of the 

corpus uteri in Connecticut, 1964-1969, in relation to consumption of exogenous estrogens. Am. J. 

Epidemiol., 116, 57-67

16. Vakil, D.V., Morgan, R.W. & Halliday, M. (1983) Exogenous estrogens and development of 

breast and endometrial cancer. Cancer Detect. Prev., 6, 415-424
17. Hoover, R., Gray, L.A., Sr, Cole, P. & MacMahon, B. (1976) Menopausal estrogens and breast 

cancer. New Engl. J. Med., 295, 401-405

18. Ross, R.K., Paganini-Hill, A., Gerkins, V.R., Mack, T.M., Pfeffer, R., Arthur, M. & Henderson, B.E. 

(1980) A case-control study of menopausal estrogen therapy and breast cancer. J. Am. med. 

Assoc., 243, 1635-1639

19. Hoover, R., Glass, A., Finkle, W.D., Azevedo, D. & Milne, K. (1981) Conjugated estrogens and 

breast cancer risk in women. J. natl Cancer Inst., 67, 815-820

20. Hulka, B.S., Chambless, L.E., Deubner, D.C. & Wilkinson, W.E. (1982) Breast cancer and 

estrogen replacement therapy. Am. J. Obstet. Gynecol., 143, 638-644

21. Gambrell, R.D., Jr, Maier, R.C. & Sanders, B.I. (1983) Decreased incidence of breast cancer in 

postmenopausal estrogen-progestogen users. Obstet. Gynecol., 62, 435-443

22. Hiatt, R.A., Bawol, R., Friedman, G.D. & Hoover, R. (1984) Exogenous estrogen and breast 

cancer after bilateral oophorectomy. Cancer, 54, 139-144

23. McDonald, J.A., Weiss, N.S., Daling, J.R., Francis, A.M. & Polissar, L. (1986) Menopausal 

estrogen use and the risk of breast cancer. Breast Cancer Res. Treat., 7, 193-199

24. Brinton, L.A., Hoover, R. & Fraumeni, J.F., Jr (1986) Menopausal oestrogens and breast cancer 

risk: an expanded case-control study. Br. J. Cancer, 54, 825-832

25. Nomura, A.M.Y., Kolonel, L.N., Hirohata, T. & Lee, J. (1986) The association of replacement 

estrogens with breast cancer. Int. J. Cancer, 37, 49-53

26. Sartwell, P.E., Arthes, F.G. & Tonascia, J.A. (1977) Exogenous hormones, reproductive history, 

and breast cancer. J. natl Cancer Inst., 59, 1589-1592

27. Ravnihar, B., Seigel, D.G. & Lindtner, J. (1979) An epidemiologic study of breast cancer and 

benign breast neoplasias in relation to the oral contraceptive and estrogen use. Eur. J. Cancer, 15, 

395-405

28. Jick, H., Walker, A.M., Watkins, R.N., D'Ewart, D.C., Hunter, J.R., Danford, A., Madsen, S., 

Dinan, B.J. & Rothman, K.J. (1980) Replacement estrogens and breast cancer. Am. J. Epidemiol., 

112, 586-594

29. Kelsey, J.L., Fischer, D.B., Holford, T.R., LiVolsi, V.A., Mostow, E.D., Goldenberg, I.S. & White, 

C. (1981) Exogenous estrogens and other factors in the epidemiology of breast cancer. J. natl 

Cancer Inst., 67, 327-333

30. Sherman, B., Wallace, R. & Bean, J. (1983) Estrogen use and breast cancer. Interaction with 

body mass. Cancer, 51, 1527-1531

31. Kaufman, D.W., Miller, D.R., Rosenberg, L., Helmrich, S.P., Stolley, P., Schottenfeld, D. & 

Shapiro, S. (1984) Noncontraceptive estrogen use and the risk of breast cancer. J. Am. med. 

Assoc., 252, 63-67

32. Horwitz, R.I. & Stewart, K.R. (1984) Effect of clinical features on the association of estrogens 

and breast cancer. Am. J. Med., 76, 192-198

33. La Vecchia, C., Decarli, A., Parazzini, F., Gentile, A., Liberati, C. & Franceschi, S. (1986) Noncontraceptive oestrogens and the risk of breast cancer in women. Int. J. Cancer, 38, 853-858
34. Wingo, P.A., Layde, P.M., Lee, N.C., Rubin, G. & Ory, H.W. (1987) The risk of breast cancer in 

postmenopausal women who have used estrogen replacement therapy. J. Am. med. Assoc., 257, 

209-215

35. Thomas, D.B., Persing, J.P. & Hutchison, W.B. (1982) Exogenous estrogens and other risk 

factors for breast cancer in women with benign breast diseases. J. natl Cancer Inst., 69, 1017-1025 

Last updated: 9 February 1998 
OESTROGENS, STEROIDAL

(Group 1)

Evidence for carcinogenicity to humans (sufficient) 

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 280) 

Conjugated oestrogens

CAS No.: N/A

Chem. Abstr. Name: N/A

Sodium oestrone sulphate

CAS No.: 438-67-5

Chem. Abstr. Name: 3-(Sulfooxy)estra-1,3,5(10)-trien-17-one sodium salt

Sodium equilin sulphate

CAS No.: 16680-47-0

Chem. Abstr. Name: 3-(Sulfooxy)estra-1,3,5(10),7-tetraen-17-one sodium salt

Piperazine oestrone sulphate

CAS No.: 17280-37-7

Chem. Abstr. Name: 3-(Sulfooxy)estra-1,3,5(10)-trien-17-one compd. with piperazine (1:1)

Oestradiol-17 β

CAS No.: 50-28-2

Chem. Abstr. Name: (17 β)-Estra-1,3,5(10)-triene-3,17-diol 

Oestradiol 3-benzoate

CAS No.: 50-50-0

Chem. Abstr. Name: Estra-1,3,5(10)-triene-3,17-diol(17β)-3-benzoate

Oestradiol dipropionate

CAS No.: 113-38-2

Chem. Abstr. Name: Estral,3,5(10)-triene-3,17-diol(17β)-dipropionate

Oestradiol-17β-valerate

CAS No.: 979-32-8

Chem. Abstr. Name: (17β)-Estra-1,3,5-triene-3,17-diol 17-pentanoate

Polyoestradiol phosphate

CAS No.: 28014-46-2

Chem. Abstr. Name: (17β)-Estra-1,3,5(10)-triene-3,17-diol polymer with phosphoric acid

Oestriol

CAS No.: 50-27-1

Chem. Abstr. Name: O(16 α,17 β)-Estra-1,3,5(10)-triene-3,16,17-triol 

Oestrone

CAS No.: 53-16-7

Chem. Abstr. Name: 3-Hydroxyestra-1,3,5(10)-trien-17-one 

Oestrone benzoate

CAS No.: 2393-53-5

Chem. Abstr. Name: 3-(Benzoyloxy)estra-1,3,5(10)-trien-17-one
Ethinyloestradiol

CAS No.: 57-63-6

Chem. Abstr. Name: (17α)-19-Norpregna-1,3,5(10)-trien-20yne-3,17-diol 

Mestranol

CAS No.: 72-33-3

Chem. Abstr. Name: (17α)-3-Methoxy-19-norpregna-1,3,5(10)-trien-20-yn-17-ol

Oestrogen replacement therapy

A. Evidence for carcinogenicity to humans (sufficient)

A number of studies, utilizing a variety of designs, have shown a consistent, strongly positive 

association between exposure to a number of oestrogenic substances and risk of endometrial 

cancer, with evidence of positive dose-response relationships both for strength of medication and 

duration of use [ref: 1]. Consistent findings have also been seen in more recent studies [ref: 2-16]. 

The rise and fall of incidence of endometrial cancer in several areas of the USA was compatible with 

trends in oestrogen use [ref: 1,15].

Of the 20 epidemiological studies of oestrogen replacement therapy and breast cancer risk [ref: 16-

35], nine show a positive relation between oestrogen use and breast cancer [ref: 17-20,22-

24,28,33]. The increased risks tend to be small; for example, a 50% increase was found with 20 

years of menopausal oestrogen replacement therapy use [ref: 24]. All except one [ref: 33] of the 

positive studies involved use of population controls (eight of the nine studies with population 

controls gave positive results), and most showed increased risk after prolonged use or after ten or 

more years since initial exposure. One study showed a positive association with current oestrogen 

use [ref: 28].

One possible reason that studies with hospital controls gave negative results and those with 

population controls positive results is that oestrogen replacement therapy may be used more 

frequently in hospitalized women than in the general population. However, in two studies involving 

use of both hospital and population control groups, one giving positive [ref: 29] and the other 

largely negative [ref: 25] results, similar results were obtained when hospital and population 

controls were used to estimate the relative risk. Three of the studies with negative results [ref: 

26,27,34] probably did not permit the authors to address satisfactorily the question of long-term 

use of oestrogen replacement therapy. The large hospital-based study that showed a positive 

finding used as controls subjects with a large spectrum of acute conditions unrelated to any of the 

known or suspected risk factors for breast cancer [ref: 33].

One cohort study of 1439 women initially treated for benign breast disease showed increased risk 

for women who took exogenous oestrogens after biopsy, but not for those who had taken them 

before biopsy. The increased risk in the former group appeared to be associated with epithelial 

hyperplasia or calcification in the initial lesion [ref: 35]. 

References

1. IARC Monographs, 21, 95-102, 147-159, 1979

2. Buring, J.E., Bain, C.J. & Ehrmann, R.L. (1986) Conjugated estrogen use and risk of endometrial 

cancer. Am. J. Epidemiol., 124, 434-441

3. Ewertz, M., Machado, S.G., Boice, J.D., Jr & Jensen, O.M. (1984) Endometrial cancer following 

treatment for breast cancer: A case-control study in Denmark. Br. J. Cancer, 50, 687-692

4. Henderson, B.E., Casagrande, J.T., Pike, M.C., Mack, T., Rosario, I. & Duke, A. (1983) The 

epidemiology of endometrial cancer in young women. Br. J. Cancer, 47, 749-756
5. Hulka, B.S., Fowler, W.C., Jr, Kaufman, D.G., Grimson, R.C., Greenberg, B.G., Hogue, C.J.R., 

Berger, G.S. & Pulliam, C.C. (1980) Estrogen and endometrial cancer: Cases and two control groups 

from North Carolina. Am. J. Obstet. Gynecol., 137, 92-101

6. Kelsey, J.L., LiVolsi, V.A., Holford, T.R., Fischer, D.B., Mostow, E.D., Schwartz, P.E., O'Connor, T. 

& White, C. (1982) A case-control study of cancer of the endometrium. Am. J. Epidemiol., 116, 333-

342

7. La Vecchia, C., Franceschi, S., Gallus, G., DeCarli, A., Colombo, E., Mangioni, C. & Tognoni, G. 

(1982) Oestrogens and obesity as risk factors for endometrial cancer in Italy. Int. J. Epidemiol., 11, 

120-126

8. La Vecchia, C., Franceschi, S., DeCarli, A., Gallus, G. & Tognoni, G. (1984) Risk factors for 

endometrial cancer at different ages. J. natl Cancer Inst., 73, 667-671

9. Öbrink, A., Bunne, G., Collén, J. & Tjernberg, B. (1981) Estrogen regimen of women with 

endometrial carcinoma. A retrospective case-control study at Radiumhemmet. Acta obstet. gynecol. 

scand., 60, 191-197

10. Shapiro, S., Kaufman, D.W., Slone, D., Rosenberg, L., Miettinen, O.S., Stolley, P.D., 

Rosenshein, N.B., Watring, W.G., Leavitt, T., Jr & Knapp, R.C. (1980) Recent and past use of 

conjugated estrogens in relation to adenocarcinoma of the endometrium. New Engl. J. Med., 303, 

485-489

11. Shapiro, S., Kelly, J.P., Rosenberg, L., Kaufman, D.W., Helmrich, S.P., Rosenshein, N.B., Lewis, 

J.L., Jr, Knapp, R.C., Stolley, P.D. & Schottenfeld, D. (1985) Risk of localized and widespread 

endometrial cancer in relation to recent and discontinued use of conjugated estrogens. New Engl. J. 

Med., 313, 969-972

12. Spengler, R.F., Clarke, E.A., Woolever, C.A., Newman, A.M. & Osborn, R.W. (1981) Exogenous 

estrogens and endometrial cancer: a case-control study and assessment of potential biases. Am. J. 

Epidemiol., 114, 497-506

13. Stavraky, K.M., Collins, J.A., Donner, A. & Wells, G.A. (1981) A comparison of estrogen use by 

women with endometrial cancer, gynecologic disorders, and other illnesses. Am. J. Obstet. Gynecol., 

141, 547-555

14. Weiss, N.S., Farewell, V.T., Szekely, D.R., English, D.R. & Kiviat, N. (1980) Oestrogens and 

endometrial cancer: effect of other risk factors on the association. Maturitas, 2, 185-190

15. Marrett, L.D., Meigs, J.W. & Flannery, J.T. (1982) Trends in the incidence of cancer of the 

corpus uteri in Connecticut, 1964-1969, in relation to consumption of exogenous estrogens. Am. J. 

Epidemiol., 116, 57-67

16. Vakil, D.V., Morgan, R.W. & Halliday, M. (1983) Exogenous estrogens and development of 

breast and endometrial cancer. Cancer Detect. Prev., 6, 415-424

17. Hoover, R., Gray, L.A., Sr, Cole, P. & MacMahon, B. (1976) Menopausal estrogens and breast 

cancer. New Engl. J. Med., 295, 401-405

18. Ross, R.K., Paganini-Hill, A., Gerkins, V.R., Mack, T.M., Pfeffer, R., Arthur, M. & Henderson, B.E. 

(1980) A case-control study of menopausal estrogen therapy and breast cancer. J. Am. med. 

Assoc., 243, 1635-1639

19. Hoover, R., Glass, A., Finkle, W.D., Azevedo, D. & Milne, K. (1981) Conjugated estrogens and 

breast cancer risk in women. J. natl Cancer Inst., 67, 815-820
20. Hulka, B.S., Chambless, L.E., Deubner, D.C. & Wilkinson, W.E. (1982) Breast cancer and 

estrogen replacement therapy. Am. J. Obstet. Gynecol., 143, 638-644

21. Gambrell, R.D., Jr, Maier, R.C. & Sanders, B.I. (1983) Decreased incidence of breast cancer in 

postmenopausal estrogen-progestogen users. Obstet. Gynecol., 62, 435-443

22. Hiatt, R.A., Bawol, R., Friedman, G.D. & Hoover, R. (1984) Exogenous estrogen and breast 

cancer after bilateral oophorectomy. Cancer, 54, 139-144

23. McDonald, J.A., Weiss, N.S., Daling, J.R., Francis, A.M. & Polissar, L. (1986) Menopausal 

estrogen use and the risk of breast cancer. Breast Cancer Res. Treat., 7, 193-199

24. Brinton, L.A., Hoover, R. & Fraumeni, J.F., Jr (1986) Menopausal oestrogens and breast cancer 

risk: an expanded case-control study. Br. J. Cancer, 54, 825-832

25. Nomura, A.M.Y., Kolonel, L.N., Hirohata, T. & Lee, J. (1986) The association of replacement 

estrogens with breast cancer. Int. J. Cancer, 37, 49-53

26. Sartwell, P.E., Arthes, F.G. & Tonascia, J.A. (1977) Exogenous hormones, reproductive history, 

and breast cancer. J. natl Cancer Inst., 59, 1589-1592

27. Ravnihar, B., Seigel, D.G. & Lindtner, J. (1979) An epidemiologic study of breast cancer and 

benign breast neoplasias in relation to the oral contraceptive and estrogen use. Eur. J. Cancer, 15, 

395-405

28. Jick, H., Walker, A.M., Watkins, R.N., D'Ewart, D.C., Hunter, J.R., Danford, A., Madsen, S., 

Dinan, B.J. & Rothman, K.J. (1980) Replacement estrogens and breast cancer. Am. J. Epidemiol., 

112, 586-594

29. Kelsey, J.L., Fischer, D.B., Holford, T.R., LiVolsi, V.A., Mostow, E.D., Goldenberg, I.S. & White, 

C. (1981) Exogenous estrogens and other factors in the epidemiology of breast cancer. J. natl 

Cancer Inst., 67, 327-333

30. Sherman, B., Wallace, R. & Bean, J. (1983) Estrogen use and breast cancer. Interaction with 

body mass. Cancer, 51, 1527-1531

31. Kaufman, D.W., Miller, D.R., Rosenberg, L., Helmrich, S.P., Stolley, P., Schottenfeld, D. & 

Shapiro, S. (1984) Noncontraceptive estrogen use and the risk of breast cancer. J. Am. med. 

Assoc., 252, 63-67

32. Horwitz, R.I. & Stewart, K.R. (1984) Effect of clinical features on the association of estrogens 

and breast cancer. Am. J. Med., 76, 192-198

33. La Vecchia, C., Decarli, A., Parazzini, F., Gentile, A., Liberati, C. & Franceschi, S. (1986) Noncontraceptive oestrogens and the risk of breast cancer in women. Int. J. Cancer, 38, 853-858

34. Wingo, P.A., Layde, P.M., Lee, N.C., Rubin, G. & Ory, H.W. (1987) The risk of breast cancer in 

postmenopausal women who have used estrogen replacement therapy. J. Am. med. Assoc., 257, 

209-215

35. Thomas, D.B., Persing, J.P. & Hutchison, W.B. (1982) Exogenous estrogens and other risk 

factors for breast cancer in women with benign breast diseases. J. natl Cancer Inst., 69, 1017-1025 

Conjugated oestrogens
A. Evidence for carcinogenicity to animals (limited)

Conjugated oestrogens were tested inadequately in rats by oral administration in one study [ref: 1]. 

In male hamsters castrated as adults, equilin administered as a subcutaneously implanted pellet 

produced renal tumours in 6/8 treated animals. In contrast, d-equilenin administered similarly did 

not induce renal tumours [ref: 2,3]. 

B. Other relevant data

No data were available on the genetic and related effects of conjugated oestrogens in humans. 

A commercial preparation of conjugated oestrogens did not induce chromosomal aberrations in 

human lymphoblastoid cells in vitro or in Chinese hamster V79 cells exposed in diffusion chambers 

implanted into mice after oestrogen treatment. It was not mutagenic to bacteria [ref: 4].

References

1. IARC Monographs, 21, 147-159, 1979

2. Li, J.J., Li, S.A., Klicka, J.K., Parsons, J.A. & Lam, L.K.T. (1983) Relative carcinogenic activity of 

various synthetic and natural estrogens in the Syrian hamster kidney. Cancer Res., 43, 5200-5204

3. Li, J.J. & Li, S.A. (1984) Estrogen-induced tumorigenesis in hamsters: roles for hormonal and 

carcinogenic activities. Arch. Toxicol., 55, 110-118

4. IARC Monographs, Suppl. 6, 187, 1987 

Oestradiol-17β and esters

A. Evidence for carcinogenicity to animals (sufficient)

Oestradiol-17β and its esters were tested in mice, rats, hamsters and guinea-pigs by oral and 

subcutaneous administration. Administration to mice increased the incidences of mammary, 

pituitary, uterine, cervical, vaginal, testicular, lymphoid and bone tumours [ref: 1-5]. In rats, there 

was an increased incidence of mammary and/or pituitary tumours [ref: 1,6]. Oestradiol-17β

produced a nonstatistically significant increase in the incidence of foci of altered hepatocytes and 

hepatic nodules induced by partial hepatectomy and administration of N-nitrosodiethylamine in rats 

[ref: 7]. In hamsters, a high incidence of malignant kidney tumours occurred in intact and castrated 

males [ref: 1,8-10] and in ovariectomized females, but not in intact females [ref: 1]. In guineapigs, diffuse fibromyomatous uterine and abdominal lesions were observed [ref: 1].

B. Other relevant data

No data were available on the genetic and related effects of oestradiol-17β in humans.

Oestradiol-17β did not induce chromosomal aberrations in bone-marrow cells of mice treated in 

vivo. Unusual nucleotides were found in kidney DNA of treated hamsters. It induced micronuclei but 

not aneuploidy, chromosomal aberrations or sister chromatid exchanges in human cells in vitro. In 

rodent cells in vitro, it induced aneuploidy and unscheduled DNA synthesis but was not mutagenic 

and did not induce DNA strand breaks or sister chromatid exchanges. Oestradiol-17β was not 

mutagenic to bacteria [ref: 11].

References

1. IARC Monographs, 21, 279-326, 1979
2. Huseby, R.A. (1980) Demonstration of a direct carcinogenic effect of estradiol on Leydig cells of 

the mouse. Cancer Res., 40, 1006-1013

3. Highman, B., Roth, S.I. & Greenman, D.L. (1981) Osseous changes and osteosarcomas in mice 

continuously fed diets containing diethylstilbestrol or 17β-estradiol. J. natl Cancer Inst., 67, 653-662

4. Highman, B., Greenman, D.L., Norvell, M.J., Farmer, J. & Shellenberger, T.E. (1980) Neoplastic 

and preneoplastic lesions induced in female C3H mice by diets containing diethylstilbestrol or 17βestradiol. J. environ. Pathol. Toxicol., 4, 81-95

5. Nagasawa, H., Mori, T. & Nakajima, Y. (1980) Long-term effects of progesterone or 

diethylstilbestrol with or without estrogen after maturity on mammary tumorigenesis in mice. Eur. J. 

Cancer, 16, 1583-1589

6. Inoh, A., Kamiya, K., Fujii, Y. & Yokoro, K. (1985) Protective effects of progesterone and 

tamoxifen in estrogen-induced mammary carcinogenesis in ovariectomized W/FU rats. Jpn. J. 

Cancer Res. (Gann), 76, 699-704

7. Yager, J.D., Campbell, H.A., Longnecker, D.S., Roebuck, B.D. & Benoit, M.C. (1984) 

Enhancement of hepatocarcinogenesis in female rats by ethinyl estradiol and mestranol but not 

estradiol. Cancer Res., 44, 3862-3869

8. Li, J.J., Li, S.A., Klicka, J.K., Parsons, J.A. & Lam, L.K.T. (1983) Relative carcinogenic activity of 

various synthetic and natural estrogens in the Syrian hamster kidney. Cancer Res., 43, 5200-5204

9. Li, J.J. & Li, S.A. (1984) Estrogen-induced tumorigenesis in hamsters: roles for hormonal and 

carcinogenic activities. Arch. Toxicol., 55, 110-118

10. Liehr, J.G., Stancel, G.M., Chorich, L.P., Bousfield, G.R. & Ulubelen, A.A. (1986) Hormonal 

carcinogenesis: separation of estrogenicity from carcinogenicity. Chem.-biol. Interactions, 59, 173-

184

11. IARC Monographs, Suppl. 6, 437-439, 1987

Oestriol

A. Evidence for carcinogenicity to animals (limited)

Oestriol was tested by subcutaneous implantation in castrated mice and in rats and hamsters. It 

increased the incidence and accelerated the appearance of mammary tumours in both male and 

female mice and produced kidney tumours in hamsters [ref: 1].

B. Other relevant data

No data were available on the genetic and related effects of oestriol in humans. It did not induce 

aneuploidy in cultured lymphocytes from one pregnant woman; results for induction of sister 

chromatid exchange were inconclusive. No effect was seen in lymphocytes from one man [ref: 2].

References

1. IARC Monographs, 21, 327-341, 1979

2. IARC Monographs, Suppl. 6, 440-441, 1987
Oestrone

A. Evidence for carcinogenicity to animals (sufficient)

Oestrone was tested in mice by oral administration, in mice, rats and hamsters by subcutaneous 

injection and implantation, and in mice by skin painting. Its administration resulted in an increased 

incidence of mammary tumours in mice, in pituitary, adrenal and mammary tumours in rats, and in 

renal tumours in both castrated and intact male hamsters [ref: 1]. Oestrone implanted 

subcutaneously as a pellet produced renal tumours in 80% of treated male hamsters castrated as 

adults [ref: 2,3].

B. Other relevant data

No data were available on the genetic and related effects of oestrone in humans. It was not 

mutagenic to Chinese hamster cells in vitro [ref: 4].

References

1. IARC Monographs, 21, 343-362, 1979

2. Li, J.J., Li, S.A., Klicka, J.K., Parsons, J.A. & Lam, L.K.T. (1983) Relative carcinogenic activity of 

various synthetic and natural estrogens in the Syrian hamster kidney. Cancer Res., 43, 5200-5204

3. Li, J.J. & Li, S.A. (1984) Estrogen-induced tumorigenesis in hamsters: roles for hormonal and 

carcinogenic activities. Arch. Toxicol., 55, 110-118

4. IARC Monographs, Suppl. 6, 442-443, 1987

Ethinyloestradiol

A. Evidence for carcinogenicity to animals (sufficient)

Ethinyloestradiol was tested in mice, rats, dogs and monkeys by oral administration and in rats by 

subcutaneous injection. In mice, it increased the incidences of pituitary tumours and of malignant 

mammary tumours in both males and females and produced malignant tumours of the uterus and 

cervix in females [ref: 1]. In rats, it increased the incidence of liver-cell tumours [ref: 1,2], pituitary 

chromophobe adenomas [ref: 2] and mammary adenocarcinomas [ref: 2,3]. Ethinyloestradiol 

administered as a subcutaneous injection of pellets produced a low but increased incidence of renal 

tumours in hamsters castrated as adults [ref: 4,5]. In rats, it induced foci of altered hepatocytes, a 

presumed preneoplastic lesion; when administered following initiation of hepatocarcinogenesis with 

N-nitrosodiethylamine, ethinyloestradiol enhanced the development of foci of altered hepatocytes 

and of hepatic nodules [ref: 6]. In female rats given partial hepatectomy and treated with Nnitrosodiethylamine, ethinyloestradiol potentiated the development of foci of altered hepatocytes 

and of hepatocellular carcinomas [ref: 7]. In N-nitrosodiethylamine-initiated rats, ethinyloestradiol 

increased the number of γ-glutamyl transpeptidase-positive hepatic foci [ref: 8]. Dietary 

administration of ethinyloestradiol combined with subcutaneous injections of 3,2'-dimethyl-4-

aminobiphenyl caused a high incidence of prostatic carcinomas in male rats [ref: 9]. In rats, 

ethinyloestradiol significantly enhanced the development of tumours of the liver and kidneys 

induced by several agents [ref: 10].

B. Other relevant data

No data were available on the genetic and related effects of ethinyloestradiol alone in humans. See, 

however, the summary of data for combined oral contraceptives.

Ethinyloestradiol did not induce chromosomal aberrations in human lymphocytes, chromosomal 
aberrations or mutation in Chinese hamster cells or unscheduled DNA synthesis in rat hepatocytes in 

vitro. Studies on cell transformation were inconclusive. It was weakly active in an assay for 

inhibition of intercellular communication in Chinese hamster V79 cells. It did not induce sex-linked 

recessive lethal mutations in Drosophila or mutation in yeast and did not induce mutation or DNA 

damage in bacteria [ref: 11].

References

1. IARC Monographs, 21, 233-255, 1979

2. Schardein, J.L. (1980) Studies of the components of an oral contraceptive agent in albino rats. I. 

Estrogenic component. J. Toxicol. environ. Health, 6, 885-894

3. Holtzman, S., Stone, J.P. & Shellabarger, C.J. (1981) Synergism of estrogens and X-rays in 

mammary carcinogenesis in female ACI rats. J. natl Cancer Inst., 67, 455-459

4. Li, J.J., Li, S.A., Klicka, J.K., Parsons, J.A. & Lam, L.K.T. (1983) Relative carcinogenic activity of 

various synthetic and natural estrogens in the Syrian hamster kidney. Cancer Res., 43, 5200-5204

5. Li, J.J. & Li, S.A. (1984) Estrogen-induced tumorigenesis in hamsters: roles for hormonal and 

carcinogenic activities. Arch. Toxicol., 55, 110-118

6. Wanless, I.R. & Medline, A. (1982) Role of estrogens as promoters of hepatic neoplasia. Lab. 

Invest., 46, 313-320

7. Yager, J.D., Campbell, H.A., Longnecker, D.S., Roebuck, B.D. & Benoit, M.C. (1984) 

Enhancement of hepatocarcinogenesis in female rats by ethinyl estradiol and mestranol but not 

estradiol. Cancer Res., 44, 3862-3869

8. Yager, J.D., Roebuck, B.D., Paluszcyk, T.L. & Memoli, V.A. (1986) Effects of ethinyl estradiol and 

tamoxifen on liver DNA turnover and new synthesis and appearance of gamma glutamyl 

transpeptidase-positive foci in female rats. Carcinogenesis, 12, 2007-2014

9. Shirai, T., Fukushima, S., Ikawa, E., Tagawa, Y. & Ito, N. (1986) Induction of prostate carcinoma 

in situ at high incidence on F344 rats by a combination of 3,2'-dimethyl-4-aminobiphenyl and 

ethinyl estradiol. Cancer Res., 46, 6423-6426

10. Shirai, T., Tsuda, H., Ogiso, T., Hirose, M. & Ito, N. (1987) Organ specific modifying potential of 

ethinyl estradiol on carcinogenesis initiated with different carcinogens. Carcinogenesis, 8, 115-119

11. IARC Monographs, Suppl. 6, 293-295, 1987

Mestranol

A. Evidence for carcinogenicity to animals (sufficient)

Mestranol was tested in mice, rats, dogs and monkeys by oral administration. It increased the 

incidence of pituitary tumours and malignant mammary tumours in mice [ref: 1,2] and increased 

the incidence of malignant mammary tumours in female rats. Studies in monkeys were still in 

progress; although no tumour had been observed after seven years, no conclusive evaluation could 

be made [ref: 1]. Feeding of mestranol to rats following partial hepatectomy and treatment with Nnitrosodiethylamine enhanced the development of foci of altered hepatocytes and of hepatocellular 

carcinomas [ref: 3,4]. No significant increase in mammary tumour occurrence was seen in dogs 

treated with mestranol [ref: 5,6].

B. Other relevant data
No data were available on the genetic and related effects of mestranol alone in humans. See, 

however, the summary of data for combined oral contraceptives.

Mestranol did not induce DNA strand breaks in hepatocytes of rats or chromosomal aberrations in 

bone-marrow cells of mice treated in vivo. It did not induce chromosomal aberrations in human 

lymphocytes in vitro. It was weakly active in an assay for inhibition of intercellular communication in 

Chinese hamster V79 cells. It did not induce unscheduled DNA synthesis in cultured rat hepatocytes 

or sex-linked recessive lethal mutations in Drosophila. It was not mutagenic to bacteria [ref: 7].

References

1. IARC Monographs, 21, 257-278, 1979

2. El Etreby, M.F. & Neumann, F. (1980) Influence of sex steroids and steroid antagonists on 

hormone-dependent tumors in experimental animals. In: Iacobelli, S., King, R.J.B., Lindner, H.R. & 

Lippman, M.E., eds, Hormones and Cancer, New York, Raven Press, pp. 321-336

3. Yager, J.D., Jr & Yager, R. (1980) Oral contraceptive steroids as promoters of 

hepatocarcinogenesis in female Sprague-Dawley rats. Cancer Res., 40, 3680-3685

4. Yager, J.D., Campbell, H.A., Longnecker, D.S., Roebuck, B.D. & Benoit, M.C. (1984) 

Enhancement of hepatocarcinogenesis in female rats by ethinylestradiol and mestranol but not 

estradiol. Cancer Res., 44, 3862-3869

5. El Etreby, M.F. & Graf, K.-J. (1979) Effect of contraceptive steroids on mammary gland of beagle 

dog and its relevance to human carcinogenicity. Pharmacol. Ther., 5, 369-402

6. Kwapien, R.P., Giles, R.C., Geil, R.G. & Casey, H.W. (1980) Malignant mammary tumors in beagle 

dogs dosed with investigational oral contraceptive steroids. J. natl Cancer Inst., 65, 137-144

7. IARC Monographs, Suppl. 6, 369-371, 1987 

Overall evaluation

Steroidal oestrogens are carcinogenic to humans (Group 1).

N.B. - This evaluation applies to the group of chemicals as a whole and not necessarily to all 

individual chemicals within the group.

For definition of the italicized terms, see Preamble Evaluation.

Also previous evaluations: Vol. 6 (1974); Vol. 21 (1979)

Synonyms for Conjugated oestrogens

● Amnestrogen 

● Ces 

● Climestrone 

● Co-Estro 

● Conest 

● Conestron 

● Conjes 

● Equigyne 

● Estratab 
● Estrifol 

● Estroate 

● Estrocon 

● Estromed 

● Estropan 

● Evex 

● Femacoid 

● Femest 

● Fem H 

● Femogen 

● Formatrix 

● Ganeake 

● Genisis 

● Glyestrin 

● Kestrin 

● Menest 

● Menogen 

● Menotab 

● Menotrol 

● Milprem 

● MsMed 

● Neo-Estrone 

● Novoconestron 

● Oestrilin 

● Oestro-Feminal 

● Oestropak Morning 

● Ovest 

● Palopause 

● Par Estro 

● Piperazine oestrone sulphate 

● PMB 

● Premarin 

● Presomen 

● Promarit 

● SK-Estrogens 

● Sodestrin-H 

● Sodium equilin sulphate 

● Tag-39 

● Transannon 

● Trocosone 

● Zeste 

Synonyms for Sodium oestrone sulphate

● Conestoral 

● Estrone hydrogen sulfate sodium salt 

● Estrone sodium sulfate 

● Estrone sulfate sodium 

● Evex 

● Morestin 

● Oestrone hydrogen sulphate sodium salt 

● Oestrone sodium sulphate 

● Oestrone sulphate sodium 

● Sodium estrone 3-monosulfate 

● Sodium estrone sulfate 

● Sodium estrone-3-sulfate 

● Sodium oestrone 3-monosulphate 

● Sodium oestrone sulphate 

● Sodium oestrone-3-sulphate 

Synonyms for sodium equilin sulphate

● Equilin sodium sulfate 
● Equilin sodium sulphate 

● Estra-1,3,5(l0),7-tetraen-17-one hydrogen sulfate sodium salt 

● Oestra-1,3,5(10),7-tetraen-17-one hydrogen sulphate sodium salt 

● Sodium equilin 3-monosulfate 

● Sodium equilin 3-monosulphate 

● Sodium equilin sulfate 

Synonyms for Piperazine oestrone sulphate

● Estrone, hydrogen sulfate, compd. with piperazine (1:1) 

● Harmogen 

● Ogen 

● Oestrone, hydrogen sulphate, compd. with piperazine (1:1) 

● Piperazine estrone sulfate 

● Piperazine 17-oxo-oestra-1,3,5(10)-trien-3-yl sulphate 

● Sulestrex 

● Sulestrex Piperazine 

Synonyms for Oestradiol-17 β

● Altrad 

● Aquadiol 

● Aquagen 

● Bardiol 

● Corpagen 

● C-Progynova 

● Dihydrofollicular hormone 

● Dihydrofolliculin 

● Dihydromenformon 

● Dihydrotheelin 

● 3,17β-Dihydroxyestra-1,3,5-triene 

● 3,17β-Dihydroxyestra-1,3,5(10)-triene 

● dihydroxyestrin 

● 3,17β-Dihydroxyoestra-1,3,5-triene; 

● β-Dihydroxyoestra-1,3,5(10)-triene 

● Dihydroxyoestrin 

● Dimenformon 

● Diogyn 

● Diogynets 

● E(2) 

● 3,17-Epidihydroxyestratriene 

● Estrace 

● Estradiol 

● β-Estradiol 

● 17β-eEtradiol 

● Estradiol-17β

● 3,17β-Estradiol 

● d-3,17β-Estradiol 

● cis-Estradiol 

● Estra-1,3,5(10)-triene-3,17β-diol 

● Estraldine 

● Estrobe 

● Estrovite 

● Femestral 

● Femogen 

● Follicyclin 

● Ginosedol 

● Gynergon 

● Gynoestryl 

● Lamdiol 

● Lip-Oid 

● Macrodiol 

● Macrol 
● Microdiol 

● Nordicol 

● Oestergon 

● Oestradiol 

● β-Oestradiol 

● 17β-Oestradiol 

● 3,17β-Oestradiol 

● d-3,17β-Oestradiol 

● cis-oestradiol 

● Oestra-1,3,5(10)-triene-3,17 β-diol 

● Oestroglandol 

● Ormogamma 

● Ovahormon 

● Ovasterol 

● Ovastevol 

● Ovocyclin 

● Ovocylin 

● Perlatanol 

● Primofol 

● Profoliol 

● Progynon 

● Progynon-DH 

● Propagon-E 

● Syndiol 

● Test-Estrin 

Synonyms for Oestradiol 3-benzoate

● Benovocylin 

● Benzhormovarine 

● Benzoestrofol 

● Benzofoline 

● Benzo-Gynoestryl 

● De Graafina 

● Diffollisterol 

● Difolliculine 

● Dimenformon benzoate 

● Diogyn B 

● Eston-B 

● Estradiol benzoate 

● β-Estradiol benzoate 

● β-Estradiol 3-benzoate 

● 17β-Estradiol 3-benzoate 

● Estradiol monobenzoate 

● 1,3,5(10)-Estratriene-3,17β-diol 3-benzoate 

● Femestrone 

● Follicormon 

● Follidrin 

● Graafina 

● Gynecormone 

● Gynformone 

● Hidroestron 

● Hormogynon 

● Oestradiol benzoate 

● β-Oestradiol benzoate 

● β-Oestradiol 3-benzoate 

● 17β-Oestradiol 3-benzoate 

● Oestradiol monobenzoate 

● 1,3,5(10)-Oestratriene-3, 17β-diol 3-benzoate 

● Oestroform (BDH) 

● Ovahormon benzoate 

● Ovasterol-B 

● Ovex 

● Ovocyclin benzoate 
● Ovocyclin M 

● Ovocyclin-MB 

● Primogyn B 

● Primogyn Boleosum 

● Primogyn I 

● Progynon B 

● Progynon-B 

● Progynon benzoate 

● Recthormone Oestradiol 

● Solestro 

● Unistradiol 

Synonyms for Oestradiol diproprionate

● Agofollin 

● Dimenformon dipropionate 

● Diovocyclin 

● Diovocylin 

● Diprostron 

● Endofollicolina D.P. 

● Estradiol dipropionate 

● β-Estradioldipropionate 

● 17β-Estradiol dipropionate 

● 3,17β-Estradiol dipropionate 

● Estroici 

● Estronex 

● Follicyclin P 

● Nacyclyl 

● Oestradiol 3,17-dipropionate 

● β-Oestradiol dipropionate 

● 17β-Oestradiol dipropionate 

● 3,17β-Oestradiol dipropionate 

● Ovocyclin dipropionate 

● Ovocyclin P 

● Ovocyclin-P 

● Progynon-DP 

Synonyms for Oestradiol-17β-valerate

● Ardefem 

● Atladiol 

● Bimone-L.A. 

● Cyclo-Progynova 

● Deladiol 

● Deladumone 

● Delahormone unimatic 

● Delestrogen 

● Delestrogen 4X 

● Depogen 

● Diol-20 

● Dioval 

● Ditate 

● Ditate DS 

● Duoval-P.A. 

● Dura-Estradiol 

● Duragen 

● Duratrad 

● Estate 

● Estradiol-L.A. 

● Estradiol valerate 

● Estradiol 17-valerate 

● Estradiol 17β-valerate 

● Estradiol valerianate 
● Estra-L 

● Estratab 

● Estraval 

● Estraval-P.A. 

● Estroval-10 

● Eval 

● Femogen 

● Femogen-L.A. 

● Femogex 

● Lastrogen 

● Mal-O-Fem LA 

● Neofollin 

● Oestradiol retard Pharlon 

● Oestradiol valerate 

● Oestradiol 17-valerate 

● Oestradiol 17β-valerate 

● Oestradiol valerianate 

● Oestragynol sine 

● Pharlon 

● Primogyn-Depot 

● Progynon-Depot 

● Progynova 

● Rep-Estra 

● Repestrogen 

● Rep-Estro Med 

● Retestrin 

● Span-Est 

● Teev 

● Testadiate 

● Valergen 

● Valertest No. 1 

● Valertest No. 2 

● 17β-Valeryl-oxyoestra-1,3,5(10)-trien-3-ol 

Synonyms for Polyoestradiol phosphate

● Estradiol phosphate polymer 

● Estradiol polyester with phosphoric acid 

● Oestradiol phosphate polymer 

● Oestradiol polyester with phosphoric acid 

● PEP 

● Poly(estradiolphosphate) 

● Poly(oestradiol phosphate) 

Synonyms for Oestriol

● Aacifemine 

● Destriol 

● Deuslon-A 

● 1,3,5-Estratriene-3β,16,17β-triol 

● Estra-1,3,5(10)-triene-3,16α,17β-triol 

● Estra-1,3,5(10)-triene-3,16α,17β-triol 

● Estratriol 

● Estriol 

● 16α,17β-Estriol 

● 3,16α,17β-Estriol 

● Follicular hormone hydrate 

● Hemostyptanon 

● Holin 

● Hormomed 

● Hormonin 

● 16α-Hydroxy-estradiol 

● 16α-Hydroxyoestradiol 
● Klimoral 

● NSC-12169 

● OE3 

● 1,3,5-Oestratriene-3β,16,17β-triol 

● Oestra-1,3,5(10)-triene-3,16α,17β-triol 

● Oestra-1,3,5(10)-triene-3,16α,17 β-triol 

● Oestratriol 

● 16α,17 β-Oestriol 

● 3,16α,17β-Oestriol 

● Orgastyptin 

● Ovesterin 

● Ovestin 

● Ovestrion 

● Stiptanon 

● Synapause 

● Theelol 

● Tridestrin 

● 3,16α,17β-Trihydroxyestra-1,3,5(10)-triene 

● 3,16α,-17β-Trihydroxyoestra-1,3,5(10)-triene 

● 3,16α,17β-Trihydroxy-1,3,5-estratriene 

● Trihydroxyestrin 

● 3,16α,17β-Trihydroxy-1,3,5-oestratriene 

● Trihydroxyoestrin 

● Triodurin 

● Triovex 

Synonyms for Oestrone

● Andrestraq 

● Aquacrine 

● A.T.V. 

● Bestrone 

● Centrogen-20 

● Cormone 

● Crinovaryl 

● Cristallovar 

● Crystogen 

● Destrone 

● Di-Est Modified 

● Di-Met 

● Disynformon 

● Duogen 

● E(1) 

● Endofolliculina 

● Esterone 

● 1,3,5-Estratrien-3-ol-17-one 

● Estrol 

● Estrolin 

● Estromone 

● Estron 

● Estrone 

● Estronol 

● Estrovag 

● Estrovarin 

● Estrugenone 

● Estrusol 

● Evagen 

● Femestrone injection 

● Femidyn 

● Femogen 

● Femspan 

● Folikrin 

● Folipex 

● Folisan 
● Follestrine 

● Follestrol 

● Follicormone 

● Follicular hormone 

● Folliculin 

● Follicunodis 

● Follidrin 

● Follikulin 

● Foygen 

● Glandubolin 

● Glyestrin 

● Gravigen 

● Hiestrone 

● Hormofollin 

● Hormovarine 

● Kestrin 

● Kestrone 

● Ketodestrin 

● Ketohydroxyestrin 

● Ketohydroxyoestrin 

● Kolpon 

● Mal-O-Fem 

● Menagen 

● Menformon 

● Mer-Estrone 

● Neo-Genic DA 

● 1,3,5-Oestratrien-3-ol-17-one 

● Oestrilin 

● Oestrin 

● Oestroform 

● Oestroglandol 

● Oestroperos 

● Ovex 

● Ovifollin 

● Perlatan 

● Solestrin 

● Solliculin 

● Spanestrin 

● Testagen 

● Theelin 

● Thelestrin 

● Thelykinin 

● Tokokin 

● Thynestron 

● Tri-Es 

● Tri-Estrin 

● Unden 

● Urestrin 

● Wehgen 

● Wynestron 

Synonyms for Ethinyloestradiol

● Amenoron 

● Brevicon 

● Brevicon 28-Day 

● Cavomen-F 

● Chee-O-Gen 

● Chee-O-Genf 

● Climatone 

● Declimone 

● Demulen 

● Demulen 28 

● Diogyn-E 
● Dylofor 

● Edrol 

● EE 

● EE2 

● EED 

● Esteed 

● Estigyn 

● Estinyl 

● Eston-E 

● Estoral 

● Estorals 

● Ethidol 

● Ethinoral 

● Ethinylestradiol 

● 17-Ethinylestradiol 

● 17α-Ethinylestradiol 

● 17α-Ethinyl-17β-estradiol 

● 17-Ethinyl-3,17-estradiol 

● Ethinylestriol 

● 17-Ethinyloestradiol 

● 17α-Ethinyloestradiol 

● 17α-Ethinyl-17 β-oestradiol 

● 17-Ethinyl-3,17-oestradiol 

● Ethinyloestriol 

● Ethy 

● Ethy 11 

● Ethynylestradiol 

● 17-Ethynylestradiol 

● 17α-Ethynylestradiol 

● 17α-Ethynyl-1,3,5(10)-estratriene-3,17β-diol 

● Ethynyloestradiol 

● 17-Ethynyloestradiol 

● 17α-Ethynyloestradiol 

● 17α-Ethynyl-1,3,5(10)-oestratriene-3,17β-diol 

● Eticyclin 

● Eticyclol 

● Etifollin 

● Etinestrol 

● Etinestryl 

● Etinoestryl 

● Etistradiol 

● Etivex 

● Feminone 

● Follicoral 

● Follikoral 

● Ginestrene 

● Gynetone 

● Gynolett 

● Gynostat 

● Halodrin 

● Inestra 

● Kolpolyn 

● Linoral 

● Loestrin 

● Loestrin 21 

● Lo/Ovral 

● Lo/Ovral-28 

● Lynoral 

● Menolet Sublets 

● Menolyn 

● Menopax 

● Menopax Forte 

● Mepilin 

● Metroval 

● Mixogen 
● Modicon 

● Modicon 28 

● Neo-Estrone 

● Nogest-S 

● 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol 

● Norlestrin 21 

● Norlestrin 28 

● Norlestrin Fe 

● Normaoestren 

● Norma-ostren 

● Novestrol 

● Oestradin 

● Oradiol 

● Orestralyn 

● Os-cal Mone 

● Ovcon 35 

● Ovcon 50 

● Ovral 

● Ovral 28 

● Palonyl 

● Perovex 

● Primogyn 

● Primogyn C 

● Primogyn M 

● Progynon C 

● Progynon M 

● Roldiol 

● Spanestrin 

● Test-Estrin 

● Trimone Sublets 

● Ylestrol 

● Zorane 

Synonyms for Mestranol

● Conovid 

● C-Quens 

● Demulen 

● Devocin 

● EE3ME 

● Emetin 

● Enavid 

● Enavid E 

● Enovid 

● Enovid-E 

● Enovid-E21 

● Ethinylestradiol 3-methyl ether 

● 17α-Ethinylestradiol 3-methyl ether 

● Ethinyloestradiol 3-methyl ether 

● 17α-Ethinyloestradiol 3-methyl ether 

● Ethynylestradiol methyl ether 

● Ethynylestradiol 3-methyl ether 

● 17-Ethynylestradiol 3-methyl ether 

● 17α-Ethynylestradiol methyl ether 

● 17α-Ethynylestradiol 3-methyl ether 

● 17α-Ethynyl-3-methoxy-1,3,5(10)-estratrien-17β-ol 

● Ethynyloestradiol methyl ether 

● Ethynyloestradiol 3-methyl ether 

● 17-Ethynyloestradiol 3-methyl ether 

● 17α-Ethynyloestradiol methyl ether 

● 17α-Ethynyloestradiol 3-methyl ether 

● 17α,-Ethynyl-3-methoxy-1,3,5(10)-oestratrien-17β-ol 

● Inostral 

● Lyndiol 2.5 
● Menophase 

● 3-Methoxy-17α-ethinylestradiol 

● 3-Methoxy-17α-ethinyloestradiol 

● 3-Methoxyethynylestradiol 

● 3-Methoxy-17α-ethynylestradiol 

● 3-Methoxyethynyloestradiol 

● 3-Methoxy-17α-ethynyloestradiol 

● 3-Methoxy-19-nor-17α,-pregna-1,3,5(10)-trien-20-yn-17-ol 

● 3-Methylethynylestradiol 

● 3-Methylethynyloestradiol 

● -MVE 

● Metrulen 

● Norinyl 

● Norinyl 1 

● Norinyl 2 

● Norquen 

● Ortho-Novin 2 

● Ortho-Novum 

● Ovanon 

● Ovastol 

● Ovulen 

● Ovulen-21 

● Ovulen-28 

● Previson 

● SC 4725 

● Sequens 

● Sophia 

● Syntex menophase 

Last updated: 9 February 1998 
ORAL CONTRACEPTIVES, COMBINED

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 296) 

A. Evidence for carcinogenicity to humans (sufficient)

There is sufficient evidence that combined oral contraceptives cause benign and malignant liver 

tumours. There is also conclusive evidence that these agents protect against cancers of the ovary 

and endometrium. 

Liver cancer

Numerous case reports and series of hepatic-cell adenomas occurring almost exclusively in women 

who had used combined oral contraceptives strongly suggest that such benign tumours may result 

from exposure to these products [ref: 1]. Two case-control studies [ref: 1] have shown that risk of 

hepatic-cell adenomas increases strongly with duration of use and have provided estimates of the 

relative risk in users for more than seven and nine years duration of 500 [ref: 2] and 25 [ref:3], 

respectively. The many reports of focal nodular hyperplasia occurring in users of oral contraceptives 

could also represent a causal relationship, but these lesions also occur in men and older women, and 

no case-control study on these populations has been conducted. 

Reports of hepatocellular carcinomas occurring in conjunction with liver-cell adenomas in users of 

oral contraceptives have been published [ref: 1]. In addition, three case-control studies of 

hepatocellular carcinomas, one in the USA [ref: 4] and two in the UK [ref: 5,6], have shown strong 

trends of increasing risk with duration of use. Relative risks (95% confidence limits) in the three 

studies in users of more than five, eight and eight years' duration, respectively, were estimated to 

be [13.5 (1.2-152.2)] [ref: 4], 7.2 (2.0-25.7) [ref: 5] and 20.1 (2.3-175.7) [ref: 4], respectively. 

When data for all three studies are combined, relative risks of 2.5 (1.1-5.5) and 10.0 (3.7-27.2) in 

'ever' users and users for more than five to eight years (depending on the study) were derived by 

the Working Group. Although all three case-control studies of liver cancers and oral contraceptives 

are small and have methodological deficiencies that could have resulted in biased results, the 

magnitude of the relative risks and the consistency of the results provide strong evidence that the 

results are not spurious. Case reports of cholangiocarcinoma in users of oral contraceptives have 

also been published, but one case-control study of 11 cases [ref: 6] showed no association with use 

of oral contraceptives [(relative risk, 0.3 in women who ever used oral contraceptives; 0.9 in users 

of four or more years)]. 

Ovarian cancer

Ten case-control studies have provided the following estimates of the relative risk (95% confidence 

limits) for ovarian cancer in women who had ever used combined oral contraceptives: 0.6 [0.3-1.1] 

[ref: 7], [0.7 (0.4-1.1)] [ref: 8], 0.8 (0.4-1.5) [ref: 9], 0.5 (0.2-1.5) [ref: 10], 0.6 [0.4-1.0] [ref: 

11], 0.7 (0.4-1.1) [ref: 12], 0.4 (0.2-1.0) [ref: 13], 0.6 (0.4-0.9) [ref: 14], 0.6 (0.4-0.9) [ref: 15] 

and 0.6 (0.4-1.0) [ref: 16]. Six of these studies assessed risk in relation to duration of use and five 

provide at least some evidence that the risk declines with years of exposure, although this trend is 

less striking than that for endometrial cancer (see below). Relative risks in women who had used 

combined oral contraceptives for up to or more than five, five, seven and nine years were found in 

four different studies to be 0.3 (0.1-0.8) [ref: 14], 0.4 (0.2-0.6) [ref: 15], 0.6 [0.3-1.4] [ref: 8] and 

0.4 (0.2-1.3) [ref: 11]. 

Endometrial cancer

Five case-control studies have provided the following estimates of the relative risk (95% confidence 

limits) for endometrial cancer in women who had ever used combined oral contraceptives: 0.5 (0.1-

1.0) [ref: 17], 0.4 (0.2-0.8) [ref: 18], 0.4 [0.2-1.2] [ref: 19], 0.5 (0.3-0.8) [ref: 20] and 0.6 (0.2-
1.3) [ref: 16]. Three of these [ref: 18-20], and two others [ref: 21,22], assessed risk in relation to 

duration of use, and all showed a decline in risk with duration of exposure. Relative risks in users of 

five or more years' duration were estimated in two studies to be 0.3 (0.1-1.3) [ref: 19] and 0.6 (0.4-

0.9) [ref: 20], and one study showed a relative risk of 0.1 [ref: 22] in women with six or more years 

of use. 

Cervical cancer

Four case-control studies [ref: 23-26] of cervical squamous dysplasia provide estimates of relative 

risk in women who had ever used combined oral contraceptives ranging from 1.2 to 3, and the lower 

limit of the 95% confidence limits of two of the estimates was greater than one. Relative risks (95% 

confidence limits) from two cohort studies were [5.0 (1.2-20.8)] [ref: 1], 1.5 [(0.8-2.6)] [ref: 27] 

and 1.1 [(0.8-1.7)] [ref: 28]. Relative risks for squamous dysplasia were found to increase with 

duration of use in two [ref: 24,26] of three case-control studies in which risk in relation to length of 

exposure was considered, and those for women who had used oral contraceptives for more than four 

years were found in two cohort studies to be [4.9 (1.1-21.8) [ref: 1]] and 2.0 [(1.1-3.6)] [ref: 27]. 

Four case-control studies of cervical carcinoma in situ [ref: 1,23-25] provide estimates of relative 

risks in women who had ever used combined oral contraceptives ranging from 0.6 to 1.1 [ref: 25], 

with 95% confidence limits that include 1.0; but one additional such study yielded an estimated 

relative risk of [1.6 (1.2-2.0)] [ref: 1], and estimates from three cohort studies were [3.7 (1.5-9.0)] 

[ref: 1], 1.6 [(0.8-3.0)] [ref: 27] and 1.2 (0.8-1.7) [ref: 28]. One case-control study showed a 

strong increase in risk for carcinoma in situ with duration of use [ref: 24], but two others did not 

[ref: 1,25]. Relative risks in users of more than four years' duration were estimated in two cohort 

studies to be [5.4 (2.1-13.7)] [ref: 1] and 1.7 [(0.9-3.2)] [ref: 27]. Another cohort study [ref: 1] 

showed the risk of progression from dysplasia to carcinoma in situ to be six times greater in users 

than in nonusers of oral contraceptives. 

Three case-control studies of invasive cervical cancer yielded relative risks in women who had ever 

used combined oral contraceptives of 1.2 (1.0-1.4) [ref: 29], 1.5 (1.1-2.1) [ref: 30] and 1.7 (0.8-

3.6) [ref: 16]; and three cohort studies gave incidence rates of invasive cervical cancer per 1000 

women years in users and nonusers of oral contraceptives of 0.20 and 0 [ref: 27], 0.15 and 0.07 

[ref: 31] and 0.12 and 0 [ref: 28]. All three case-control studies also showed that risk increased with 

duration of use; and the two in which relative risks were assessed in women who had used oral 

contraceptives for more than five years gave values of 1.5 (1.1-2.1) [ref: 29] and [1.9 (1.3-2.7)] 

[ref: 30]. 

There is evidence that one or more sexually transmitted, infective agents play an important role in 

the development of cervical cancer. Since this agent(s) has not been unequivocally identified, and, in 

particular, was not considered in the studies under review, surrogate measures were used to reflect 

degree of sexual activity and to adjust for this. Any observed effect of oral contraceptives on risk of 

cervical cancer may therefore be confounded by an association of oral contraceptive use with 

exposure to the putative infective agent. Since the specific factor by which the analysis should be 

adjusted is not known, the Working Group considered that adjusting for age at first intercourse and 

number of sexual partners may not be sufficient to remove the confounding and, therefore, that they 

could not regard a causal association of oral contraceptives and cervical cancer as proven. 

Breast cancer

Relative risks for breast cancer in women who had ever used combined oral contraceptives have 

been assessed in 18 case-control studies [ref: 1,16,32-43] and in seven cohort studies [ref: 1,44-

47]. All provide point estimates of relative risk close to unity, with 95% confidence intervals that 

include 1.0. Six case-control studies have provided estimates of the relative risk in women who had 

used combined oral contraceptives for more than a decade: four [ref: 36,39,40,43] yield relative 

risks between 0.7 and 1.1 with 95% confidence limits that included 1.0 in users of ten or more 

years' duration; another [ref: 48] provides a relative risk estimate of 2.2 (1.2-4.0) in users of 12 or 

more years' duration; and one [ref: 42] gives a relative risk of 0.6 (0.4-0.9) in women who had used 

oral contraceptives for 15 or more years. Eight case-control studies [ref: 16,36-38,40,42,43,48] and 

two cohort studies [ref: 44,45] give estimated relative risks for breast cancer ten or more to 20 or 

more years after initial exposure to combined oral contraceptives, and all are close to 1.0, with 95% 

confidence intervals that include unity. Eleven case-control studies have assessed risk for breast 
cancer among women who had used combined oral contraceptives before their first full-term 

pregnancy. The results are inconsistent, six studies [ref: 39,40,43,47,49,50] showing no significant 

elevation in risk, three [ref: 34,37,51] showing a significant trend of increasing risk with duration of 

use, and two [ref: 48,52] showing an increased risk without a significant trend. The reasons for 

these discrepant findings have not been identified. Five case-control studies have assessed risk in 

women who had used combined oral contraceptives before 25 years of age. The initial study of this 

issue showed a strong trend of increasing risk with years of use before age 25 [ref: 53]. A 

subsequent study from Sweden [ref: 54] showed a relative risk of 3.3 in women who had ever used 

oral contraceptives at age 20-24, but ascertainment of prior use was not comparable for cases and 

controls, rendering this finding suspect. Another study from Norway and Sweden [ref: 48] gave a 

relative risk of 2.7 in women who had used oral contraceptives for eight or more years before the 

age of 25, but the confidence limits for this included 1.0 (0.7-11.0), and no consistent trend of 

increasing risk with duration of use was observed. The fourth study, from New Zealand [ref: 43], 

showed a nonsignificant (p = 0.4) trend of declining risk with duration of use before age 25 and 

estimated the relative risk in users of six or more years to be 0.6. The fifth study [ref: 50] gave 

relative risks of 1.0 to 1.3 in six categories of duration of use (< 12, 13-48 and > 48 months in 

women less than 20 and in women 20-24 years of age) but no trend of increasing risk with duration 

of use. Risk was also initially reported to be particularly enhanced by use before age 25 [ref: 53] of 

oral contraceptives with a high progestogen potency, but the authors' classification has been 

disputed; and results from a large collaborative study in the USA do not confirm their findings [ref: 

50]. 

Other tumours

The relative risk for malignant melanoma in women who had ever taken oral contraceptives has 

been estimated in eight case-control [ref: 1,55-61] and in three cohort [ref: 55,62,63] studies. 

Values from all the case-control studies were close to unity, with 95% confidence limits that included 

1.0. Values from the three cohort studies were 0.3 [0.1-0.8] [ref: 55], 1.5 (0.7-2.9) [ref: 62] and 

3.5 (1.4-9.0) [ref: 63]. The reasons for these widely discrepant results are unknown. Trends of 

increasing risk with duration of use have been observed in some investigations but not in others. The 

two case-control studies in which analyses were performed to estimate the relative risk in users of 

more than two [ref: 56] and five [ref: 59] years' duration, ten or more years after initial exposure, 

showed elevated risks of 2.3 (0.8-6.9) and 1.5 (1.0-2.1), respectively. Two case-control studies 

showed trends of increasing risk specifically for superficial spreading melanoma with increasing 

duration of use [ref: 57,60], although a third did not [ref: 63]. Also, two studies have shown relative 

risks for superficial spreading-type melanoma to be increased in users of five or more years' duration 

after latent periods of over ten [ref: 59] and 12 [ref: 57] years: [1.6 (1.0-2.6)] and 4.4 (2.0-9.7), 

respectively. 

Two case-control studies and two prospective studies have shown no increase in risk for pituitary 

adenomas [ref: 1,64,65]. 

Women who took oral contraceptives after evacuation of a hydatidiform mole were reported in one 

study [ref: 1] subsequently to have developed trophoblastic tumours more frequently than women 

who had used other methods of contraception after a molar evacuation, but this was not confirmed 

in another investigation [ref: 66]. 

A single case-control study showed a reduction in risk for carcinomas of the colon and rectum with 

duration of use of combined oral contraceptives [ref: 67], but two cohort studies showed no 

alteration in risk for these neoplasms in users [ref: 63,68]. 

A protective effect of combined oral contraceptives against both fibroadenoma and fibrocystic 

disease of the breast has been found in many investigations [ref: 1,63,69-72], although a single 

recent study found an increase in risk for the latter condition in postmenopausal women [ref: 73]. 

One study showed no protective effect of oral contraceptives against fibrocystic disease with atypical 

histological features [ref: 1], but one subsequent investigation did [ref: 70]. 

A reduction in risk for retention cysts of the ovary has been documented in two cohort studies and in 

one case-control study [ref: 1]. A reduction in risk for uterine leiomyoma has been documented in 

one case-control study [ref: 74].
B. Evidence for carcinogenicity to animals (sufficient for norethynodrel in combination with 

mestranol; limited for chlormadinone acetate in combination with mestranol or ethinyloestradiol, for 

ethynodiol acetate in combination with mestranol or ethinyloestradiol, for megestrol acetate in 

combination with ethinyloestradiol, for norethisterone in combination with mestranol or 

ethinyloestradiol, for progesterone in combination with oestradiol-17β, and for investigational 

contraceptives; inadequate for lynoestrenol in combination with mestranol and for norgestrel in 

combination with ethinyloestradiol) 

Chlormadinone acetate and oestrogens

Chlormadinone acetate, in combination with mestranol, was tested for carcinogenicity by oral 

administration to mice; an increased incidence of pituitary tumours was observed in animals of each 

sex. Oral administration of chlormadinone acetate in combination with ethinyloestradiol to mice 

resulted in an increased incidence of mammary tumours in intact and castrated males [ref: 75]. 

Ethynodiol diacetate and oestrogens

Following oral administration of ethynodiol diacetate plus mestranol to mice, increased incidences of 

pituitary tumours were observed in animals of each sex. Ethynodiol diacetate plus ethinyloestradiol 

was tested for carcinogenicity by oral administration to mice and rats. In mice, it induced increased 

incidences of pituitary tumours in animals of each sex and of malignant tumours of connective 

tissues of the uterus. In rats, malignant mammary tumours were produced in animals of each sex 

[ref: 76]. 

Lynoestrenol and oestrogens

Lynoestrenol, in combination with mestranol, was tested in mice and female rats by oral 

administration. A slight, nonsignificant increase in the incidence of malignant mammary tumours was 

observed in female mice [ref: 77]. 

Megestrol acetate and oestrogens

Megestrol acetate plus ethinyloestradiol was tested for carcinogenicity by oral administration to mice 

and rats. In mice, increased incidences of malignant mammary tumours were observed in animals of 

each sex. No increase in tumour incidence was observed in rats [ref: 78]. 

Norethisterone and oestrogens

Norethisterone acetate plus ethinyloestradiol was tested for carcinogenicity by oral administration to 

mice, rats and monkeys. In mice, pituitary tumours were observed in animals of each sex. In rats, 

increased incidences of benign mammary tumours were found in males in one study and of benign 

liver-cell and mammary tumours in animals of each sex in the other [ref: 79]. Norethisterone 

acetate plus ethinyloestradiol administered orally to rats induced endometrial carcinomas [ref: 80]. 

Oral administration of norethisterone acetate plus ethinyloestradiol to female rats for 12 months 

resulted in hyperplastic nodules of the liver in all animals and a hepatocellular carcinoma in one 

(preliminary results) [ref: 81]. Norethisterone acetate and ethinyloestradiol given orally to monkeys 

for ten years did not produce malignant tumours [ref: 82]. 

Norethisterone plus mestranol was tested for carcinogenicity in mice and rats by oral administration. 

In mice, pituitaty tumours developed in animals of each sex. In rats, an increased incidence of 

malignant mammary tumours was found in females. Norethisterone plus ethinyloestradiol, tested in 

mice by oral administration, induced an increased incidence of pituitary tumours in females [ref: 79]. 

Norethynodrel and oestrogens

Norethynodrel in combination with mestranol was tested for carcinogenicity in mice, rats, hamsters 

and monkeys orally and by subcutaneous implantation. Increased incidences of pituitary, mammary, 

vaginal and cervical tumours were found in female mice and of pituitary tumours in male mice. In 
castrated male mice, the combined treatment resulted in an increase in the incidence of mammary 

tumours. In rats, benign liver-cell tumours were observed in males and pituitary tumours and 

malignant mammary tumours in animals of each sex. A study of hamsters was of too short a 

duration to be considered for evaluation. The combined treatment given to Macaca mulatta monkeys 

for five years did not increase the incidence of mammary tumours [ref: 83]. 

Norgestrel and oestrogens

Norgestrel plus ethinyloestradiol was tested for carcinogenicity in mice and rats by oral 

administration. No increase in the incidence of tumours was observed in either species [ref: 84]. 

Progesterone and oestrogen

Neonatal exposure of mice to progesterone plus oestradiol-17β resulted in an increased incidence of 

mammary tumours [ref: 85]. 

Investigational oral contraceptives

Three investigational oral contraceptives (ethynerone, chloroethynyl norgestrel or anagestone 

acetate plus mestranol) were tested for carcinogenicity by oral administration to dogs. An increased 

incidence of malignant mammary tumours was observed after treatment with chloroethynyl 

norgestrel plus mestranol or with anagestone acetate plus mestranol; no difference in the total 

number of mammary-gland nodules was observed with these two contraceptives. One dog given 

ethynerone plus mestranol had 14 malignant mammary fibrosarcomas [ref: 86]. 

C. Other relevant data 

The results reported in the available studies related to a variety of different oral contraceptives. 

Several studies showed no increase in the incidence of structural chromosomal changes in 

lymphocytes taken from women after oral contraceptive use (norethisterone with mestranol or 

ethynodiol diacetate with mestranol). In contrast to an earlier report, no increase in the incidence of 

sister chromatid exchanges was observed in 52 women taking oral contraceptives as compared with 

63 controls when results were adjusted for smoking [ref: 87]. 

No significant difference in the frequency of abnormal karyotypes or in sex ratio was seen in a study 

of spontaneous abortuses of women who had taken oral contraceptives; the contraceptives used 

were norgestrel, norethisterone acetate or medroxyprogesterone acetate in combination with 

ethinyloestradiol; or ethynodiol acetate, megestrol acetate or lynoestrenol in combination with 

mestranol. Similarly, a large cohort study showed no increase in risk for chromosomal anomalies in 

live births and abortuses of oral contraceptive users [ref: 87]. 

High doses of one oral contraceptive (lynoestrenol and mestranol) administered to two strains of 

female mice induced dominant lethal mutations, whereas high doses of another (norethisterone and 

ethinyl oestradiol) did not. In a later report using even higher doses of the oral contraceptive that 

induced dominant lethal mutations and of another (norethisterone acetate and ethinyloestradiol), the 

same authors reported no increase in the incidence of dominant lethal, recessive lethal or visible 

mutations in mice. Combinations of progestins (norethynodrel and ethynodiol diacetate) and 

oestrogens (mestranol and ethinyloestradiol) did not induce sex-linked recessive lethal mutations in 

Drosophila [ref: 87]. 

Overall evaluation

Combined oral contraceptives are carcinogenic to humans (Group 1).

N.B. - There is also conclusive evidence that these agents have a protective effect against cancers of 

the ovary and endometrium.
For definition of the italicized terms, see Preamble Evaluation.

Also previous evaluations: Vol. 6 (1974); Vol. 21 (1979)

Subsequent evaluation: Vol. 72 (1999)

References

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27. Vessey, M.P., McPherson, K., Lawless, M. & Yeates, D. (1983) Neoplasia of the cervix uteri and 

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31. Kay, C.R. (1983) Oral contraceptives and cancer. Lancet, ii, 1018 
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609-614 

33. Ravnihar, B., Seigel, D.G. & Lindtner, J. (1979) An epidemiologic study of breast cancer and 

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34. Pike, M.C., Henderson, B.E., Casagrande, J.T., Rosario, I. & Gray, G.E. (1981) Oral contraceptive 

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Inst., 67, 327-333 

36. Brinton, L.A., Hoover, R., Szklo, M. & Fraumeni, J.F., Jr (1982) Oral contraceptives and breast 

cancer. Int. J. Epidemiol., 11, 316-322 

37. Harris, N.V., Weiss, N.S., Francis, A.M. & Polissar, L. (1982) Breast cancer in relation to patterns 

of oral contraceptive use. Am. J. Epidemiol., 116, 643-651 

38. Vessey, M., Baron, J., Doll, R., McPherson, K. & Yeates, D. (1983) Oral contraceptives and breast 

cancer: final report of an epidemiological study. Br. J. Cancer, 47, 455-462 

39. Hennekens, C.H., Speizer, F.E., Lipnick, R.J., Rosner, B., Bain, C., Belanger, C., Stampfer, M., 

Willett, W. & Peto, R. (1984) A case-control study of oral contraceptive use and breast cancer. J. natl 

Cancer Inst., 72, 39-42 

40. Rosenberg, L., Miller, D.R., Kaufman, D.W., Helmrich, S.P., Stolley, P.D., Schottenfeld, D. & 

Shapiro, S. (1984) Breast cancer and oral contraceptive use. Am. J. Epidemiol., 119, 167-176 

41. Talamini, R., La Vecchia, C., Franceschi, S., Colombo, F., Decarli, A., Grattoni, E., Grigoletto, E. 

& Tognoni, G. (1985) Reproductive and hormonal factors and breast cancer in a northern Italian 

population. Int. J. Epidemiol., 14, 70-74 

42. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National 

Institute of Child Health and Human Development (1986) Oral-contraceptive use and the risk of 

breast cancer. New Engl. J. Med., 315, 405-411 

43. Paul, C., Skegg, D.C.G., Spears, G.F.S. & Kaldor, J.M. (1986) Oral contraceptives and breast 

cancer: a national study. Br. med. J., 293, 723-726 

44. Vessey, M.P., McPherson, K. & Doll, R. (1981) Breast cancer and oral contraceptives: findings in 

Oxford-Family Planning Association contraceptive study. Br. med. J., 282, 2093-2094 

45. Trapido, E.J. (1981) A prospective cohort study of oral contraceptives and breast cancer. J. natl 

Cancer Inst., 67, 1011-1015 

46. Royal College of General Practitioners (1981) Breast cancer and oral contraceptives: findings in 

Royal College of General Practitioners' study. Br. med. J., 282, 2089-2093 

47. Lipnick, R.J., Buring, J.E., Hennekens, C.H., Rosner, B., Willett, W., Bain, C., Stampfer, M.J., 

Colditz, G.A., Peto, R. & Speizer, F.E. (1986) Oral contraceptives and breast cancer. A prospective 

cohort study. J. Am. med. Assoc., 255, 58-61 
48. Meirik, O., Adami, H.-O., Christoffersen, T., Lund, E., Bergström, R. & Bergsjö, P. (1986) Oral 

contraceptive use and breast cancer in young women. A joint national case-control study in Sweden 

and Norway. Lancet, ii, 650-654 

49. Vessey, M.P., McPherson, K., Yeates, D. & Doll, R. (1982) Oral contraceptive use and abortion 

before first term pregnancy in relation to breast cancer risk. Br. J. Cancer, 45, 327-331 

50. Stadel, B.V., Webster, L.A., Rubin, G.L., Schlesselman, J.J. & Wingo, P.A. (1985) Oral 

contraceptives and breast cancer in young women. Lancet, ii, 970-973 

51. McPherson, K., Neil, A., Vessey, M.P. & Doll, R. (1983) Oral contraceptives and breast cancer. 

Lancet, ii, 1414-1415 

52. Paffenbarger, R.S., Jr, Kampert, J.B. & Chang, H.-G. (1980) Characteristics that predict risk of 

breast cancer before and after the menopause. Am. J. Epidemiol., 112, 258-268 

53. Pike, M.C., Krailo, M.D., Henderson, B.E., Duke, A. & Roy, S. (1983) Breast cancer in young 

women and use of oral contraceptives: possible modifying effect of formulation and age at use. 

Lancet, ii, 926-930 

54. Olsson, H., Olsson, M.L., Möller, T.R., Ranstam, J. & Holm, P. (1985) Oral contraceptive use and 

breast cancer in young women in Sweden. Lancet, i, 748-749 

55. Adam, S.A., Sheaves, J.K., Wright, N.H., Mosser, G., Harris, R.W. & Vessey, M.P. (1981) A casecontrol study of the possible association between oral contraceptives and malignant melanoma. Br. 

J. Cancer, 44, 45-50 

56. Bain, C., Hennekens, C.H., Speizer, F.E., Rosner, B., Willett, W. & Belanger, C. (1982) Oral 

contraceptive use and malignant melanoma. J. natl Cancer Inst., 68, 537-539 

57. Holly, E.A., Weiss, N.S. & Liff, J.M. (1983) Cutaneous melanoma in relation to exogenous 

hormones and reproductive factors. J. natl Cancer Inst., 70, 827-831 

58. Helmrich, S.P., Rosenberg, L., Kaufman, D.W., Miller, D.R., Schottenfeld, D., Stolley, P.D. & 

Shapiro, S. (1984) Lack of an elevated risk of malignant melanoma in relation to oral contraceptive 

use. J. natl Cancer Inst., 72, 617-620 

59. Beral, V., Evans, S., Shaw, H. & Milton, G. (1984) Oral contraceptive use and malignant 

melanoma in Australia. Br. J. Cancer, 50, 681-685 

60. Holman, C.D.J., Armstrong, B.K. & Heenan, P.J. (1984) Cutaneous malignant melanoma in 

women: exogenous sex hormones and reproductive factors. Br. J. Cancer, 50, 673-780 

61. Gallagher, R.P., Elwood, J.M., Hill, G.B., Coldman, A.J., Threlfall, W.J. & Spinelli, J.J. (1985) 

Reproductive factors, oral contraceptives and risk of malignant melanoma: Western Canada 

melanoma study. Br. J. Cancer, 52, 901-907 

62. Kay, C.R. (1981) Malignant melanoma and oral contraceptives. Br. J. Cancer, 44, 479 

63. Ramcharan, S., Pellegrin, F.A., Ray, R. & Hsu, J.-P. (1981) The Walnut Creek Contraceptive Drug 

Study. A Prospective Study of the Side Effects of Oral Contraceptives (NIH Publ. No. 81-564), 

Bethesda, MD, National Institutes of Health, pp. 49, 53-55 

64. Wingrave, S.J., Kay, C.R. & Vessey, M.P. (1980) Oral contraceptives and pituitary adenomas. Br. 

med. J., i, 685-686 
65. Shy, K.K., McTiernan, A.M., Daling, J.R. & Weiss, N.S. (1983) Oral contraceptive use and the 

occurrence of pituitary prolactinoma. J. Am. med. Assoc., 249, 2204-2207 

66. Berkowitz, R.S., Marean, A.R., Goldstein, D.P. & Bernstein, M.R. (1980) Oral contraceptives and 

post-molar trophoblastic tumours. Lancet, ii, 752 

67. Potter, J.D. & McMichael, A.J. (1983) Large bowel cancer in women in relation to reproductive 

and hormonal factors: a case-control study. J. natl Cancer Inst., 71, 703-709 

68. Weiss, N.S., Daling, J.R. & Chow, W.H. (1981) Incidence of cancer of the large bowel in women 

in relation to reproductive and hormonal factors. J. natl Cancer Inst., 67, 57-60 

69. Brinton, L.A., Vessey, M.P., Flavel, R. & Yeates, D. (1981) Risk factors for benign breast disease. 

Am. J. Epidemiol., 113, 203-214 

70. Pastides, H., Kelsey, J.L., LiVolsi, V.A., Holford, T.R., Fischer, D.B. & Goldenberg, I.S. (1983) 

Oral contraceptive use and fibrocystic breast disease with special reference to its histopathology. J. 

natl Cancer Inst., 71, 5-9 

71. Hsieh, C.-C., Crosson, A.W., Walker, A.M., Trapido, E.J. & MacMahon, B. (1984) Oral 

contraceptive use and fibrocystic breast disease of different histologic classifications. J. natl Cancer 

Inst., 72, 285-290 

72. Hislop, T.G. & Threlfall, W.J. (1984) Oral contraceptives and benign breast disease. Am. J. 

Epidemiol., 120, 273-280 

73. Berkowitz, G.S., Kelsey, J.L., LiVolsi, V.A., Holford, T.R., Merino, M.J., Ort, S., O'Connor, T.Z., 

Goldenberg, I.S. & White, C. (1984) Oral contraceptive use and fibrocystic breast disease among preand postmenopausal women. Am. J. Epidemiol., 120, 87-96 

74. Ross, R.K., Pike, M.C.,Vessey, M.P., Bull, D., Yeates, D. & Casagrande, J.T. (1986) Risk factors 

for uterine fibroids: reduced risk associated with oral contraceptives. Br. med. J., 293, 359-362 

75. IARC Monographs, 21, 233-255, 257-278, 365-365, 1979 

76. IARC Monographs, 21, 233-255, 257-278, 387-395, 1979 

77. IARC Monographs, 21, 233-255, 407-415, 1979 

78. IARC Monographs, 21, 257-278, 431-439, 1979 

79. IARC Monographs, 21, 233-255, 257-278, 441-460, 1979 

80. El Etreby, M.F. & Neumann, F. (1980) Influence of sex steroids and steroid antagonists on 

hormone-dependent tumors in experimental animals. In: Iacobelli, S., King, R.J.B., Lindner, H.R. & 

Lippman, M.E., eds, Hormones and Cancer, New York, Raven Press, pp. 321-336 

81. Higashi, G., Tomita, T., Mizumoto, R. & Nakakuki, K. (1980) Development of hepatoma in rats 

following oral administration of synthetic oestrogen and progesterone. Gann, 71, 576-577 

82. Fitzgerald, J., de la Iglesia, F. & Goldenthal, E.I. (1982) Ten-year oral toxicity study with 

norlestin in rhesus monkeys. J. Toxicol. environ. Health, 10, 879-896 

83. IARC Monographs, 21, 233-255, 461-477, 1979 
84. IARC Monographs, 21, 257-278, 479-490, 1979 

85. IARC Monographs, 21, 279-326, 491-515, 1979 

86. Kwapien, R.P., Giles, R.C., Gell, R.G. & Casey, H.W. (1980) Malignant mammary tumors in 

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87. IARC Monographs, Suppl. 6, 444, 1987

Last updated: 9 February 1998 
ORAL CONTRACEPTIVES, SEQUENTIAL

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 296) 

A. Evidence for carcinogenicity to humans (sufficient)

Case reports of endometrial cancer occurring at an unusually young age in users of sequential oral 

contraceptives provide evidence that these preparations can cause endometrial cancer [ref: 1]. 

Three case-control studies have provided the following estimates of the relative risk (and 95% 

confidence intervals) for endometrial cancer in women who had used sequential oral contraceptives: 

2.2 (0.6-7.3) [ref: 2], 2.1 (0.8-5.8) [ref: 3] and [1.9 (0.7-5.3)] [ref: 4]. One study [ref: 2] showed 

a relative risk of 7.3 (1.4-38.8) in users of a preparation that contained a relatively large amount of 

a potent oestrogen (0.1 mg ethinyloestradiol) and only a weak progestin (25 mg dimethisterone); 

another [ref: 4] showed a relative risk of 4.6 in users of more than two years' duration. The finding 

of an increased risk for endometrial cancer in relation to sequential oral contraceptives is in contrast 

with a reduction in risk for endometrial cancer found in association with the use of combined oral 

contraceptives. 

B. Evidence for carcinogenicity to animals (inadequate for dimethisterone in combination with 

ethinyloestradiol)

Dimethisterone and oestrogen

When dimethisterone and ethinyloestradiol were given sequentially to female dogs by oral 

administration, a few palpable mammary nodules were reported to have occurred in treated (4/16) 

and in untreated animals (2/16) [ref: 5]. 

C. Other relevant data

No adequate data were available on the genetic and related effects of sequential oral contraceptives 

in humans. See, however, the summaries of data on individual compounds commonly found in 

sequential oral contraceptives: chlormadinone acetate, dimethistereone, ethinyloestradiol and 

mestranol. 

Overall evaluation

Sequential oral contraceptives are carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also previous evaluations: Vol. 6 (1974); Vol. 21 (1979)

References

1. IARC Monographs, 21, 111-112, 133, 1979

2. Weiss, N.S. & Sayvetz, T.A. (1980) Incidence of endometrial cancer in relation to the use of oral 

contraceptives. New Engl. J. Med., 302, 551-554

3. Centers for Disease Control Cancer and Steroid Hormone Study (1983) Oral contraceptive use 

and the risk of endometrial cancer. J. Am. med. Assoc., 249, 1600-1604
4. Henderson, B.E., Casagrande, J.T., Pike, M.C., Mack, T., Rosario, I. & Duke, A. (1983) The 

epidemiology of endometrial cancer in young women. Br. J. Cancer, 47, 749-756

5. IARC Monographs, 21, 233-255, 377-385, 1979 

Last updated: 10 February 1998 
PHENACETIN

(Group 2A)

and ANALGESIC MIXTURES CONTAINING PHENACETIN

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p.310) 

Phenacetin:

CAS No.: 62-44-2

Chem. Abstr. Name: Acetamide, N-(4-ethoxyphenyl)- 

A. Evidence for carcinogenicity to humans (limited for phenacetin; sufficient for analgesic 

mixtures containing phenacetin)

There have been many case reports of renal pelvic and other urothelial tumours in patients who had 

used large amounts of phenacetin-containing analgesics [ref: 1-13]. Case-control studies have been 

consistent in showing a positive association between cancer of the renal pelvis and cancer of the 

bladder and use of phenacetin-containing analgesics, with relative risks varying from 2.4 to over 6; 

these associations have not been explained by confounding with other causes of urothelial cancer 

and, where looked for, a positive dose-response relationship has been evident [ref: 14-19]. In one 

study [ref: 14], use of nonphenacetin-containing analgesics appeared to increase the risk of cancer 

of the renal pelvis to the same extent as did phenacetin-containing analgesics. This result was not 

obtained in other studies [ref: 15,17,18]. 

B. Evidence for carcinogenicity to animals (sufficient for phenacetin; limited for analgesic 

mixtures containing phenacetin)

Phenacetin given orally induced benign and malignant tumours of the urinary tract in mice [ref: 20] 

and rats [ref: 1,21] and of the nasal cavity in rats [ref: 1]. When given in combination with aspirin 

and caffeine to rats or mice, no significant association was found between the administration of the 

mixture and the incidence of tumours [ref: 1]. In rats, phenacetin alone or in combination with 

phenazone slightly increased the incidences of renal-cell and renal-pelvic tumours; rats treated with 

phenacetin, phenazone and caffeine in combination developed hepatomas [ref: 22]. In rats, 

phenacetin enhanced the incidence of urinary bladder tumours induced by N-nitrosobutyl-N-(4-

hydroxybutyl)amine [ref: 1], and prevented the induction of hepatocellular carcinomas by 2-

acetylaminofluorene [ref: 23]. 

C. Other relevant data

No data were available on the genetic and related effects of phenacetin in humans. 

The results of studies on the induction of chromosomal aberrations, sister chromatid exchanges and 

micronuclei in rodents treated with phenacetin in vivo were equivocal. Phenacetin induced 

chromosomal aberrations in Chinese hamster cells in vitro but not DNA strand breaks in rat 

hepatocytes. It did not induce sex-linked recessive lethal mutations in Drosophila. Phenacetin was 

mutagenic to bacteria when tested in the presence of a metabolic system derived from hamster but 

not mouse or rat liver. The urine from phenacetin-treated Chinese hamsters, but not that from rats, 

was mutagenic to bacteria [ref: 24]. 

Overall evaluation

Phenacetin is probably carcinogenic to humans (Group 2A).

Analgesic mixtures containing phenacetin are carcinogenic to humans (Group 1).
For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 13 (1977); Vol. 24 (1980)

References

1. IARC Monographs, 24, 135-161, 1980 

2. Christensen, T.E. & Ladefoged, J. (1979) Carcinomata in the urinary tract in patients with 

contracted kidneys and massive abuse of analgesics (phenacetin) (Dan.). Ugeskr. Laeg., 141, 3522-

3524 

3. Gonwa, T.A., Corbett, W.T., Schey, H.M. & Bukalew, V.M., Jr (1980) Analgesic-associated 

nephropathy and transitional cell carcinoma of the urinary tract. Ann. intern. Med., 93, 249-252 

4. Mihatsch, M.J., Manz, T., Knüsli, C., Hofer, H.O., Rist, M., Guetg, R., Rutishauser, G. & Zollinger, 

H.U. (1980) Phenacetin abuse. III. Malignant urinary tract tumours with phenacetin abuse in Basel, 

1963-1977 (Ger.). Schweiz. med. Wochenschr., 110, 255-264 

5. Orell, S.R., Nanra, R.S. & Ferguson, N.W. (1979) Renal pelvic carcinoma in the Hunter Valley. 

Med. J. Aust., 524, 555-557 

6. Blohmé, I. & Johansson, S. (1981) Renal pelvic neoplasms and atypical urothelium in patients 

with end-stage analgesic nephropathy. Kidney int., 20, 671-675 

7. Syré, G. & Matejka, M. (1981) Phenacetin abuse and renal pelvis carcinomas (Ger.). Wien. klin. 

Wochenschr., 93, 420-423 

8. Porpáczy, P. & Schramek, P. (1981) Analgesic nephropathy and phenacetin-induced transitional 

cell carcinoma - analysis of 300 patients with long-term consumption of phenacetin-containing 

drugs. Eur. Urol., 7, 349-354 

9. Mihatsch, M.J., Brunner, F.P., Korteweg, E., Rist, M., Dalquen, P. & Thiel, G. (1982) Phenacetin 

abuse. VII. Tumours of the urinary tract in haemodialysis and kidney transplant patients (Ger.). 

Schweiz. med. Wochenschr., 112, 1468-1472 

10. Novák, J. & Zidek, I. (1983) Phenacetin as a carcinogen for the renal pelvis (Czech.). Cas. Lék. 

ces., 122, 1149-1152 

11. Mihatsch, M.J. & Knüsli, C. (1982) Phenacetin abuse and malignant tumors. An autopsy study 

covering 25 years (1953-1977). Klin. Wochenschr., 60, 1339-1349 

12. Marek, J. & Hradec, E. (1985) Chronic sclerosing ureteritis and nephrogenic adenoma of the 

ureter in analgesic abuse. Pathol. Res. Pract., 180, 569-573 

13. Kliment, J. (1979) Renal pelvis tumours and abuse of analgesics (Czech.). Bratisl. lék. Listy, 72, 

641-764 

14. McCredie, M., Ford, J.M., Taylor, J.S. & Stewart, J.H. (1982) Analgesics and cancer of the renal 

pelvis in New South Wales. Cancer, 49, 2617-2625 

15. McCredie, M., Stewart, J.H., Ford, J.M. & MacLennan, R.A. (1983) Phenacetin-containing 

analgesics and cancer of the bladder or renal pelvis in women. Br. J. Urol., 55, 220-224 
16. McCredie, M., Stewart, J.H. & Ford, J.M. (1983) Analgesics and tobacco as risk factors for cancer 

of the ureter and renal pelvis. J. Urol., 130, 28-30 

17. McLaughlin, J.K., Mandel, J.S., Blot, W.J., Schuman, L.M., Mehl, E.S. & Fraumeni, J.F., Jr (1984) 

A population-based case-control study of renal cell carcinoma. J. natl Cancer Inst., 72, 275-284 

18. Piper, J.M., Tonascia, J. & Matanoski, G.M. (1985) Heavy phenacetin use and bladder cancer in 

women aged 20 to 49 years. New Engl. J. Med., 313, 292-295 

19. Piper, J.M., Matanoski, G.M. & Tonascia, J. (1986) Bladder cancer in young women. Am. J. 

Epidemiol., 123, 1033-1042 

20. Nakanishi, K., Kurata, Y., Oshima, M., Fukushima, S. & Ito, N. (1982) Carcinogenicity of 

phenacetin: long-term feeding study in B6C3F1 mice. Int. J. Cancer, 29, 439-444 

21. Muradyan, R.Y. (1986) Experimental studies of phenacetin carcinogenicity (Russ.). Vopr. Onkol., 

32, 63-70 

22. Johansson, S.L. (1981) Carcinogenicity of analgesics: Long-term treatment of Sprague-Dawley 

rats with phenacetin, phenazone, caffeine and paracetamol (acetamidophen). Int. J. Cancer, 27, 

521-529 

23. Yamamoto, R.S., Frankel, H.H. & Weisburger, E.K. (1979) Effect of phenacetin and Nalkylacetanilides on N-2-fluorenylacetamide hepatocarcinogenesis. Cancer Lett., 8, 183-188 

24. IARC Monographs, Suppl. 6, 448-450, 1987 

Synonyms for Phenacetin

● 1-Acetamido-4-ethoxybenzene 

● Aceto-para-phenalide 

● para-Acetophenetide 

● para-Acetophenetidide 

● Aceto-para-phenetidide 

● Acetophenetidin 

● para-Acetophenetidine 

● para-Acetphenetidin 

● Acet-para-phenetidin 

● Aceto-4-phenetidine 

● Acetophenetidine 

● Acetophenetin 

● Acetphenetidin 

● Acetyl-phenetidine 

● Acetylphenetidin 

● N-Acetyl-para-phenetidine 

● Achrocidin 

● Anapac 

● APC 

● ASA compound 

● Bromo Seltzer 

● Buff-A-comp 

● Citra-fort 

● Clistanol 

● Codempiral 

● Commotional 

● Contra-douleur 

● Contradol 

● Coricidin 

● Coriforte 
● Coryban-D 

● Daprisal 

● Darvon compound 

● Dasikon 

● Dasin 

● Dasin CH 

● Dolostop 

● Dolviran 

● Edrisal 

● Empiral 

● Empirin compound 

● Emprazil 

● Emprazil-C 

● Epragen 

● para-Ethoxy-acetanilid 

● 4'-Ethoxyacetanilide 

● para-Ethoxyacetanilide 

● 4-Ethoxyacetanilide 

● Fenacetina 

● Fenedina 

● Fenidina 

● Fenina 

● Fiorinal 

● Fortacyl 

● Gelonida 

● Gewodin 

● Helvagit 

● Hjorton's powder 

● Hocophen 

● Kafa 

● Kalmin 

● Malex 

● Melabon 

● Melaforte 

● N-para-Ethoxyphenylacetamide 

● Norgesic 

● Pamprin 

● Paracetophenetidin 

● Paramette 

● Paratodol 

● Percobarb 

● Percodan 

● Pertonal 

● Phenacet 

● Phenacetine 

● para-Phenacetin 

● Phenacetinum 

● Phenacitin 

● Phenacon 

● Phenalgin 

● Phenaphen 

● Phenaphen plus 

● Phenazetin 

● Phenazetina 

● Phenedina 

● Phenidin 

● Phenin 

● Phenodyne 

● Pyrroxate 

● Quadronal 

● Reformin 

● Robaxisal-PH 

● Salgydal 

● Sanalgine 

● Saridon 
● Seranex 

● Sinedal 

● Sinubid 

● Sinutab 

● Sinutab II 

● Soma 

● Stellacyl 

● Super nahist 

● Supralgin 

● Synalgos-DC 

● Synalogos 

● Tacol 

● Terracydin 

● Tetracydin 

● Thephorin A-C 

● Treupel 

● Veganine 

● Viden 

● Wigraine 

● Xaril 

● Zactirin compound-100 

Last updated: 6 February 1998 
PHENAZOPYRIDINE HYDROCHLORIDE

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 312) 

CAS No.: 136-40-3 

Chem. Abstr. Name: 2,6-Pyridinediamine,3-(phenylazo)-,monohydrochloride 

A. Evidence for carcinogenicity to humans (inadequate) 

In one limited epidemiological study, no significant excess of any cancer was observed among 2214 

patients who received phenazopyridine hydrochloride and were followed for a minimum of three 

years [ref: 1]. 

B. Evidence for carcinogenicity to animals (sufficient) 

Oral administration of phenazopyridine hydrochloride increased the incidence of hepatocellular 

adenomas and carcinomas in female mice and induced tumours of the colon and rectum in rats [ref: 

1]. 

C. Other relevant data

No data were available on the genetic and related effects of phenazopyridine hydrochloride in 

humans. It did not induce sex-linked recessive lethal mutations in Drosophila and was not 

mutagenic to bacteria [ref: 2]. 

Overall evaluation

Phenazopyridine hydrochloride is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 8 (1975); Vol. 24 (1980)

References

1. IARC Monographs, 24, 175-184, 1980

2. IARC Monographs, Suppl. 6, 451-452, 1987 

Synonyms

● Azo gantrisin 

● Azo gastanol 

● Azo-mandelamine 

● Azo-standard 

● Azo-stat 

● Azodine 

● Azodium 

● Azodyne 

● Azotrex 

● Baridium 
● Bisteril 

● Cystamine McClung 

● Cystopyrin 

● Cystural 

● 2,6-Diamino-3-(phenylazo)pyridine monohydrochloride 

● 2,6-Diamino-3-phenylazopyridine hydrochloride 

● Di-Azo 

● Diridone 

● Dolonil 

● Eucistin 

● Giracid 

● Mallofeen 

● Mallophene 

● NC 150 

● Nefrecil 

● PAP 

● Phenazo 

● Phenazodine 

● Phenazopyridinium chloride 

● 3-Phenylazo-2,6-diaminopyridine hydrochloride 

● Phenyl-Idium 

● Phenyl-Idium 200 

● Phenylazo 

● Phenylazodiaminopyridine HCl 

● β-Phenylazo-α,α'-diaminopyridine hydrochloride 

● Phenylazopyridine HCl 

● Pirid 

● Piridacil 

● Pyrazodine 

● Pyrazofen 

● Pyredal 

● Pyridacil 

● Pyridenal 

● Pyridene 

● Pyridiate 

● Pyridium 

● Pyridivite 

● Pyripyridium 

● Pyrizin 

● Sedural 

● Sulodyne 

● Thiosulfil-A forte 

● Urazium 

● Uridinal 

● Uriplex 

● Urobiotic-250 

● Urodine 

● Urofeen 

● Uromide 

● Urophenyl 

● Uropyridin 

● Uropyrine 

● Utostan 

● Vestin 

● W 1655 

Last updated: 3 March 1998 
PHENELZINE SULPHATE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 312) 

CAS No.: 156-51-4

Chem. Abstr. Name: Hydrazine(2-phenylethyl)-, sulfate(1:1) 

A. Evidence for carcinogenicity to humans (inadequate) 

A liver angiosarcoma was reported in one person who had taken phenelzine sulphate for six years 

preceding tumour diagnosis [ref: 1]. 

B. Evidence for carcinogenicity to animals (limited) 

Phenelzine sulphate was administered to mice in drinking-water for life. Incidences of lung and 

blood-vessel tumours were significantly increased in female but not in male mice [ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of phenelzine sulphate in humans. It did 

not induce DNA strand breaks in mice treated in vivo. In bacteria, it was mutagenic and induced 

DNA damage [ref: 2]. 

Overall evaluation

Phenelzine sulphate is not classifiable as to its carcinogenicity to humans (Group 3). 

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 24 (1980)

References

1. IARC Monographs, 24, 175-184, 1980 

2. IARC Monographs, Suppl. 6, 453-454, 1987 

Synonyms

● Alazin 

● Estinerval 

● Fenelzin 

● Fenelzine 

● 1-Hydrazino-2-phenylethane hydrogen sulfate 

● Phenalzine dihydrogen sulfate 

● Phenalzine hydrogen sulfate 

● Phenelzine bisulfate 

● Phenethylhydrazine sulfate(1:1) 

● Phenethylhydrazine sulfate 

● Phenodyn 

● Phenylethylhydrazine dihydrogen sulfate 
● 2-Phenylethylhydrazine dihydrogen sulfate 

● β-Phenylethylhydrazine dihydrogen sulfate 

● 2-Phenylethylhydrazine hydrogen sulfate 

● β-Phenylethylhydrazine hydrogen sulfate 

● Phenylethylhydrazine sulfate 

● 2-Phenylethylhydrazine sulfate 

● β-Phenylethylhydrazine sulfate 

● Kalgan 

● Mao-rem 

● Monofen 

● Nardelzine 

● Nardil 

● Stinerval 

Last updated: 11 March 1998 
PHENOBARBITAL

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 313) 

CAS No.: 50-06-6 

Chem. Abstr. Name: 5-Ethyl-5-phenyl-2,4,6-(1H,3H,5H)pyrimidinetrione 

A. Evidence for carcinogenicity to humans (inadequate) 

Phenobarbital has been associated with increased frequencies of several cancers [ref: 1]. Excesses of 

brain tumours have been reported in studies of epileptics, most of whom were treated with 

phenobarbital, often in combination with other drugs [ref: 2,3]. The role of anticonvulsant therapy in 

the origin of these brain tumours is not clear, however, since the tumours may have been the 

precipitating cause of the epilepsy. In the largest study [ref: 2,4], there was an almost 12-fold 

excess of brain tumours in the first ten years of follow-up (45 observed, 3.8 expected) but this 

decreased with duration of follow-up to 1.3 (2 observed, 1.5 expected) 30 or more years following 

admission. A case-control study involving 84 children with brain tumours [ref: 5] showed a two-fold 

increase in the incidence of these tumours associated with prenatal or childhood exposure to 

barbiturates (mostly phenobarbital [ref: 6]). In a study of 11 169 matched case-control pairs of 

childhood cancers and controls, epilepsy was reported by 39 mothers of cases and 22 mothers of 

controls (20 and 12, respectively, having used phenobarbital). The number of brain tumours among 

the 39 cancers was not reported [ref: 7].

Lung cancer was reported in excess in 5834 members of a prepaid health plan prescribed 

phenobarbital during 1969-1973 and followed to 1976. The standardized mortality ratio (SMR) was 

1.5 [95% confidence interval, 1.1-1.9]. Excesses were also found in users of pentobarbital sodium 

and secobarbital sodium. When users of the three drugs were considered together, the excess of 

lung cancer was found in both men and women, appeared to be accounted for only partly by 

cigarette smoking and persisted when cases diagnosed during the first two years of follow-up were 

excluded. There was no apparent relation with duration of use [ref: 8]. Small increases in lung 

cancer incidence were also observed in two cohort studies of epileptics [ref: 3,4], 'largely ascribable 

to tobacco' in one study [ref: 4], although the effects of smoking were not studied. In the larger of 

the two [ref: 4], the SMR was 1.3 [1.0-1.6]; in the other [ref: 3], it was 1.4 (0.9-2.1).

Liver cancer occurred in excess in the larger cohort study of epileptics [ref: 4] (SMR, 3.8 [2.7-4.9]). 

However, ten of the 13 observed cancers occurred in individuals exposed to thorotrast. Histology was 

available for nine of these: two were reported to be haemangiosarcomas, four, cholangiocarcinomas, 

one, a hepatocellular carcinoma, and two, adenocarcinomas [ref: 2]. In the other cohort study with 

data available [ref: 3], no primary liver tumour was observed although 0.6 cases of cancer of the 

liver and gall-bladder were expected.

B. Evidence for carcinogenicity to animals (sufficient) 

Phenobarbital produced benign and malignant hepatocellular tumours in mice and hepatocellular 

tumours in rats after its oral administration [ref: 1,9,10]. Experiments with mice and rats in which 

phenobarbital was studied for its promoting activity included comparison groups given phenobarbital 

alone. Oral administration of phenobarbital enhanced the incidence of liver tumours in mice by Nnitrosodimethylamine [ref: 11] or N-methyl-N-nitrosourea [ref: 12] and of benign or malignant liver 

tumours induced in rats by 2-acetylaminofluorene [ref: 13-16], N-nitrosodiethylamine [ref: 17,18], 2-

methyl-N,N-dimethyl-4-aminoazobenzene [ref: 19], benzo[a]pyrene [ref: 20], cycasin [ref: 21], Nhydroxy-N-formyl- or -acetylaminobiphenyl [ref: 22], N-nitroso-N-(4-hydroxybutyl) butylamine [ref: 

16] or N-nitrosomorpholine [ref: 23]. In rats, oral administration of phenobarbital in combination 

with DDT resulted in a high incidence of liver tumours [ref: 24]. Phenobarbital enhanced the 

development of thyroid tumours [ref: 25,26] and of liver foci [ref: 26] induced in rats by Nnitrosodi(2-hydroxypropyl)amine and enhanced the incidences of liver foci, thyroid adenocarcinomas 

and forestomach carcinomas induced in rats by N-methyl-N-nitrosourea [ref: 27].
C. Other relevant data

No data were available on the genetic and related effects of phenobarbital in humans.

Neither phenobarbital nor its sodium salt induced sister chromatid exchanges, chromosomal 

aberrations, micronuclei or sperm abnormalities in mice treated in vivo. Phenobarbital induced 

chromosomal aberrations and mutation but not sister chromatid exchanges in cultured human cells. 

Both positive and negative results were obtained for transformation in rodent cells in vitro. 

Phenobarbital enhanced transformation of virus-infected rat embryo cells initiated with 3-

methylcholanthrene in a two-stage transformation assay. It induced sister chromatid exchanges and 

chromosomal aberrations in cultured Chinese hamster cells, but not in cultured rat liver cells; 

micronuclei and aneuploidy were not induced in Chinese hamster cells. Phenobarbital induced 

mutation in Chinese hamster cells, but conflicting or negative results were obtained in other rodent 

cells. Phenobarbital and its sodium salt did not induce DNA strand breaks, and phenobarbital did not 

induce unscheduled DNA synthesis, in cultured rodent cells. Phenobarbital inhibited intercellular 

communication in human hepatoma cells and both phenobarbital and its sodium salt did so in rodent 

systems. Phenobarbital induced neither somatic mutation nor recombination in Drosophila; the 

sodium salt did not induce sex-linked recessive lethal mutations. Phenobarbital induced aneuploidy 

but not mutation or gene conversion in fungi. Conflicting results were obtained concerning the 

mutagenicity of these compounds in bacteria [ref: 28]. 

Overall evaluation

Phenobarbital is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Subsequent evaluation: Vol. 79 (2001) Also see previous evaluation: Vol. 13 (1977)

References

1. IARC Monographs, 13, 157-181, 1977

2. Clemmesen, J. & Hjalgrim-Jensen, S. (1978) Is phenobarbital carcinogenic? A follow-up of 8078 

epileptics. Ecotoxicol. environ. Saf., 1, 457-470

3. White, S.J., McLean, A.E.M. & Howland, C. (1979) Anticonvulsant drugs and cancer. A cohort 

study in patients with severe epilepsy. Lancet, ii, 458-461

4. Clemmesen, J. & Hjalgrim-Jensen, S. (1981) Does phenobarbital cause intracranial tumors? A 

follow-up through 35 years. Ecotoxicol. environ. Saf., 5, 255-260

5. Gold, E., Gordis, L., Tonascia, J. & Szklo, M. (1978) Increased risk of brain tumors in children 

exposed to barbiturates. J. natl Cancer Inst., 61, 1031-1034

6. Gold, E.B., Gordis, L., Tonascia, J.A. & Szklo, M. (1979) Brain tumors in children exposed to 

barbiturates. J. natl Cancer Inst., 63, 3-4

7. Sanders, B.M. & Draper, G.J. (1979) Childhood cancer and drugs in pregnancy. Br. med. J., i, 717-

718

8. Friedman, G.D. (1981) Barbiturates and lung cancer in humans. J. natl Cancer Inst., 67, 291-295

9. Feldman, D., Swarm, R.L. & Becker, J. (1981) Ultrastructural study of rat liver and liver neoplasms 

after long-term treatment with phenobarbital. Cancer Res., 41, 2151-2162
10. Ward, J.M. (1983) Increased susceptibility of livers of aged F344/NCr rats to the effects of 

phenobarbital on the incidence, morphology, and histochemistry of hepatocellular foci and 

neoplasms. J. natl Cancer Inst., 71, 815-823

11. Uchida, E. & Hirono, I. (1979) Effect of phenobarbital on induction of liver and lung tumors by 

dimethylnitrosamine in newborn mice. Gann, 70, 639-644

12. Pereira, M.A., Knutsen, G.L. & Herren-Freund, S.L. (1985) Effect of subsequent treatment of 

chloroform or phenobarbital on the incidence of liver and lung tumors initiated by ethylnitrosourea in 

15 day old mice. Carcinogenesis, 6, 203-207

13. Watanabe, K. & Williams, G.M. (1978) Enhancement of rat hepatocellular-altered foci by the liver 

tumor promoter phenobarbital: evidence that foci are precursors of neoplasms and that the promoter 

acts on carcinogenic-induced lesions. J. natl Cancer Inst., 61, 1311-1314

14. Peraino, C., Staffeldt, E.F., Haugen, D.A., Lombard, L.S., Stevens, F.J. & Fry, R.J.M. (1980) 

Effects of varying the dietary concentration of phenobarbital on its enhancement of 2-

acetylaminofluorene-induced hepatic tumorigenesis. Cancer Res., 40, 3268-3273

15. Takano, T., Tatematsu, M., Hasegawa, R., Imaida, K. & Ito, N. (1980) Dose-response 

relationship for the promoting effect of phenobarbital on the induction of liver hyperplastic nodules in 

rats exposed to 2-fluorenylacetamide and carbon tetrachloride. Gann, 71, 580-581

16. Nakanishi, K., Fukushima, S., Hagiwara, A., Tamano, S. & Ito, N. (1982) Organ-specific 

promoting effects of phenobarbital sodium and sodium saccharin in the induction of liver and urinary 

bladder tumors in male F344 rats. J. natl Cancer Inst., 68, 497-500

17. Farwell, D.C., Nolan, C.E. & Herbst, E.J. (1978) Liver ornithine decarboxylase during 

phenobarbital promotion of nitrosamine carcinogenesis. Cancer Lett., 5, 139-144

18. Nishizumi, M. (1979) Effect of phenobarbital, dichlorodiphenyltrichloroethane, and 

polychlorinated biphenyls on diethylnitrosamine-induced hepatocarcinogenesis. Gann, 70, 835-837

19. Kitagawa, T., Pitot, H.C., Miller, E.C. & Miller, J.A. (1979) Promotion by dietary phenobarbital of 

hepatocarcinogenesis by 2-methyl-N,N-dimethyl-4-aminoazobenzene in the rat. Cancer Res., 39, 112-

115

20. Kitagawa, T., Hirakawa, T., Ishikawa, T., Nemoto, N. & Takayama, S. (1980) Induction of 

hepatocellular carcinoma in rat liver by initial treatment with benzo[a]pyrene after partial 

hepatectomy and promotion by phenobarbital. Toxicol. Lett., 6, 167-171

21. Uchida, E. & Hirono, I. (1981) Effect of phenobarbital on the development of neoplastic lesions in 

the liver of cycasin-treated rats. J. Cancer Res. clin. Oncol., 100, 231-238

22. Shirai, T., Lee, M.-S., Wang, C.Y. & King, C.M. (1981) Effects of partial hepatectomy and dietary 

phenobarbital in liver and mammary tumorigenesis by two N-hydroxy-N-acylaminobiphenyls in 

female CD rats. Cancer Res., 41, 2450-2456

23. Moore, M.A., Hacker, H.-J., Kunz, H.W. & Bannasch, P. (1983) Enhancement of NNM-induced 

carcinogenesis in the rat liver by phenobarbital: a combined morphological and enzyme 

histochemical approach. Carcinogenesis, 4, 473-479

24. Barbieri, O., Rossi, L., Cabral, J.R.P. & Santi, L. (1983) Carcinogenic effects induced in Wistar 

rats by combined treatment with technical-grade dichlorodiphenyltrichloroethane and sodium 

phenobarbital. Cancer Lett., 20, 223-229
25. Hiasa, Y., Kitahori, Y., Ohshima, M., Fujita, T., Yuasa, T., Konishi, N. & Miyashiro, A. (1982) 

Promoting effects of phenobarbital and barbital on development of thyroid tumors in rats treated 

with N-bis(2-hydroxypropyl)nitrosamine. Carcinogenesis, 3, 1187-1190

26. Moore, M.A., Thamavit, W., Tsuda, H. & Ito, N. (1986) The influence of subsequent 

dehydroepiandrosterone, diaminopropane, phenobarbital, butylated hydroxyanisole and butylated 

hydroxytoluene treatment on the development of preneoplastic and neoplastic lesions in the rat 

initiated with di-hydroxy-di-N-propyl nitrosamine. Cancer Lett., 30, 153-160

27. Tsuda, H., Sakata, T., Shirai, T., Kurata, Y., Tamano, S. & Ito, N. (1984) Modification of Nmethyl-N-nitrosourea initiated carcinogenesis in the rat by subsequent treatment with antioxidants, 

phenobarbital and ethinyl estradiol. Cancer Lett., 24, 19-27

28. IARC Monographs, Suppl. 6, 455-458, 1987 

Synonyms

● Adonal 

● Aephenal 

● Agrypnal 

● Amylofene 

● Aphenylbarbit 

● Aphenyletten 

● Austrominal 

● Barbapil 

● Barbellen 

● Barbellon 

● Barbenyl 

● Barbilettae 

● Barbinal 

● Barbiphen 

● Barbiphenyl 

● Barbipil 

● Barbita 

● Barbivis 

● Barbonal 

● Barbophen 

● Bardorm 

● Bartol 

● Bialminal 

● Blu-phen 

● Cabronal 

● Calmetten 

● Calminal 

● Cardenal 

● Cemalonal 

● Codibarbital 

● Coronaletta 

● Damoral 

● Dezibarbitur 

● Dormina 

● Dormiral 

● Doscalun 

● Duneryl 

● Ensobarb 

● Ensodorm 

● Epanal 

● Epidorm 

● Epilol 

● Episedal 

● Epsylone 

● Eskabarb 

● 5-Ethyl-5-phenylbarbituric acid 
● Etilfen 

● Euneryl 

● Fenbital 

● Fenemal 

● Fenobarbital 

● Fenosed 

● Fenylettae 

● Gardenal 

● Gardepanyl 

● Glysoletten 

● Haplopan 

● Haplos 

● Helional 

● Hennoletten 

● Hypnaletten 

● Hypno-tablinetten 

● Hypnogen 

● Hypnolone 

● Hypnotal 

● Hysteps 

● Lefebar 

● Leonal 

● Lephebar 

● Lepinal 

● Linasen 

● Liquital 

● Lixophen 

● Lubergal 

● Lukrokol 

● Lumen 

● Lumesettes 

● Lumesyn 

● Luminal 

● Lumofridetten 

● Luphenil 

● Luramin 

● Molinal 

● Neurobarb 

● Nirvonal 

● Noptil 

● Nova-Pheno 

● Numol 

● Nunol 

● Parkotal 

● PEBA 

● Pharmetten 

● Phen-Bar 

● Phenaemal 

● Phenemal 

● Phenobal 

● Phenobarbitone 

● Phenobarbituric acid 

● Phenobarbyl 

● Phenoluric 

● Phenonyl 

● Phenoturic 

● Phenylbarbital 

● Phenylethylbarbiturate 

● 5-Phenyl-5-ethylbarbituric acid 

● Phenylethylbarbituric acid 

● Phenylethylmalonylurea 

● Phenyletten 

● Phenyral 

● Phob 

● Polcominal 

● Promptonal 
● Seda-tablinen 

● Sedabar 

● Sedicat 

● Sedizorin 

● Sedlyn 

● Sedofen 

● Sedonal 

● Sedonettes 

● Sevenal 

● Sombutol 

● Somnolens 

● Somnoletten 

● Somnosan 

● Somonal 

● Spasepilin 

● Starifen 

● Starilettae 

● Stental extentabs 

● Teolaxin 

● Thenobarbital 

● Triarbarb 

● Tridezibarbitur 

● Triphenatol 

● Versomnal 

● Zadoletten 

● Zadonal 

Last updated: 3 March 1998 
PHENYLBUTAZONE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 316) 

CAS No.: 50-33-9

Chem. Abstr. Name: 4-Butyl-1,2-diphenyl-3,5-pyrazolidinedione 

A. Evidence for carcinogenicity to humans (inadequate) 

Cases of leukaemia have been reported in patients following phenylbutazone therapy [ref: 1,2], but 

their significance cannot be evaluated, given the widespread use of phenylbutazone [ref: 1]. No 

significant excess of leukaemia or other malignancy was observed during 1969-1976 among 3660 

members of a prepaid health plan prescribed phenylbutazone during 1969-1973 [ref: 3]. In a casecontrol study of 409 patients with leukaemia or lymphoma and a subset of 127 patients with 

myelocytic leukaemia, who were compared with equal numbers of hospital controls and with a 

second control series of members of a prepaid health plan, prior use of phenylbutazone was more 

frequent in cases than in members of the health plan (relative risk, 1.26; 95% confidence interval, 

0.86-1.86). This appeared to be explained by an association of musculo-skeletal disease with these 

cancers. There was no clear association between the amount or duration of phenylbutazone therapy 

and risk of leukaemia [ref: 4]. In a cohort study of 489 patients with rheumatoid arthritis, followed 

for an average of 12.2 years, seven patients developed non-Hodgkin's lymphoma compared to 0.29 

expected from regional rates (relative risk, 24.1 [20.4-27.9]), two developed Hodgkin's disease, 

one, a chronic lymphatic leukaemia and one, an acute myeloid leukaemia. A study of hospital charts 

indicated that 60% of those with malignancies had received phenylbutazone compared to 3% of the 

whole cohort; however, the author considered it likely that far more than 3% of the whole cohort 

had received phenylbutazone. Those patients with malignancies had also received other drugs: 40% 

had received gold, 20%, steroids and 10%, chloroquine, but none had received cytotoxic agents or 

radiotherapy. Further, 30% were believed not to have received any of these agents (including 

phenylbutazone) [ref: 5]. Lymphoproliferative malignancies have been recognized as a complication 

of other immune disorders, and it is possible that phenylbutazone therapy did not play a causal role 

in this study. 

B. Evidence for carcinogenicity to animals

No data were available to the Working Group. 

C. Other relevant data

In one study of patients given high doses of phenylbutazone, no chromosomal aberration was found 

in bone-marrow cells [ref: 6]. 

Phenylbutazone did not induce dominant lethality or micronuclei or chromosomal anomalies in bonemarrow cells of mice treated in vivo. It induced chromosomal aberrations in cultured Chinese 

hamster fibroblasts, but did not induce sister chromatid exchanges or chromosomal aberrations in 

cultured human cells. Phenylbutazone was not mutagenic to bacteria [ref: 6]. 

Phenylbutazone is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 13 (1977)

References
1. IARC Monographs, 13, 183-199, 1977 

2. Mitarnun, W. & Peerabool, R. (1983) Blood dyscrasia evolving into acute lymphoblastic leukemia 

following ingestion of phenylbutazone, indomethacin, dexamethasone and prednisolone. J. med. 

Assoc. Thailand, 66, 649-654 

3. Friedman, G.D. & Ury, H.K. (1980) Initial screening for carcinogenicity of commonly used drugs. 

J. natl Cancer Inst., 65, 723-733 

4. Friedman, G.D. (1982) Phenylbutazone, musculoskeletal disease, and leukemia. J. chron. Dis., 

35, 233-243 

5. Symmons, D.P.M. (1985) Neoplasms of the immune system in rheumatoid arthritis. Am. J. Med., 

78 (Suppl. 1A), 22-28 

6. IARC Monographs, Suppl. 6, 459-460, 1987 

Synonyms

● Alindor 

● Alkabutazona 

● Alqoverin 

● Anerval 

● Anpuzone 

● Antadol 

● Anuspiramin 

● Arthrizin 

● Artrizin 

● Artrizone 

● Artropan 

● Azdid 

● Azobutil 

● Benzone 

● Betazed 

● Bizolin 200 

● B.T.Z. 

● Butacote 

● Butacompren 

● Butadion 

● Butadiona 

● Butadione 

● Butagesic 

● Butalgina 

● Butalan 

● Butalidon 

● Butaluy 

● Butaphen 

● Buta-Phen 

● Butapirazol 

● Butapyrazole 

● Butarecbon 

● Butartril 

● Butartrina 

● Butazina 

● Butazolidin 

● Butazolidine 

● Butazona 

● Butazone 

● Butidiona 

● Butiwas-simple 
● Butone 

● Butoz 

● 4-Butyl-1,2-diphenyl-3,5-dioxopyrazolidine 

● 4-Butyl-1,2-diphenyl-pyrazolidine-3,5-dione 

● Butylpyrin 

● Buvetzone 

● Buzon 

● Chembutazone 

● Digibutina 

● Diossidone 

● 3,5-Dioxo-1,2-diphenyl-4-n-butylpyrazolidine 

● Diozol 

● Diphebuzol 

● Diphenylbutazone 

● 1,2-Diphenyl-4-butyl-3,5-pyrazolidinedione 

● 1,2-Diphenyl-3,5-dioxo-4-butylpyrazolidine 

● 1,2-Diphenyl-3,5-dioxo-4-n-butylpyrazolidine 

● 1,2-Diphenyl-2,3-dioxo-4-n-butylpyrazolidine 

● Ecobutazone 

● Elmedal 

● Equi Bute 

● Eributazone 

● Esteve 

● Febuzina 

● Fenartil 

● Fenibutasan 

● Fenibutazona 

● Fenilbutazona 

● Fenylbutazon 

● Fenilbutina 

● Fenilbutine 

● Fenibutol 

● Fenilidina 

● Fenotone 

● Flexazone 

● G 13,871 

● IA-But 

● Intalbut 

● Intrabutazone 

● Ipsoflame 

● Kadol 

● Lingel 

● Malgesic 

● Mephabutazone 

● Merizone 

● Nadazone 

● Nadozone 

● Neo-Zoline 

● Novo-phenyl 

● Phebuzin 

● Phebuzine 

● Phen-Buta-Vet 

● Phenbutazol 

● Phenopyrine 

● Phenylbetazone 

● Phenylbutaz 

● Phenylbutazonum 

● Phenyl-mobuzon 

● Pirarreumol B 

● Praecirheumin 

● Pyrabutol 

● Pyrazolidin 

● Rectofasa 

● Reudo 

● Reudox 
● Reumasyl 

● Reumazin 

● Reumazol 

● Reumune 

● Reupolar 

● Robizon-V 

● Rubatone 

● Scanbutazone 

● Schemergin 

● Shigrodin 

● Tazone 

● Tetnor 

● Tevcodyne 

● Therazone 

● Ticinil 

● Todalgil 

● Uzone 

● VAC-10 

● Wescozone 

● Zolaphen 

● Zolidinum 

Last updated: 11 March 1998 
N-PHENYL-2-NAPHTHYLAMINE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 318) 

CAS No.: 135-88-6

Chem. Abstr. Name: N-Phenyl-2-naphthalenamine 

A. Evidence for carcinogenicity to humans (inadequate) 

No excess of bladder tumours was found among men in a rubber processing factory with known 

exposure to N-phenyl-2-naphthylamine (which contained small amounts of 2-naphthylamine); 

however, a study of rubber workers who were not exposed to 2-naphthylamine did show an 

increased incidence of bladder tumours. In the latter study, the men were exposed to several 

compounds, which probably included N-phenyl-2-naphthylamine [ref: 1]. 

B. Evidence for carcinogenicity to animals (limited) 

N-Phenyl-2-naphthylamine was tested for carcinogenicity by oral administration in mice, rats, 

hamsters and dogs. No carcinogenicity was reported in most experiments [ref: 1-4]. In one 

experiment, the total tumour incidence and the incidence of hepatocellular tumours were increased 

in male mice of one strain [ref: 1]. In another experiment, two rare kidney tumours were seen in 

female mice [ref: 2]. Subcutaneous administration to mice increased the total tumour incidence 

[ref: 1] and the incidences of lung [ref: 5] and liver neoplasms [ref: 1]. Repeated subcutaneous 

injection after previous unilateral nephrectomy in mice resulted in a significant increase in the total 

tumour incidence and in the incidences of haemangiosarcomas of the kidney and of carcinomas of 

the lung [ref: 6,7]. Following exposure of mice by inhalation in one study, lung carcinomas were 

reported [ref: 8]. 

C. Other relevant data

There is some evidence from one study of 19 human volunteers that up to 0.03% of a single 10-mg 

dose of N-phenyl-2-naphthylamine is converted to 2-naphthylamine. Similarly, the urine of workers 

exposed to N-phenyl-2-naphthylamine was found to contain 2-naphthylamine, indicating that Nphenyl-2-naphthylamine is dephenylated in the human body [ref:1]. No data were available on the 

genetic effects of N-phenyl-2-naphthylamine in humans. It was reported not to be mutagenic to 

bacteria [ref: 9]. 

Overall evaluation

N-Phenyl-2-naphthylamine is not classifiable as to its carcinogenicity to humans (Group 3). 

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 16 (1978)

References

1. IARC Monographs, 16, 325-341, 1978 

2. National Toxicology Program (1987) Technical Report on the Toxicology and Carcinogenesis 

Studies of N-Phenyl-2-naphthylamine (CAS No. 135-88-6) in F344/N Rats and B6C3F1 Mice (Feed 

Studies) (Tech. Rep. No. 333; NIH Publ. No. 87-2589), Research Triangle Park, NC 
3. Ketkar, M.B. & Mohr, U. (1982) The chronic effects of magenta, paramagenta and phenyl-β

-naphthylamine in rats after intragastric administration. Cancer Lett., 16, 203-206 

4. Green, U., Holste, J. & Spikermann, A.R. (1979) A comparative study of the chronic effects of 

magenta, paramagenta and phenyl-β-napthylamine in Syrian golden hamsters. J. Cancer Res. clin. 

Oncol., 95, 51-55 

5. Wang, H., Dzeng, R. & Wang, D. (1982) The carcinogenicity of N-phenyl-2-naphthylamine in ICR 

mice (Chin.). Acta biol. exp. sin., 15, 199-207 

6. Wang, D., Zeng, R. & Wang, H. (1983) A comparative study on carcinogenic activity of PBNA and 

PANA in unilaterally nephrectomized TA-1 mice (Chin.). Acta sci. circumst., 3, 262-266 

7. Wang, H., Wang, D. & Dzeng, R. (1984) Carcinogenicity of N-phenyl-1-naphthylamine and Nphenyl-2-naphthylamine in mice. Cancer Res., 44, 3098-3100 

8. You, X. & Yao, Y. (1981) Experimental study of inhalation carcinogenesis of N-phenyl-2-

naphthylamine aerosol on mice (Chin.). Acta biol. exp. sinica, 14, 139-143 

9. IARC Monographs, Suppl. 6, 461-462, 1987 

Synonyms

● Aceto PBN 

● Agerite powder 

● Age rite powder 

● Anilinonaphthalene 

● 2-Anilinonaphthalene 

● Antioxidant 116 

● Antioxidant PBN 

● N-(2-Naphthyl)aniline 

● 2-Naphthylphenylamine 

● β-Naphthylphenylamine 

● Neosone D 

● Neozon D 

● Neozone 

● Neozone D 

● Nilox PBNA 

● Nonox D 

● PBNA 

● 2-Phenylamino-naphthalene 

● Phenyl-2-naphthylamine 

● Phenyl(β-naphthyl)amine 

● Phenyl-β-naphthylamine 

● N-Phenyl-β-naphthylamine 

● Stabilizator AR 

Last updated: 11 March 1998 
POLYBROMINATED BIPHENYLS

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 321) 

Hexabromobiphenyl

CAS No.: 59080-40-9 

Octabromobiphenyl

CAS No.: 27858-07-7 

Decabromobiphenyl

CAS No.: 13654-09-6

A. Evidence for carcinogenicity to humans (inadequate) 

The mortality has been studied of a cohort of over 3500 male workers with potential exposure to 

several brominated compounds, including polybrominated biphenyls, who were employed between 

1935 and 1976 at chemical plants. Due to a lack of quantitative data, potential exposures of 

workers to polybrominated biphenyls were categorized as 'routine' and 'nonroutine'. Of the 91 

workers potentially exposed on a 'routine' basis, none died during the study period; among the 237 

'nonroutinely' exposed, two deaths were observed, with 6.4 expected, one of which was due to 

cancer of the large intestine [ref: 1]. 

B. Evidence for carcinogenicity to animals (sufficient) 

The carcinogenicity of a commercial preparation of polybrominated biphenyls (FireMaster FF-1, 

various lots), composed primarily of hexabromobiphenyl with smaller amounts of penta- and 

heptabrominated isomers, was tested by oral administration in mice and rats. In mice, it produced 

malignant liver tumours. In five studies in rats, it produced benign and malignant hepatic tumours, 

including cholangiocarcinomas, depending on the exposure conditions. Oral administration of 

polybrominated biphenyls enhanced the incidence of liver nodules induced by N-nitrosodiethylamine 

[ref: 2], but cutaneous application did not increase the incidence of skin tumours induced by 2-

acetylaminofluorene [ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of polybrominated biphenyls in humans.

Polybrominated biphenyls did not induce chromosomal aberrations in bone-marrow cells of rats or 

mice nor in rat spermatogonia and did not induce micronuclei in mice treated in vivo. They did not 

induce mutation in human or rodent cells in vitro or unscheduled DNA synthesis in rodent 

hepatocytes in vitro. Polybrominated biphenyls were not mutagenic to bacteria in vitro or in a hostmediated assay [ref: 3].

2,4,5,2',4',5'-Hexabromobiphenyl, 2,3,4,5,2',4',5'-heptabromobiphenyl and 2,3,4,5,2',3',4',5'-

octabromobiphenyl inhibited intercellular communication in Chinese hamster V79 cells; other 

congeners tested were only weakly active or were inactive [ref: 3]. 

Overall evaluation

Polybrominated biphenyls are possibly carcinogenic to humans (Group 2B).
For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 18 (1978); Vol. 41 (1986)

References

1. IARC Monographs, 41, 261-292, 1986

2. Jensen, R.K. & Sleight, S.D. (1986) Sequential study on the synergistic effects of 2,2',4,4',5,5'-

hexabromobiphenyl and 3,3',4,4',5,5'-hexabromobiphenyl on hepatic tumour promotion. 

Carcinogenesis, 7, 1771-1774

3. IARC Monographs, Suppl. 6, 466-468, 1987 

Synonym for Hexabromobiphenyl [technical grade]

● Hexabromodiphenyl 

Synonym for Octabromobiphenyl [technical grade]

● Bromkal 80 

Synonyms for Decabromobiphenyl [technical grade]

● Adine 0102 

● Berkflam B-10 

● Decabromodiphenyl 

● Flammex B-10 

● Perbromobiphenyl 

Last updated: 3 March 1998 
POLYCHLORINATED BIPHENYLS

(Group 2A)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 322) 

CAS No.: 1336-36-3

Chem. Abstr. Name: Polychlorinated Biphenyls 

Biphenyl:

CAS No.: 92-52-4 

Chem. Abstr. Name: 1,1'-Biphenyl 

2-Chlorobiphenyl:

CAS No.: 2051-60-7 

Chem. Abstr. Name: 2-Chloro-1,1'-biphenyl 

4-Chlorobiphenyl:

CAS No.: 2051-62-9 

Chem. Abstr. Name: 4-Chloro-1,1'-biphenyl 

2,2'-Dichlorobiphenyl:

CAS No.: 13029-08-8 

Chem. Abstr. Name: 2,2'-Dichloro-1,1'-biphenyl 

2,3'-Dichlorobiphenyl:

CAS No.: 25569-80-6 

Chem. Abstr. Name: 2,3'-Dichloro-1,1'-biphenyl 

2,4'-Dichlorobiphenyl:

CAS No.: 34883-43-7 

Chem. Abstr. Name: 2,4'-Dichloro-1,1'-biphenyl 

4,4'-Dichlorobiphenyl:

CAS No.: 2050-68-2 

Chem. Abstr. Name: 4,4'-Dichloro-1,1'-biphenyl 

2,2',3-Trichlorobiphenyl:

CAS No.: 38444-78-9

Chem. Abstr. Name: 2,2',3-Trichloro-1,1'-biphenyl 

2,2',5-Trichlorobiphenyl:

CAS No.: 37680-65-2

Chem. Abstr. Name: 2,2',5-Trichloro-1,1'-biphenyl 

2,3',4-Trichlorobiphenyl:

CAS No.: none available 

Chem. Abstr. Name: 2,3',4-Trichloro-1,1'-biphenyl 

2',3,4-Trichlorobiphenyl:

CAS No.: 38444-86-9 

Chem. Abstr. Name: 2',3,4-Trichloro-1,1'-biphenyl 

2,4,4'-Trichlorobiphenyl:

CAS No.: 7012-37-5 
Chem. Abstr. Name: 2,4,4'-Trichloro-1,1'-biphenyl 

2,4',5-Trichlorobiphenyl:

CAS No.: 16606-02-3 

Chem. Abstr. Name: 2,4',5-Trichloro-1,1'-biphenyl 

2,2'3,5'-Tetrachlorobiphenyl:

CAS No.: 41464-39-5

Chem. Abstr. Name: 2,2',3,5'-Tetrachloro-1,1'-biphenyl 

2,2',4,5'-Tetrachlorobiphenyl:

CAS No.: 41464-40-8 

Chem. Abstr. Name: 2,2',4,5'-Tetrachloro-1,1'-biphenyl 

2,2',5,5'-Tetrachlorobiphenyl:

CAS No.: 35693-99-3 

Chem. Abstr. Name: 2,2',5,5'-Tetrachloro-1,1'-biphenyl 

2,3,4,4'-Tetrachlorobiphenyl:

CAS No.: 33025-41-1

Chem. Abstr. Name: 2,3,4,4'-Tetrachloro-1,1'-biphenyl 

2,3',4,4'-Tetrachlorobiphenyl:

CAS No.: 32598-10-0 

Chem. Abstr. Name: 2,3',4,4'-Tetrachloro-1,1'-biphenyl 

2,3',4',5-Tetrachlorobiphenyl:

CAS No.: 32598-11-1 

Chem. Abstr. Name: 2,3',4',5-Tetrachloro-1,1'-biphenyl 

3,3',4,4'-Tetrachlorobiphenyl:

CAS No.: 32598-13-3 

Chem. Abstr. Name: 3,3',4,4'-Tetrachloro-1,1'-biphenyl 

2,2',3,3',6-Pentachlorobiphenyl:

CAS No.:52663-60-2 

Chem. Abstr. Name: 2,2',3,3',6-Pentachloro-1,1'-biphenyl 

2,2',3,4,5'-Pentachlorobiphenyl:

CAS No.: 38380-02-8

Chem. Abstr. Name: 2,2',3,4,5'-Pentachloro-1,1'-biphenyl 

2,2',3',4,5-Pentachlorobiphenyl:

CAS No.: 41464-51-1

Chem. Abstr. Name: 2,2',3'4,5-Pentachloro-1,1'-biphenyl 

2,2',3,4',6-Pentachlorobiphenyl:

CAS No.: none available 

Chem. Abstr. Name: 2,2',3,4',6-Pentachloro-1,1'-biphenyl 

2,2',3,5',6-Pentachlorobiphenyl:

CAS No.: 38379-99-6 

Chem. Abstr. Name: 2,2',3,5',6-Pentachloro-1,1'-biphenyl 

2,2',4,4',5-Pentachlorobiphenyl:

CAS No.: 38380-01-7 

Chem. Abstr. Name: 2,2',4,4',5-Pentachloro-1,1'-biphenyl 
2,2',4,5,5'Pentachlorobiphenyl:

CAS No.: 37680-73-2 

Chem. Abstr. Name: 2,2',4,5,5'-Pentachloro-1,1'-biphenyl 

2,3,3',4,4'-Pentachlorobiphenyl:

CAS No.: 32598-14-4 

Chem. Abstr. Name: 2,3,3',4,4'-Pentachlorol-1,1'-biphenyl 

2,3,3',4',6-Pentachlorobiphenyl:

CAS No.: 38380-03-9

Chem. Abstr. Name: 2,3,3',4',6-Pentachlorol-1,1'-biphenyl 

2,3',4,4',5-Pentachlorobiphenyl:

CAS No.:31508-00-6 

Chem. Abstr. Name: 2,3',4,4',5-Pentachlorol-1,1'-biphenyl 

2,2',3,3',4,6-Hexachlorobiphenyl:

CAS No.: 38380-05-1

Chem. Abstr. Name: 2,2',3,3',4,6-Hexachloro-1,1'-biphenyl 

2,2', 3,3',6,6'-Hexachlorobiphenyl:

CAS No.: 38411-22-2 

Chem. Abstr. Name: 2,2',3,3',6,6'-Hexachloro-1,1'-biphenyl 

2,2',3,4,4',5-Hexachlorobiphenyl:

CAS No.: 35694-06-5 

Chem. Abstr. Name: 2,2',3,4,4',5-Hexachloro-1,1'-biphenyl 

2,2',3,4,4',5'-Hexachlorobiphenyl:

CAS No.: 35065-28-2 

Chem. Abstr. Name: 2,2',3,4,4',5'-Hexachloro-1,1'-biphenyl 

2,2',3',4,5,6'-Hexachlorobiphenyl:

CAS No.: 38380-04-0

Chem. Abstr. Name: 2,2',3',4,5,6'-Hexachloro-1,1'-biphenyl 

2,2',4,4',5,5'-Hexachlorobiphenyl:

CAS No.: 35065-27-1

Chem. Abstr. Name: 2,2',4,4',5,5'-Hexachloro-1,1'-biphenyl 

2,2',3,3',4,4',5-Heptachlorobiphenyl:

CAS No.: 35065-30-6 

Chem. Abstr. Name: 2,2',3,3',4,4',5-Heptachloro-1,1'-bipheny 

2,2',3,3',4,5,6'-Heptachlorobiphenyl:

CAS No.: 38441-25-5

Chem. Abstr. Name: 2,2',3,3',4,5,6'-Heptachloro-1,1'-biphenyl 

2,2',3,4,4',5,5'-Heptachlorobiphenyl:

CAS No.: 35065-29-3

Chem. Abstr. Name: 2,2',3,4,4',5,5'Heptachloro-1,1'-biphenyl 

A. Evidence for carcinogenicity to humans (limited)

Information on the possible carcinogenic risk of human exposure to polychlorinated biphenyls (PCBs) 

comes from studies of occupational populations and of populations exposed to the compounds 
accidentally. PCB mixtures may be contaminated with polychlorinated dibenzofurans and 

polychlorinated dibenzodioxins.

A slight increase in the incidence of cancer, particularly melanoma of the skin, was reported in a 

small group of men exposed to Aroclor 1254, a mixture of PCBs [ref: 1]. In a study of over 2500 US 

workers exposed to a similar mixture of PCBs during the manufacture of electrical capacitors, five 

deaths due to cancer of the liver and biliary passages were observed, whereas 1.9 would have been 

expected. This increase was sustained mainly by female workers in one of the two plants in the 

study (four of the five deaths), and all five had first been employed before the early 1950s [ref: 

2,3]. Another study of workers in a capacitor plant was conducted in Italy. Exposure in the early 

years of production (until 1964) was to PCB mixtures containing 54% chlorine (mainly Aroclor 1254 

and Pyralene 1476), which were later replaced by mixtures containing 42% chlorine (mainly 

Pyralene 3010 and 3011). Early results showed a significant excess of all cancers among male 

workers, which was due mainly to cancers of the digestive system and of the lymphatic and 

haematopoietic tissues. Among female workers, a slight increase in mortality from cancer of the 

lymphatic and haematopoietic tissues was reported [ref: 4]. The study was later enlarged and 

extended to include 2100 workers and to cover the period 1946-1982. Both male and female 

workers exhibited significantly increased cancer mortality in comparison with rates for the local 

population (14 observed, 7.6 expected; and 12 and 5.3, respectively, for men and women). Among 

male workers, cancers of the gastrointestinal tract (two stomach, two pancreas, one liver and one 

biliary passages) taken together were significantly increased (6 observed, 2.2 expected). Female 

workers showed a significant increase in deaths from haematological neoplasms (4 observed, 1.1 

expected) [ref: 5]. In Sweden, among 142 male workers employed between 1965 and 1978 in a 

capacitor manufacturing plant when PCB mixtures containing up to 42% chlorine had been used, no 

significant excess of cancer deaths was noted. Cancer incidence was also examined: the number of 

cases observed corresponded well to that expected. One individual in a subgroup with higher 

exposure developed two relatively rare tumours, both of which occurred ten years after the start of 

exposure: a slow-growing mesenchymal tumour (desmoid) and a malignant lymphoma [ref: 6].

After contamination of cooking oil with a mixture of PCBs (Kanechlor 400) in Japan in 1968, a large 

population was intoxicated ('Yusho' disease). An early report on mortality from 1963-1983 showed a 

significantly increased risk of all cancers, and an almost five-fold significantly elevated risk of 

primary liver cancer. The edible rice oil had also been contaminated by polychlorinated 

quaterphenyls and polychlorinated dibenzofurans. Dose-response relationships were not clarified 

[ref: 7]. A further comprehensive study of 887 male 'Yusho' patients showed statistically 

significantly increased mortality from all malignancies (33 observed, 15.5 expected), from liver 

cancer (9 observed, 1.6 expected) and from lung cancer (8 observed, 2.5 expected). Use of local 

rather than national rates in calculating expected number of deaths decreased the 

observed:expected ratio for liver cancer from 5.6 to 3.9, which was still statistically significant. A 

closer look at the geographical distribution of liver cancer cases did not allow exclusion of factors 

other than PCB poisoning as a possible explanation for this finding. For the 874 female patients 

examined, none of the noted observed:expected ratios was significant [ref: 8]. In a series of ten 

autopsies of 'Yusho' patients, two adenocarcinomas of the liver were found, with no indication of a 

direct association with exposure to PCBs [ref: 9]. Ultrasonic and tumour marker examination of two 

series of 79 and 125 patients with 'Yusho' disease in 1983 and 1984, respectively, did not reveal any 

case of hepatic-cell carcinoma [ref: 10]. Two studies of the PCB content of fat tissues and cancer 

occurrence were available. An association was suggested between PCB concentrations in 

subcutaneous abdominal adipose tissue and the occurrence of cancers of the stomach, colon, 

pancreas, ovaries and prostate [ref: 11]. No indication emerged of a relationship between PCB 

content in extractable breast fat tissue and the occurrence of breast cancer [ref: 12].

The available studies suggest an association between cancer and exposure to PCBs. The increased 

risk from hepatobiliary cancer emerged consistently in different studies. Since, however, the 

numbers were small, dose-response relationships could not be evaluated, and the role of compounds 

other than PCBs could not be excluded, the evidence was considered to be limited. 

B. Evidence for carcinogenicity to animals (sufficient)

Certain PCBs (particularly with greater than 50% chlorination) produced benign and malignant liver 

neoplasms in mice and rats after their oral administration [ref: 1,13,14]. Oral administration of 

Aroclor 1254 to rats yielded hepatocellular adenomas and carcinomas as well as intestinal 

metaplasia and a low, not statistically significant incidence of stomach adenocarcinomas [ref: 15]. 
PCBs were inadequately tested in mice for induction of skin tumours [ref: 16,17]. In several studies, 

oral or intraperitoneal administration of PCBs enhanced the incidences of preneoplatic lesions [ref: 

18-20] and of neoplasms [ref: 21,22] of the liver induced in rats by N-nitrosodiethylamine or 2-

acetylaminofluorene. In one study, intragastric administration of PCBs to mice increased the 

incidence of lung tumours induced by intraperitoneal administration of N-nitrosodimethylamine [ref: 

23]. 

C. Other relevant data

No data were available on the genetic and related effects of PCBs in humans.

Dominant lethal effects were not induced in rats administered PCBs orally, but were produced in rats 

nursed by females that had received PCBs orally. PCBs did not induce chromosomal aberrations in 

bone-marrow cells or spermatagonia of rats treated in vivo; micronuclei were not induced in bonemarrow cells of mice in one study, while equivocal results were obtained in a second study in which 

the PCBs were administered in corn oil. They did not transform Syrian hamster embryo cells in vitro. 

PCBs induced DNA strand breaks and unscheduled DNA synthesis in rat hepatocytes in vitro. Neither 

chromosomal breakage nor aneuploidy was induced in Drosophila. PCB mixtures did not induce SOS 

repair and were not mutagenic to bacteria [ref: 24].

2,2',5,5'-Tetrachlorophenyl induced DNA strand breaks in mouse cells in vitro. 2,4,5,2',4',5'-

Hexachlorobiphenyl but not 3,4,5,3',4',5'-hexachlorobiphenyl inhibited intercellular communication in 

Chinese hamster V79 cells. Purified 2,4,2',4'-, 2,5,2',5'- and 3,4,3',4'-tetrachloro- and 2,4,6,2',4',6'-

hexachlorobiphenyl were not mutagenic to bacteria [ref: 24]. 

Overall evaluation

Polychlorinated biphenyls are probably carcinogenic to humans (Group 2A).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 7 (1974); Vol. 18 (1978)

References

1. IARC Monographs, 18, 43-103, 1978

2. Brown, D.P. & Jones, M. (1981) Mortality and industrial hygiene study of workers exposed to 

polychlorinated biphenyls. Arch. environ. Health, 36, 120-129

3. Brown, D.P. (1987) Mortality of workers exposed to polychlorinated biphenyls. An update. Arch. 

environ. Health (in press)

4. Bertazzi, P.A., Zocchetti, C., Guercilena, S., Della Foglia, M., Pesatori, A. & Riboldi, L. (1982) 

Mortality study of male and female workers exposed to PCB's. In: Proceedings of the International 

Symposium on Prevention of Occupational Cancer, Helsinki, 1981, Geneva, International Labour 

Office, pp. 242-248

5. Bertazzi, P.A., Riboldi, L., Pesatori, A., Radice, L. & Zocchetti, C. (1987) Cancer mortality of 

capacitor manufacturing workers. Am. J. ind. Med., 11, 165-176

6. Gustavsson, P., Hogstedt, C. & Rappe, C. (1986) Short-term mortality and cancer incidence in 

capacitor manufacturing workers exposed to polychlorinated biphenyls (PCBs). Am. J. ind. Med., 10, 

341-344

7. Umeda, G. (1984) Studies on long-term effects of PCBs on human body: mortality from primary 
liver cancer and prevalence of ischemic heart disease (Abstract No. 19.8). In: Eustace, I.E., ed., 

Proceedings of the XXI International Congress on Occupational Health, Dublin, 1984, p. 166

8. Kuratsune, M., Nakamura, Y., Ikeda, M. & Hirohata, T. (1986) Analysis of deaths seen among 

patients with Yusho (Abstract FL17). In: Dioxin 86. Proceedings of the VI International Symposium 

on Chlorinated Dioxins and Related Compounds, Fukuoka, Japan, 1986, p. 179

9. Kikuchi, M. (1984) Autopsy of patients with Yusho. Am. J. ind. Med., 5, 19-30

10. Okumura, M. & Sakaguchi, S. (1985) Hepatic cell carcinoma and the patients with Yusho (Jpn.). 

Fukuoka Igaku Zasshi, 76, 229-232

11. Unger, M., Olsen, J. & Clausen, J. (1982) Organochlorine compounds in the adipose tissue of 

deceased persons with and without cancer: a statistical survey of some potential confounders. 

Environ. Res., 29, 371-376

12. Unger, M., Kiaer, H., Blichert-Toft, M., Olsen, J. & Clausen, J. (1984) Organochlorine compounds 

in human breast fat from deceased persons with and without breast cancer and in a biopsy material 

from newly diagnosed patients undergoing breast surgery. Environ. Res., 34, 24-28

13. Norback, D.H. & Weltman, R.H. (1985) Polychlorinated biphenyl induction of hepatocellular 

carcinoma in the Sprague-Dawley rat. Environ. Health Perspect., 60, 97-105

14. Schaeffer, E., Greim, H. & Goessner, W. (1984) Pathology of chronic polychlorinated biphenyl 

(PCB) feeding in rats. Toxicol. appl. Pharmacol., 75, 278-288

15. Ward, J.M. (1985) Proliferative lesions of the glandular stomach and liver in F344 rats fed diets 

containing Aroclor 1254. Environ. Health Perspect., 40, 89-95

16. DiGiovanni, J., Viaje, A., Berry, D.L., Slaga, T.J. & Juchau, M.R. (1977) Tumor-initiating ability of 

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and Aroclor 1254 in the two-stage system of mouse skin 

carcinogenesis. Bull. environ. Contam. Toxicol., 18, 552-557

17. Hori, M., Fujita, K., Yamashiro, K., Toriyama, F., Hirose, R., Shukuwa, T., Toyoshima, H. & 

Yoshida, H. (1985) Methylcholanthrene induced mouse skin cancer. Fukuoka Igaku Zasshi, 76, 208-

214

18. Pereira, M.A., Herren, S.L., Britt, A.L. & Khoury, M.M. (1982) Promotion by polychlorinated 

biphenyls of enzyme-altered foci in rat liver. Cancer Lett., 15, 185-190

19. Buchmann, A., Kunz, W., Wolf, C.R., Oesch, F. & Robertson, L.W. (1986) Polychlorinated 

biphenyls, classified as either phenobarbital or 3-methylcholanthrene-type inducers of cytochrome P450, are both hepatic tumor promoters in diethylnitrosamine-initiated rats. Cancer Lett., 32, 243-

253

20. Tatematsu, M., Nakanishi, K., Murasaki, G., Miyata, Y., Hirose, M. & Ito, N. (1979) Enhancing 

effect of inducers of liver microsomal enzymes on induction of hyperplastic liver nodules by N-2-

fluorenylacetamine in rats. J. natl Cancer Inst., 63, 1411-1416

21. Nishizumi, M. (1979) Effect of phenobarbital, dichlorodiphenyltrichloroethane, and 

polychlorinated biphenyls on diethylnitrosamine-induced hepatocarcinogenesis. Gann, 70, 835-837

22. Preston, B.D., Van Miller, J.P., Moore, R.W. & Allen, J.R. (1981) Promoting effects of 

polychlorinated biphenyls (Aroclor 1254) and polychlorinated dibenzofuran-free Aroclor 1254 on 

diethylnitrosamine-induced tumorigenesis in the rat. J. natl Cancer Inst., 66, 509-515
23. Anderson, L.M., Ward, J.M., Fox, S.D., Isaaq, H.J. & Riggs, C.W. (1986) Effects of a single dose 

of polychlorinated biphenyls to infant mice on N-nitrosodimethylamine-initiated lung and liver 

tumors. Int. J. Cancer, 38, 109-116

24. IARC Monographs, Suppl. 6, 469-471, 1987 

Synonyms for Polychlorinated biphenyls:

● Chlorinated biphenyl 

● Chlorinated diphenyl 

● Chlorobiphenyl 

● PCB 

● PCBs 

● Polychlorinated biphenyl 

● Polychlorobiphenyl 

Trade names for Polychlorinated biphenyls (The producing country is given in parentheses):

● Aroclor (USA) 

● Chlorextol (USA) 

● Clophen (FRG) 

● Dykanol (USA) 

● Fenclor (Italy) 

● Inerteen (USA) 

● Kanechlor (Japan) 

● Noflamol (USA) 

● Phenoclor (France) 

● Pyralene (as formulated, no longer contains PCBs) (France) 

● Pyranol (USA) 

● Santotherm (Japan) 

● Sovol (USSR) 

● Therminol (USA) 

Last updated: 11 February 1998 
PREDNISONE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 326) 

CAS No.: 53-03-2

Chem. Abstr. Name: Pregna-1,4-diene-3,11,20-trione, 17,21-dihydroxyA. Evidence for carcinogenicity to humans (inadequate) 

Many case reports of cancer include a mention of previous treatment with prednisone, as would be 

expected by chance alone in view of the very wide use of this drug in many different disorders. 

Prednisone is a common drug, prescribed for long periods in the treatment of many chronic 

conditions [ref: 1]. Patients treated with prednisone for rheumatoid arthritis appear to have, if 

anything, a lower than expected cancer risk. Over an average follow-up period of 12 years, 11% of 

153 deaths that occurred in patients who had received prednisone were due to malignancies, 

compared to 20% of 74 deaths among patients who had not received prednisone [ref: 2]. The 

strong link between combination therapy for Hodgkin's disease and subsequent second malignancies 

(see summary of data on MOPP and other chemotherapy including alkylating agents) is much more 

plausibly explained on the basis of concurrent administration of clearly carcinogenic agents than of 

prednisone. 

A study of cancers that appeared within four years after documented use of common drugs showed 

that prednisone was among the 53 (of 95) drugs associated positively with cancer at least once. 

However, the excess consisted of 12 cases of lung cancer (31 observed, 19 expected), known to be 

largely related to cigarette smoking (which was not measured) and known to occur after a latent 

period much longer than the interval under observation. Of more interest is the absence of those 

neoplasms, such as acute nonlymphocytic leukaemia and non-Hodgkin's lymphoma, which have 

been linked to chemotherapy and immunosuppression [ref: 3]. 

Thus, the evidence for a carcinogenic action of prednisone was not compelling. The evidence did 

not, however, 'suggest lack of carcinogenicity', because there is no well-designed analytical study of 

prednisone alone. 

B. Evidence for carcinogenicity to animals (inadequate) 

Prednisone was tested for carcinogenicity in mice and rats by intraperitoneal administration. A 

significant increase in the total number of tumours was reported in female rats, but the study 

suffered from limitations in both design and reporting [ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of prednisone in humans. It did not induce 

chromosomal aberrations in bone-marrow cells of rats treated in vivo. It was not mutagenic to 

bacteria [ref: 4]. 

Overall evaluation

Prednisone is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 26 (1981)
References

1. IARC Monographs, 26, 293-309, 1981 

2. Fries, J.F., Bloch, D., Spitz, P. & Mitchell, D.M. (1985) Cancer in rheumatoid arthritis: a 

prospective long-term study of mortality. Am. J. Med., 78 (Suppl. 1A), 56-59 

3. Friedman, G.D. & Ury, H.K. (1980) Initial screening for carcinogenicity of commonly used drugs. 

J. natl Cancer Inst., 65, 723-733 

4. IARC Monographs, Suppl. 6, 472-473, 1987 

Synonyms

● Adasone 

● Alto-pred 

● Ancortone 

● Ancotone 

● Antison 

● Benison 

● Bicortone 

● Bidelta 

● Buffacort 

● Co-deltra 

● Colisone 

● Cortancyl 

● Cortane 

● Cortialer 

● Corticor 

● Cortidelt 

● Cortinter 

● Cortiol 

● Cortisid 

● Dabroson 

● Dacortin 

● Decortancyl 

● Decortin 

● Decortisyl 

● Decorton 

● Dehydrocortisone 

● 1-Dehydrocortisone 

● 1,2-Dehydrocortisone 

● 17,21-Dehydrocortisone 

● Deidrocortisone 

● Dekortin 

● Delco-Cortex 

● Delcort 

● Delcortin 

● δ-Corlin 

● δ-Cortelan 

● Deltacortene 

● Deltacortisone 

● δ-Cortisone 

● δ1-Cortisone 

● Deltacortisyl 

● Deltacortone 

● δ1-Dehydrocortisone 

● δ-Dome 

● δ E 

● Deltalone 

● Deltasone 
● Deltasson 

● Deltastendiolo 

● Deltatrione 

● Deltison 

● Deltisone 

● Deltra 

● Di-Adreson 

● 17,21-Dihydroxy-pregna-1,4-diene-3,11,20-trione 

● 17alpha,21-Dihydroxy-1,4-pregnadiene-3,11,20-trione 

● 17,21-Dihydroxypregna-1,4-diene-3,11,20-trione 

● 17α,21-Dihydroxypregna-1,4-diene-3,11,20-trione 

● 17,21-Dihydroxypregn-1,4-diene-3,11,20-trione 

● Dispersona 

● Ejizon 

● Encorton 

● Encortone 

● Enkorton 

● Erftopred 

● Fernisone 

● Fernisone buffered 

● Fiasone 

● Hicorton 

● Homozol 

● Hostacortin 

● Idrosone 

● Inocortyl 

● In-sone 

● Intalsone 

● Juvason 

● Keteocort 

● Keysone 

● Kolpisone 

● Leocortine-D 

● Lisacort 

● Marnisonal 

● Marsone 

● Marvidiene 

● Marvisona 

● Mediasone 

● Me-Korti 

● Meprison 

● Metacortandracin 

● Metacortin 

● Metasone 

● Meticortem 

● Meticorten 

● Meticortene 

● Metisone 

● Metreton 

● Neoaltesona 

● Nisone 

● Nizon 

● Novoprednisone 

● NSC 10023 

● Nurison 

● Orasone 

● Panafcort 

● Paracort 

● Parmenison 

● Precortal 

● Predeltin 

● Predni-artrit 

● Prednicen-M 

● Prednicorm 

● Prednifor 
● Prednilong 

● Prednilonga 

● Predniment 

● Predniseguer 

● Prednisol 

● Predni-tablinen 

● Prednital 

● Prednison 

● Predni-wolner 

● Prednizon 

● Prednovister 

● Predorgasona 

● Predsol 

● Predsone 

● 1,4-Pregnadiene-17α,21-diol-3,11,20-trione 

● δ-Prenovis 

● Presone 

● Pronison 

● Propred 

● Rectodelt 

● Retrocortin 

● Ropred 

● δ-Scheroson 

● Servisone 

● Solisone 

● Sone 

● Sterapred 

● Supercortil 

● Supernisona 

● Supopred 

● Taracorten 

● Ultracorten 

● Ultracortene 

● Ultrilone 

● Urtilone 

● Vitazon 

● Wescopred 

● Winpred 

● Xynisone 

● Zenidrid 

Last updated: 11 March 1998 
PROCARBAZINE HYDROCHLORIDE

(Group 2A)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 327) 

CAS No.: 366-70-1

Chem. Abstr. Name: Benzamide, N-(1-methylethyl)-4-[(2-methylhydrazino)-methyl]-, 

monohydrochloride 

A. Evidence for carcinogenicity to humans (inadequate)

No epidemiological study of procarbazine as a single agent was available to the Working Group. In 

various combinations with other chemotherapeutic agents, given for Hodgkin's disease, 

procarbazine use has repeatedly been shown to lead to the appearance of acute nonlymphocytic 

leukaemia. These combinations usually also include nitrogen mustard, an alkylating agent which is 

also a potent animal carcinogen, and these many observations do not permit conclusions about the 

independent effect of either drug [ref: 1]. 

B. Evidence for carcinogenicity to animals (sufficient)

Procarbazine hydrochloride administered by repeated intraperitoneal injections produced malignant 

tumours of the nervous system and haematopoietic system in mice and rats of each sex and 

adenocarcinomas of the mammary gland in rats only [ref: 1]. Repeated intravenous injections 

induced malignant tumours in different organs of rats [ref: 1]. Oral administration produced 

pulmonary tumours and leukaemias in mice [ref: 1,2] and mammary tumours in rats [ref: 1,3]. 

Leukaemias, haemangioendothelial sarcomas and osteogenic sarcomas were induced in rhesus, 

cynomolgus and African green monkeys of each sex by intraperitoneal, subcutaneous, intravenous 

or oral administration of procarbazine hydrochloride [ref: 1,4]. 

C. Other relevant data

Procarbazine generates an alkylating species [ref: 1].

No data were available on the genetic and related effects of procarbazine hydrochloride in humans.

Procarbazine gave positive results for germinal mutation in the mouse specific-locus test and caused 

mutation in the mouse spot test. It induced micronuclei and structural chromosomal aberrations in 

mice treated in vivo, but conflicting results were obtained in tests for dominant lethal mutations and 

negative results in the heritable-translocation test. It induced sister chromatid exchanges in mice 

and Chinese hamsters and caused DNA damage in rodents treated in vivo. Procarbazine did not 

transform Syrian hamster embryo cells. It induced mutation but not sister chromatid exchanges in 

rodent cells in vitro. It induced aneuploidy, dominant lethal mutations, sex-linked recessive lethal 

mutations and somatic mutation and recombination in Drosophila, but did not cause heritable 

translocations. It induced mutation, gene conversion and mitotic recombination in fungi. Conflicting 

results were obtained for mutation in bacteria, both in vitro and in host-mediated assays; it induced 

DNA damage in bacteria [ref: 5]. 

Overall evaluation

Procarbazine hydrochloride is probably carcinogenic to humans (Group 2A).

For definition of the italicized terms, see Preamble Evaluation.
Also see previous evaluation: Vol. 26 (1981)

References

1. IARC Monographs, 26, 311-339, 1981

2. Bacci, M., Cavaliere, A. & Fratini, D. (1982) Lung carcinogenesis by procarbazine chlorate in 

BALB/c mice. Carcinogenesis, 3, 71-73

3. Bacci, M., Cavaliere, A. & Amorosi, A. (1984) Procarbazine hydrochlorate carcinogenesis in 

Osborne-Mendel rats. Oncology, 41, 106-108

4. Adamson, R.H. & Sieber, S.M. (1982) Studies on the oncogenicity of procarbazine and other 

compounds in nonhuman primates. In: Rosenberg, S. & Kaplan, H., eds, Malignant Lymphomas: 

Etiology, Immunology, Pathology, Treatment (Bristol-Myers Cancer Symposia Series Vol. 3), 

Orlando, FL, Academic Press, pp. 239-257

5. IARC Monographs, Suppl. 6, 474-478, 1987 

Synonyms

● Ibenzmethyzin hydrochloride 

● Ibenzmethyzine hydrochloride 

● IBZ 

● N-4-Isopropylcarbamoylbenzyl-N'-methylhydrazine hydrochloride 

● 2-[para-(Isopropylcarbamoyl)benzyl]-1-methylhydrazine hydrochloride 

● N-Isopropyl-para-(2-methyl-hydrazinomethyl)benzamide hydrochloride 

● N-Isopropyl-α-(2-methylhydrazino)-para-toluamide monohydrochloride 

● MBH 

● para-(N1-Methylhydrazino-methyl)-N-isopropylbenzamide hydrochloride 

● 1-Methyl-2-[para-(isopropylcarbamoyl)benzyl]hydrazine hydrochloride 

● 1-Methyl-2-para-(isopropylcarbamoyl)benzylhydrazine hydrochloride 

● MIH 

● Matulane 

● Natulanar 

● Natulan 

● NSC 77213 

● PRO 

● Ro 4-6467 

● Ro 46467/1 

Last updated: 11 February 1998 
PROGESTINS

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 289) 

Medroxyprogesterone acetate

CAS No.: 71-58-9

Chem. Abstr. Name: (6α)-17-(Acetyloxy)-6-methylpregn-4-ene-3,20-dione 

A. Evidence for carcinogenicity to humans (inadequate)

The results of one cross-sectional study of the development of breast nodules in women given 

medroxyprogesterone acetate was difficult to interpret because of methodological considerations 

[ref: 1]. Two small cohort studies in the USA showed relative risks (and 95% confidence limits) of 

breast cancer in women exposed to medroxyprogesterone acetate of 0.69 (0.3-1.4) [ref: 2] and 1.1 

(0.5-2.4) [ref: 3], but both included only women with short-term exposure and limited duration of 

follow-up. A case-control study of 30 women with breast cancer and 179 controls [ref: 4] yielded a 

relative risk of 1.0 (no confidence limits given) for use of medroxyprogesterone acetate at some 

time. Preliminary analyses of a collaborative case-control study in Thailand, Kenya and Mexico 

sponsored by the World Health Organization [ref: 5], based on 427 cases (39 'ever' users) and 5951 

controls (557 'ever' users), provided estimates of relative risk (and 95% confidence limits) for breast 

cancer of 1.0 (0.7-1.5) in women who 'ever' used medroxyprogesterone acetate, 1.1 (0.7-1.9) for 

users for 1-12 months, 1.2 (0.7-2.2) for users for 13-36 months and 0.8 (0.4-1.7) for users for 37 

months or more.

Medroxyprogesterone acetate causes reversible changes in the endometrium, from proliferative to 

secretory or suppressed [ref: 4]. In one small cohort study, one case of uterine leiomyosarcoma was 

found, with 0.83 cancers of the uterine corpus expected, giving a relative risk of 1.2 [0.03-6.7] [ref: 

2]. In the collaborative study [ref: 5], the estimated a relative risk for endometrial cancer in 'ever' 

users of medroxyprogesterone acetate was 0.3 (0.04-2.4), based on 57 cases, only one of which 

was exposed, and 316 matched controls (30 exposed).

In the small cohort study [ref: 2], one ovarian cancer case occurred in a medroxyprogesterone 

acetate user, with 1.16 expected, giving a relative risk of 0.86 [0.02-4.6]. Preliminary analysis of 

data from the collaborative study [ref: 5], based on 105 cases (seven exposed) and 637 matched 

controls (74 exposed) yielded a relative risk for ovarian cancer of 0.7 (0.3-1.7) in 'ever' users of 

medroxyprogesterone acetate.

The results of two cohort studies of dysplasia and of carcinoma in situ of the uterine cervix in women 

given medroxyprogesterone acetate were conflicting and difficult to interpret because of 

methodological problems [ref: 1]. Preliminary results from the collaborative study [ref: 5], based on 

920 cases of invasive cervical carcinoma (126 exposed to medroxyprogesterone acetate) and 5833 

controls (545 exposed) yielded estimated relative risks of 1.2 (0.9-1.5) in 'ever' users, after 

controlling for parity, history of vaginal discharge, age at first sexual relationship, number of sexual 

partners, number of prior Pap smears and use of an intrauterine device and oral contraceptives. 

Relative risks in users for 1-12, 13-24, 25-60 and 61 months or more were estimated to be 1.4 (1.0-

2.0), 1.2 (0.7-2.0), 0.6 (0.4-1.1) and 1.4 (0.9-2.2), respectively.

Preliminary analyses of data from the collaborative study [ref: 5] showed the relative risk for 

primary liver cancer (all histological types combined) in women who had ever used 

medroxyprogesterone acetate to be 1.0 (0.4-2.8), based on 57 cases (seven exposed) and 290 

controls (34 exposed). 

B. Evidence for carcinogenicity to animals (sufficient)
Medroxyprogesterone acetate was tested by intramuscular injection in dogs and by subcutaneous 

implantation in mice. It induced adenocarcinomas of the mammary gland in one study in female 

mice [ref: 6], and produced malignant mammary tumours in dogs [ref: 1]. After four years of 

intramuscular treatment of dogs with a human contraceptive dose, a dose-related increase in the 

incidence of mammary nodules was seen; the incidence of mammary-gland nodules at that time was 

comparable with that seen in dogs given progesterone at 25 times the canine luteal level [ref: 7]. 

Female dogs treated with medroxyprogesterone acetate for at least one year had a significant 

increase in the incidence of large and small mammary nodules as compared with control animals in 

one study [ref: 8], and a dose-related increase in the incidence of large mammary nodules was 

found in another after intramuscular administration [ref: 9]. 

C. Other relevant data

No data were available on the genetic and related effects of medroxyprogesterone acetate alone in 

humans. See, however, the summary of data for combined oral contraceptives. 

Medroxyprogesterone acetate induced sister chromatid exchanges in mouse cells in vitro. 

References

1. IARC Monographs, 21, 417-429, 1979

2. Liang, A.P., Levenson, A.G., Layde, P.M., Shelton, J.D., Hatcher, R.A., Potts, M. & Michelson, M.J. 

(1983) Risk of breast, uterine corpus, and ovarian cancer in women receiving medroxyprogesterone 

injections. J. Am. med. Assoc., 249, 2909-2912

3. Danielson, D.A., Jick, H., Hunter, J.R., Stergachis, A. & Madsen, S. (1982) Nonestrogenic drugs 

and breast cancer. Am. J. Epidemiol., 116, 329-332

4. Greenspan, A.R., Hatcher, R.A., Moore, A., Rosenberg, M.J. & Ory, H.W. (1980) The association of 

depo-medroxyprogesterone acetate and breast cancer. Contraception, 21, 563-569

5. Special Programme of Research, Development and Research Training in Human Reproduction 

(1986) Depot-medroxyprogesterone acetate DMPA and cancer. Memorandum from a WHO meeting. 

WHO Bull., 64, 375-382

6. Lanari, C., Molinolo, A.A. & Pasqualini, C.D. (1986) Induction of mammary adenocarcinomas by 

medroxyprogesterone acetate in BALB/c female mice. Cancer Lett., 33, 215-223

7. Frank, D.W., Kirton, K.T., Murchison, T.E., Quinlan, W.J., Coleman, M.E., Gilbertson, T.J., 

Feenstra, E.S. & Kimball, F.A. (1979) Mammary tumors and serum hormones in the bitch treated 

with medroxyprogesterone acetate or progesterone for four years. Fertil. Steril., 31, 340-346

8. van Os, J.L., van Laar, P.H., Oldenkamp, E.P. & Verschoor, J.S.C. (1981) Oestrus control and the 

incidence of mammary nodules in bitches, a clinical study with two progestogens. Vet. Q., 3, 46-56

9. Concannon, P.W., Spraker, T.R., Casey, H.W. & Hansel, W. (1981) Gross and histopathologic 

effects of medroxyprogesterone acetate and progesterone on the mammary glands of adult beagle 

bitches. Fertil. Steril., 36, 373-387

10. IARC Monographs, Suppl. 6, 359-360, 1987 

Synonyms for Medroxyprogesterone acetate

● 17α-Acetoxy-6α-methylprogesterone 

● Amen 

● Clinovir 

● Depcorlutin 
● Depo-clinovir 

● Depomedroxyprogesterone acetate 

● Depo-provera 

● Deporone 

● Farlutal 

● Farlutin 

● Gesinal 

● Gestapuran 

● Gestapuron 

● 17-Hydroxy-6α-methylpregn-4-ene-3,20-dione acetate 

● 17α-Hydroxy-6α-methylprogesterone acetate 

● Luteocrin 

● Lutopolar 

● Lutoral 

● MAP 

● Metigestrona 

● Metilgestene 

● Metipregnone 

● 6α-Methyl-17-acetoxyprogesterone 

● 6α-Methyl-17α-hydroxyprogesterone acetate 

● MPA 

● Nogest 

● Oragest 

● Perlutex 

● Prodasone 

● Progestalfa 

● Progevera 

● Promone-E 

● Provera 

● Proverone 

● Provest 

● Repromix 

● Sirprogen 

● Sodelut G 

● U 8839 

● Veramix 

Chlormadinone acetate

CAS No.: 302-22-7

Chem. Abstr. Name: 17-(Acetyloxy)-6-chloropregna-4,6-diene-3,20-dione 

A. Evidence for carcinogenicity to animals (limited)

Chlormadinone acetate was tested in mice, rats and dogs by oral administration. In dogs, it 

produced mammary tumours in one study [ref: 1] and increased the incidence of mammary-gland 

hyperplasia and mammary nodules in another [ref: 2].

B. Other relevant data

No data were available on the genetic and related effects of chlormadinone acetate alone in humans. 

See, however, the summary of data for combined oral contraceptives. Chlormadinone acetate did 

not induce chromosomal aberrations in cultured human lymphocytes and was not mutagenic to 

bacteria [ref: 3].

References

1. IARC Monographs, 21, 365-375, 1979

2. El Etreby, M.F. & Gräf, K.-J. (1979) Effect of contraceptive steroids on mammary gland of beagle 
dog and its relevance to human carcinogenicity. Pharmacol. Ther., 5, 369-402

3. IARC Monographs, Suppl. 6, 148-149, 1987

Synonyms for Chlormadinone acetate

● 17α-Acetoxy-6-chloro-6,7-dehydroprogesterone 

● 17α-Acetoxy-6-chloro-4,6-pregnadiene-3,20-dione 

● Amenyl 

● Ay 13390-6 

● Bovisynchron 

● CAP 

● Cero 

● Chlordion 

● Chlormadinon acetate 

● 6-Chloro-∆6-17-acetoxyprogesterone 

● 6-Chloro-∆6-(17α)acetoxyprogesterone 

● 6-Chloro-6-dehydro-17α-acetoxyprogesterone 

● 6-Chloro-6-dehydro-17α-hydroxyprogesterone acetate 

● 6-Chloro-17-hydroxypregna-4,6-diene-3,20-dione acetate 

● Chloromadinone acetate 

● Clordion 

● C-Quens 

● Gestafortin 

● Gestogan 

● Lormin 

● Luteran 

● Lutestral 

● Lutinyl 

● Lutoral 

● Matrol 

● Menova 

● Menstridyl 

● Normenen 

● Normenon 

● Retex 

● RS 1280 

● Sequens 

● Skedule 

● Skedule TM 

● Synchrosyn 

● Synchrosyn P 

● Traslan 

● Verton 

Dimethisterone

CAS No.: 79-64-1

Chem. Abstr. Name: (6α,17β)-17-Hydroxy-6-methyl-17-(1-propynyl)-androst-4-en-3-one 

A. Evidence for carcinogenicity to animals (inadequate)

Dimethisterone was reported to have been tested in monkeys in one study. No increase in tumour 

incidence was found [ref: 1].

B. Other relevant data

No data were available on the genetic and related effects of dimethisterone in humans. It did not 

induce chromosomal aberrations in cultured human lymphocytes [ref: 2].
References

1. Weikel, J.H., Jr & Nelson, L.W. (1977) Problems in evaluating chronic toxicity of contraceptive 

steroids in dogs. J. Toxicol. environ. Health, 3, 167-177

2. IARC Monographs, Suppl. 6, 260-261, 1987

Synonyms for Dimethisterone

● Dimethisteron 

● 6α,21-Dimethylethisterone 

● 6α,21-Dimethyl-17β-hydroxy-17alpha-pregn-4-en-20-yn-3-one 

● 17α-Ethynyl-6α,21-dimethyltestosterone 

● 17α-Ethynyl-17-hydroxy-6α,21-dimethylandrost-4-en-3-one 

● 17β-Hydroxy-6α-methyl-17-(1-propynyl)-androst-4-en-3-one 

● Lutogan 

● 6α-Methyl-17α-propynyltestosterone 

● 6α-Methyl-17-(1-propynyl)testosterone 

● Oracon 

● Ovin 

● P-5048 

● Secrosteron 

● Tova 

Ethynodiol diacetate

CAS No.: 297-76-7

Chem. Abstr. Name: (3β,17α)-19-Norpregn-4-en-20-yne-3,17-diol diacetate 

A. Evidence for carcinogenicity to animals (limited)

Ethynodiol diacetate was tested in mice and rats by oral administration. It increased the incidence of 

benign liver tumours in male mice and of mammary tumours in castrated male mice, and produced 

benign mammary tumours in male rats [ref: 1].

B. Other relevant data

No data were available on the genetic and related effects of ethynodiol diacetate alone in humans. 

See, however, the summary of data for combined oral contraceptives. Ethynodiol diacetate did not 

induce sex-linked recessive lethal mutations in Drosophila [ref: 2].

References

1. IARC Monographs, 21, 387-398, 1979

2. IARC Monographs, Suppl. 6, 308-309, 1987

Synonyms for Ethynodiol diacetate

● CB 8080 

● Cervicundin 

● Demulen 

● Demulen 28 

● Demulen 50 

● 3β,17β-Diacetoxy-17α-ethynyl-4-estrene 

● 3β,17β-Diacetoxy-17α-ethynyl-4-oestrene 
● Ethinodiol diacetate 

● Ethynodiol acetate 

● β-Ethynodiol diacetate 

● Femulen 

● Luto-metrodiol 

● Metrodiol 

● Metrodiol diacetate 

● Metrulen 

● Metrulene 

● 19-Nor-17α-pregn-4-en-20-yne-3β,17-diol diacetate 

● Neovulen 

● Ovulen 

● SC 11800 

17α-Hydroxyprogesterone caproate

CAS No.: 630-56-8

Chem. Abstr. Name: 17-[(1-Oxohexyl)oxy]pregn-4-ene-3,20-dione

A. Evidence for carcinogenicity to animals (inadequate)

17α-Hydroxyprogesterone caproate was tested in rabbits by repeated intramuscular injection, giving 

inconclusive results [ref: 1]. It was reported to have accelerated the growth of a transplantable 

cervical tumour line in mice [ref: 2].

B. Other relevant data

No data were available to the Working Group.

References

1. IARC Monographs, 21, 399-406, 1979

2. Umancheeva, A.F., Novikova, A.I. & Anisomov, V.N. (1981) Stimulating effect of pregnancy on 

the growth of cervical cancer (Russ.). Akush. Ginekol., 1, 53-55

Synonyms for 17α-Hydroxyprogesterone caproate

● Capron 

● Corlutin L.A. 

● Delalutin 

● Depo-proluton 

● Duralutin 

● Estralutin 

● Gesterol L.A. 

● 17α-Hexanoyloxypregn-4-ene-3,20-dione 

● Hormofort 

● HPC 

● 17-Hydroxypregn-4-ene-3,20-dione hexanoate 

● 17α-Hydroxyprogesterone n-caproate 

● 17α-Hydroxyprogesterone hexanoate 

● Hylutin 

● Hyproval-PA 

● Hyroxon 

● Idrogestene 

● Lutate 

● Luteocrin 

● Lutopron 

● Neolutin 
● Pharlon 

● Primolut depot 

● Progesterone caproate 

● Progesterone-retard pharlon 

● Proluton depot 

● Relutin 

● Squibb 

● Syngynon 

● Teralutil 

Lynoestrenol

CAS No.: 52-76-6

Chem. Abstr. Name: (17α)-19-Norpregn-4-en-20-yn-17-ol 

A. Evidence for carcinogenicity to animals (inadequate)

Lynoestrenol was tested by oral administration in mice and rats. It induced a slight increase in the 

incidence of benign liver-cell tumours in male mice and of malignant mammary tumours in female 

mice. In female rats, a slight but nonsignificant increase in the incidence of malignant mammary 

tumours was observed after administration of lynoestrenol [ref: 1].

B. Other relevant data

No data were available to the Working Group.

Reference

1. IARC Monographs, 21, 407-415, 1979

Synonyms for Lynoestrenol

● 3-Desoxynorlutin 

● Ethinylestrenol 

● ∆4-17α-Ethinylestren-17β-ol 

● 17α-Ethinyl-17β-hydroxyestr-4-ene 

● Ethinyloestrenol 

● ∆4-17α-Ethinyloestren-17β-ol 

● 17α-Ethinyl-17β-hydroxyoestr-4-ene 

● Ethynylestrenol 

● 17α-Ethynylestrenol 

● 17α-Ethynylestr-4-en-17β-ol 

● Ethynyloestrenol 

● 17α-Ethynyloestrenol 

● 17α-Ethynyloestr-4-en-17β-ol 

● Exluten 

● Exluton 

● Exlutona 

● Linestrenol 

● Linoestrenol 

● Lynenol 

● Lynestrenol 

● 19-Nor-17α-pregn-4-en-20-yn-17-ol 

● Lyndiol 

● Minilyn 

● Noracycline 

● Orgametil 

● Orgametril 

● Orgametrol 
Megestrol acetate

CAS No.: 595-33-5

Chem. Abstr. Name: 17α-(Acetyloxy)-6-methylpregna-4,6-diene-3,20-dione 

A. Evidence for carcinogenicity to animals (limited)

Megestrol acetate was tested by oral administration in mice, rats, dogs and monkeys. It produced 

nodular hyperplasia, and benign and malignant mammary tumours in dogs [ref: 1]. No tumour was 

reported in monkeys [ref: 2].

B. Other relevant data

No data were available on the genetic and related effects of megestrol acetate alone in humans. 

See, however, the summary of data for combined oral contraceptives (p. 297). Megestrol acetate did 

not induce chromosomal aberrations in cultured human lymphocytes [ref: 3].

References

1. IARC Monographs, 21, 431-439, 1979

2. Weikel, J.H., Jr & Nelson, L.W. (1977) Problems in evaluating chronic toxicity of contraceptive 

steroids in dogs. J. Toxicol. environ. Health, 3, 167-177

3. IARC Monographs, Suppl. 6, 361-362, 1987

Synonyms for Megestrol acetate

● 6-Dehydro-6-methyl-17α-acetoxyprogesterone 

● 17α-Hydroxy-6-methylpregna-4,6-diene-3,20-dione acetate 

● Megestryl acetate 

● 6-Methyl-∆4,6-pregnadien-17α-ol-3,20-dione acetate 

● BDH 1298 

● Co-Ervonum 

● Delpregnin 

● DMAP 

● Kombiguens 

● Magestin 

● Megace 

● Megage 

● Megeron 

● Minigest 

● Niagestin 

● Nuvacon 

● Ovaban 

● Ovarid 

● Ovex 

● Planovin 

● SC 10363 

● Serial 28 

● Tri-ervonum 

● Volidan 

● Volidan 21 

● Voplan 

● Weradys 

Norethisterone
CAS No.: 68-22-4

Chem. Abstr. Name: (17α)-17-Hydroxy-19-norpregn-4-en-20-yn-3-one 

Norethisterone acetate

CAS No.: 51-98-9

Chem. Abstr. Name: (17α)-17-(Acetyloxy)-19-norpregn-4-en-20-yn-3-one 

A. Evidence for carcinogenicity to animals (sufficient)

Norethisterone and its acetate were tested by oral administration in mice and rats, and by 

subcutaneous implantation in mice. In mice, norethisterone and its acetate increased the incidence 

of benign liver-cell tumours in males; norethisterone increased the incidence of pituitary tumours in 

females and produced granulosa-cell tumours in the ovaries of females. Norethisterone increased 

the incidence of benign liver-cell tumours and benign and malignant mammary tumours in male rats 

[ref: 1]. Rats fed 3-4 mg/kg bw per day norethisterone acetate (about 100 times the daily human 

dose) for two years had an increased incidence of neoplastic nodules of the liver; an increase in the 

incidence of uterine polyps was seen in females [ref: 2]. In rats given weekly intramuscular 

injections for 104 weeks of norethisterone enanthate at doses of 10, 30 and 100 mg/kg bw (20, 60 

and 200 times the daily human contraceptive dose), there was a dose-related increase in pituitarygland tumours in males, whereas in females no effect on pituitary glands was observed with the 

lowest dose and a reduction in pituitary tumours was observed with the highest dose. Benign 

mammary tumours were observed in males at all doses, but there was little effect in females; the 

incidence of malignant mammary tumours was greatly increased in both males and females given 

the two higher dose levels and was dose-related. A dose-related increase in the incidence of liver 

tumours was also seen in animals of each sex [ref: 3].

B. Other relevant data

No data were available on the genetic and related effects of norethisterone alone in humans. See, 

however, the summary of data for combined oral contraceptives.

Aneuploidy was observed in oocytes of mice treated with high doses of norethisterone acetate. In a 

test for dominant lethal mutations in which female mice were exposed orally to norethisterone 

acetate, no increase was seen in one strain of mice, and a second strain showed an increase only 

when females were mated within two weeks after treatment. The compound did not induce 

aneuploidy or chromosomal aberrations in cultured human lymphocytes. Neither norethisterone nor 

its acetate was mutagenic to bacteria [ref: 4].

References

1. IARC Monographs, 21, 441-460, 1979

2. Schardein, J.L. (1980) Studies on the components of an oral contraceptive agent in albino rats. II. 

Progestogenic component and comparison of effects of the components and the combined agent. J. 

Toxicol. environ. Health, 6, 895-906

3. El Etreby, M.F. & Neumann, F. (1980) Influence of sex steroids and steroid antagonists on 

hormone-dependent tumors in experimental animals. In: Iacobelli, S., King, R.J.B., Lindner, H.R. & 

Lippman, M.E., eds, Hormones and Cancer, New York, Raven Press, pp. 321-336

4. IARC Monographs, Suppl. 6, 427-429, 1987

Synonyms for Norethisterone

● Anhydroxynorprogesterone 
● Anovule 

● Brevicon 

● Brevicon-28 day 

● Conludaf 

● Conludag 

● 19-Nor-17α-ethynyl-17β-hydroxy-4-androsten-3-one 

● 17α-Ethinyl-19-nortestosterone 

● Ethinylnortestosterone 

● 17α-Ethynyl-19-nortestosterone 

● Ethynylnortestosterone 

● 19-Nor-17α-ethynyltestosterone 

● Gestest 

● 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one 

● Micronett 

● Micronor 

● Micronovum 

● Mini-Pe 

● Modicon 

● Modicon 28 

● Nor-QD 

● Noralutin 

● Norethindrone 

● Norethisteron 

● Norethynodrone 

● 19-Norethisterone 

● Norfor 

● Norgestin 

● Noriday 

● Norinyl 

● Norluten 

● Norlutin 

● Norluton 

● Norpregneninolone 

● NSC 9564 

● Ortho-novin 

● Ortho-novum 

● Ovcon-35 

● Ovysmen 

● Primolut N 

● Primolutin 

● Proluteasi 

● SC 4640 

Synonyms for Norethisterone acetate

● Anvlar 21 

● Controvlar 

● 17α-Ethinyl-19-nortestosterone acetate 

● 17α-Ethinyl-19-nortestosterone 17β-acetate 

● 17α-Ethynyl-19-nortestosterone acetate 

● Gynovlar 21 

● 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one acetate 

● Loestrin 

● Loestrin-21 

● Minovlar 

● Norethindrone acetate 

● Norethindrone 17-acetate 

● Norethisteron acetate 

● 19-Norethisterone acetate 

● Norethynyltestosterone acetate 

● 19-Norethynyltestosterone acetate 

● Norethysterone acetate 

● Norlestrin 

● Norlutate 
● Norlutin-A 

● Norlutin acetate 

● Orlest 21 

● Orlutate 

● Ovcon 50 

● Primodos 

● Primolut-nor 

● Primosiston 

● Prolestrin 

● SH 420 

● Zorane 

Norethynodrel

CAS No.: 68-23-5

Chem. Abstr. Name: (17α)-17-Hydroxy-19-norpregn-5(10)-en-20-yn-3-one 

A. Evidence for carcinogenicity to animals (limited)

Norethynodrel was tested by oral administration in mice and rats and by subcutaneous implantation 

in mice. It increased the incidence of pituitary tumours in mice of each sex and that of mammary 

tumours in castrated males of one strain. It also increased the incidence of benign and malignant 

liver-cell, pituitary and mammary (benign and malignant) tumours in male rats [ref: 1]. Feeding of 

norethynodrel to rats following partial hepatectomy and treatment with N-nitrosodiethylamine 

increased the number of γ-glutamyl transpeptidase-positive hepatic foci at four months, but there 

was no significant difference by nine months [ref: 2].

B. Other relevant data

No data were available on the genetic and related effects of norethynodrel alone in humans. See, 

however, the summary of data for combined oral contraceptives. Norethynodrel did not induce 

aneuploidy in human cells in culture or unscheduled DNA synthesis in rat hepatocytes in vitro. It 

inhibited intercellular communication in Chinese hamster V79 cells. The compound was not 

mutagenic to bacteria [ref: 3].

References

1. IARC Monographs, 21, 461-477, 1979

2. Yager, J.D. & Yager, R. (1980) Oral contraceptive steroids as promoters of hepatocarcinogenesis 

in female Sprague-Dawley rats. Cancer Res., 40, 3680-3685

3. IARC Monographs, Suppl. 6, 430-431, 1987

Synonyms for Norethynodrel

● Conovid E 

● Enavid E 

● Enidrel 

● Enovid-E 

● Enovid-E21 

● 17α-Ethynyl-17-hydroxy-5(10)-estren-3-one 

● 17α-Ethynyl-17-hydroxy-5(10)-oestren-3-one 

● 17-Hydroxy-19-nor-17α-pregn-5(10)-en-20-yn-3-one 

● 13-Methyl-17-ethynyl-17-hydroxy-1,2,3,4,6,7,8,9,11,12,13,14,16,17-tetradecahydro-15Hcyclopenta[a]phenanthren-3-one 

● Previson 

● SC 4642 
Norgestrel

CAS No.: 797-63-7 

Chem. Abstr. Name: (17α)(+)-13-Ethyl-17-hydroxy-18,19-dinorpregn-4-en-20-yn-3-one 

A. Evidence for carcinogenicity to animals (inadequate)

Norgestrel was tested by oral administration in mice and rats. No increase in the incidence of 

tumours was observed in either species [ref: 1].

B. Other relevant data

No data were available of the genetic and related effects of norgestrel alone in humans. See, 

however, the summary of data for combined oral contraceptives. Norgestrel gave inconclusive 

results in tests for sex-linked recessive lethal mutations in Drosophila. It was not mutagenic to 

bacteria [ref: 2].

References

1. IARC Monographs, 21, 479-490, 1979

2. IARC Monographs, Suppl. 6, 432-433, 1987

Synonyms for Norgestrel

● Levonorgestrel 

● Adepal 

● Denorgestrel 

● 13β-Ethyl-17α-ethynyl-17β-hydroxygon-4-en-3-one 

● 13-Ethyl-17-hydroxy-18,19-dinor-17alpha-pregn-4-en-20-yn-3-one 

● 17α-Ethynyl-18-homo-19-nortestosterone 

● 17-Ethynyl-18-methyl-19-nortestosterone 

● FH 122-A 

● Follistrel 

● Lo/Ovral 

● Micro-30 

● Microgynon 30 

● Microlut 

● Microluton 

● Microval 

● Mikro-30 

● Minidril 

● Monovar 

● Neogest 

● d-Norgestrel 

● Ovral 

● Ovran 

● Ovranette 

● Ovrette 

● SH 850 

● SH 70850 

● Stediril 

● TSP-6 

● Wy 3707 

Progesterone
CAS No.: 57-83-0 

Chem. Abstr. Name: Pregn-4-ene-3,20-dione 

A. Evidence for carcinogenicity to animals (sufficient)

Progesterone was tested by subcutaneous and by intramuscular injection in mice, rabbits and dogs, 

and by subcutaneous implantation in mice. It increased the incidences of ovarian, uterine and 

mammary tumours in mice. Neonatal treatment with progesterone enhanced the occurrence of 

precancerous and cancerous lesions of the genital tract and increased mammary tumorigenesis in 

female mice [ref: 1]. Dogs treated with progesterone for four years at one to 25 times the lutealphase levels for that species developed a dose-related incidence of mammary-gland nodules [ref: 

2].

B. Other relevant data

No data were available on the genetic and related effects of progesterone in humans.

Progesterone did not induce dominant lethal mutations in mice or chromosomal aberrations in rats 

treated in vivo. It did not induce chromosomal aberrations or sister chromatid exchanges in cultured 

human cells, nor chromosomal aberrations or DNA strand breaks in rodent cells. Studies on 

transformation of rodent cells in vitro were inconclusive: a clearly positive result was obtained for rat 

embryo cells, a weakly positive result for mouse cells and a negative result for Syrian hamster 

embryo cells. Progesterone was not mutagenic to bacteria [ref: 3].

References

1. IARC Monographs, 21, 491-515, 1979

2. Frank, D.W., Kirton, K.T., Murchison, T.E., Quinlan, W.J., Coleman, M.E., Gilbertson, T.J., 

Feenstra, E.S. & Kimball, F.A. (1979) Mammary tumors and serum hormones in the bitch treated 

with medroxyprogesterone acetate or progesterone for four years. Fertil. Steril., 31, 340-346

3. IARC Monographs, Suppl. 6, 479-481, 1987

Synonyms for Progesterone

● Agolutin 

● Bio-luton 

● Colprosterone 

● Corlutin 

● Corlutina 

● Corlutone 

● Corluvite 

● Corporin 

● Corpormone 

● Corpus luteum hormone 

● Cyclogesterin 

● Flavolutan 

● Fologenon 

● Gesterol 

● Gestin-E 

● Gestone 

● Gestormone 

● Gestron 

● Glanducorpin 

● Gynlutin 

● Gynolutone 

● Hormoflaveine 

● Hormoluton 
● Lipo-Lutin 

● Lucorteum 

● Lucorteum sol 

● Luteal hormone 

● Luteine 

● Luteinique 

● Luteinol 

● Luteocrin normale 

● Luteodyn 

● Luteogan 

● Luteohormone 

● Luteol 

● Luteopur 

● Luteosan 

● Luteosid 

● Luteostab 

● Luteosteron 

● Luteovis 

● Lutex 

● Lutex-leo 

● Lutidon 

● Lutin 

● Lutociclina 

● Lutocor 

● Lutocyclin 

● Lutocyclin M 

● Lutocylin 

● Lutoform 

● Lutogyl 

● Lutogynon 

● Lutren 

● Lutromone 

● Nalutron 

● Paragest 

● Paralut 

● Paralut forte 

● Percutacrine luteinique 

● Piaponon 

● ∆4-Pregnene-3,20-dione 

● Primolut 

● Profac-O 

● Progekan 

● Progelan 

● Progestasert 

● Progeste 

● Progesterol 

● Progestilin 

● Progestin 

● Progestine 

● Progestogel 

● Progestone 

● Progestron 

● Prolidon 

● Prolets 

● Prolusteron 

● Proluton 

● Protormone 

● Sistociclina 

● Syngesterone 

● Syngestrets 

● Syntolutan 

● Syntolutin 

Overall evaluation
Progestins are possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 6 (1974); Vol. 21 (1979)

Subsequent evaluation: Vol. 72 (1999)

Last updated: 3 March 1998 
PROPYLTHIOURACIL

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 329) 

CAS No.: 51-52-5 

A. Evidence for carcinogenicity to humans (inadequate) 

In one survey of 331 hyperthyroid patients treated with antithyroid drugs, including propylthiouracil, 

and later with thyroidectomy, four thyroid cancers (an excess of unspecified proportion) were 

diagnosed more than one year after the beginning of drug therapy [ref: 1]. There has been one case 

report of acute myeloblastic leukaemia following propylthiouracil treatment [ref: 2]. 

B. Evidence for carcinogenicity to animals (sufficient) 

Propylthiouracil produced thyroid tumours in mice, rats, hamsters and guinea-pigs and pituitary 

adenomas in mice after its oral administration [ref: 3]. When administered orally to rats with Nmethyl-N-nitrosourea given intravenously [ref: 4] or N-nitrosobis(2-hydroxypropyl)amine 

intraperitoneally [ref: 5], it induced malignant thyroid tumours. 

C. Other relevant data

No adequate data were available to the Working Group. 

Overall evaluation

Propylthiouracil is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Subsequent evaluation: Vol. 79 (2001)

Also see previous evaluation: Vol. 7 (1974)

References

1. Dobyns, B.M., Sheline, G.E., Workman, J.B., Tompkins, E.A., McConahey, W.M. & Becker, D.V. 

(1974) Malignant and benign neoplasms of the thyroid in patients treated for hyperthyroidism: a 

report of the cooperative thyrotoxicosis therapy follow-up study. J. clin. Endocrinol. Metab., 38, 976-

998

2. Aksoy, M., Erdem, S., Tezel, H. & Tezel, T. (1974) Acute myeloblastic leukaemia after 

propylthiouracil. Lancet, i, 928-929

3. IARC Monographs, 7, 67-76, 1974

4. Milmore, J.E., Chandrasekaran, V. & Weisburger, J.H. (1982) Effects of hypothyroidism on 

development of nitrosomethylurea-induced tumors of the mammary gland, thyroid gland, and other 

tissues. Proc. Soc. exp. Biol. Med., 169, 487-493 
5. Kitahori, Y., Hiasa, Y., Konishi, N., Enoki, N., Shimoyama, T. & Miyashiro, A. (1984) Effect of 

propylthiouracil on the thyroid tumorigenesis induced by N-bis(2-hydroxypropyl)nitrosamine in rats. 

Carcinogenesis, 5, 657-660

Synonyms

● 2,3-Dihydro-6-propyl-2-thioxo-4(1H)-pyrimidinone 

● 2-Mercapto-4-hydroxy-6-n-propylpyrimidine 

● 2-Mercapto-6-methyl-4-pyrimidone 

● 2-Mercapto-6-methylpyrimid-4-one 

● 4-Propyl-2-thiouracil 

● 6-n-Propyl-2-thiouracil 

● 6-Propyl-2-thio-2,4(1H,3H)-pyrimidinedione 

● 6-Propyl-2-thiouracil 

● 6-Propylthiouracil 

● Procasil 

● Propacil 

● Propycil 

● Propyl-thiorit 

● Propyl-Thyracil 

● Propylthiouracil 

● Prothycil 

● Prothyran 

● PTU 

● 2-Thio-4-oxo-6-propyl-1,3-pyrimidine 

● 2-Thio-6-propyl-1,3-pyrimidin-4-one 

● 6-Thio-4-propyluracil 

● Thyreostat II 

Last updated: 3 March 1998 
PULP AND PAPER MANUFACTURE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 385)

A. Evidence for carcinogenicity to humans (inadequate) 

Excess incidences of oral and pharyngeal and/or laryngeal cancers were reported in two studies 

designed to generate hypotheses. These cancer forms have not been evaluated in independent 

studies [ref: 1]. 

Some studies, based on a few cases, suggest that an increased risk of lymphoproliferative 

neoplasms, particularly Hodgkin's disease, may be linked to employment in the pulp and paper 

industries [ref: 1-3]. 

In a prospective cohort study of viscose workers exposed to carbon disulphide, 343 pulp and paper 

workers served as the reference group. During 15 years of follow-up, nine pulp and paper workers 

had died of lung cancer, compared with four viscose workers (rate ratio, 2.2; [95% confidence 

interval, 0.7-6.7]). The pulp and paper workers smoked slightly less than the viscose workers [ref: 

4]. When national rates were used as the reference, the standardized mortality ratio (SMR) was 154 

(70-292). However, a US proportionate mortality study [ref: 3] comprising 2113 deaths revealed no 

excess of lung cancer among pulp and paper workers. 

A US cohort study of 3572 pulp and paper mill workers employed for at least one year between 

1945 and 1955 and followed until 1977 showed statistically nonsignificant excesses of 

lymphosarcoma and reticulosarcoma (10 cases; SMR, 169; 92-287) and of stomach cancer (17 

cases; SMR, 123; 78-185). There was no excess of lung cancer. The excess of lymphosarcoma and 

reticulosarcoma was present only for men who had worked in sulphate mills (6 observed; SMR, 207; 

90-408), whereas the excess of stomach cancer occurred in sulphite mills (11 observed; SMR, 149; 

83-246) [ref: 5]. 

Excesses of cancers at miscellaneous sites have been mentioned in some studies on pulp and paper 

workers [ref: 1,3,6-8]. The findings may be due to chance, because the cases were generally few 

and the patterns inconsistent. 

A case-control study of the paternal occupations of 692 children who had died of cancer in 

Massachusetts, USA, showed that paternal employment as a pulp or paper mill worker was 

associated with tumours of the brain and other parts of the nervous system (six cases observed; 

relative risk, 2.8); however, as many comparisons were made, this may well be a chance finding 

[ref: 9]. 

B. Other relevant data

Workers employed for two to 30 years in a paper factory and exposed intermittently to high levels 

of formaldehyde for short periods showed a significant increase in the incidence of structural 

chromosomal aberrations associated with mean exposure to formaldehyde; however, no increase in 

the incidence of sister chromatid exchanges was observed as compared with controls. An increase in 

the incidence of chromosomal and chromatid-type aberrations was reported among seven workers 

involved in boiling pulp and handling sulphuric acid in a sulphite factory, as compared to six workers 

exposed to chlorine during the bleaching of pulp, six workers exposed to dust in a paper mill and 15 

control subjects; but the results remain uncertain due to methodological problems [ref: 10]. 

Overall evaluation

Pulp and paper manufacture entails exposures that are not classifiable as to their carcinogenicity to 
humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 25 (1981)

References

1. IARC Monographs, 25, 157-197, 1981 

2. Greene, M.H., Brinton, L.A., Fraumeni, J.F., Jr & D'Amico, R. (1978) Familial and sporadic 

Hodgkin's disease associated with occupational wood exposure. Lancet, ii, 626-627 

3. Milham, S., Jr & Demers, R.Y. (1984) Mortality among pulp and paper workers. J. occup. Med., 

26, 844-846 

4. Nurminen, M. & Hernberg, S. (1984) Cancer mortality among carbon disulfide-exposed workers. 

J. occup. Med., 26, 341 

5. Robinson, C.F., Waxweiler, R.J. & Fowler, D.P. (1986) Mortality among production workers in pulp 

and paper mills. Scand. J. Work Environ. Health, 12, 552-560 

6. Okubo, T. & Tsuchiya, K. (1974) An epidemiological study on the cancer mortality in various 

industries in Japan (Jpn.). Jpn. J. ind. Health, 16, 438-452 

7. Malker, H.S.R., McLaughlin, J.K., Malker, B.K., Stone, B.J., Weiner, J.A., Erickson, J.L.E. & Blot, 

W.J. (1986) Biliary tract cancer and occupation in Sweden. Br. J. ind. Med., 43, 257-262 

8. Malker, H.S.R., McLaughlin, J.K., Malker, B.K., Stone, B.J., Weiner, J.A., Erickson, J.L.E. & Blot, 

W.J. (1985) Occupational risks for pleural mesothelioma in Sweden, 1961-79. J. natl Cancer Inst., 

74, 61-66 

9. Kwa, S.-L. & Fine, L.J. (1980) The association between parental occupation and childhood 

malignancy. J. occup. Med., 22, 792-794 

10. IARC Monographs, Suppl. 6, 573, 1987 

Last updated: 11 March 1998 
RESERPINE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 330) 

CAS No.: 50-55-5

Chem. Abstr. Name: Yohimban-16-carboxylic acid, 11,17-dimethoxy-18-[(3,4,5-

trimethoxybenzoyl)oxy]-, methyl ester (3β,16β,17α,18β,20α)- 

A. Evidence for carcinogenicity to humans (inadequate) 

Sixteen case-control and three cohort studies on the relationship between reserpine and breast 

cancer were available to the Working Group [ref: 1-6]. Between and within studies, estimates of 

relative risk for different degrees of reserpine use varied from 0.6 to over 3. Many of the positive 

findings were not coherent with one another; and the studies considered to be most satisfactory 

methodologically showed little or no evidence of increased risk. However, a recent, large casecontrol study of breast screening participants showed that, although use of rauwolfia (reserpine) was 

not significantly associated with an overall increase in risk (odds ratio, 1.2; 95% confidence interval, 

0.9-1.8), users for ten years or more had a risk ratio of 4.5 [2.3-11.6] [ref: 7]. A study of prolactin 

levels in 15 women who had taken reserpine for five years or longer showed only 50% greater 

elevation of levels than in 15 women taking non-reserpine-containing medications and in 15 women 

taking no hypertensive medication. Elevated prolactin levels have been postulated as the mechanism 

for increased breast cancer risk following reserpine use, and the authors postulated that the increase 

in prolactin observed would probably cause only small increases in breast cancer risk [ref: 8]. 

B. Evidence for carcinogenicity to animals (limited) 

Reserpine was tested for carcinogenicity in three experiments in mice by oral administration; in two 

experiments, it induced malignant mammary tumours in females, and in one experiment it induced 

carcinomas of the seminal vesicles in males [ref: 1,9]. It was tested in four experiments in rats by 

oral administration; in two, it increased the incidence of phaeochromocytomas [ref: 1,9]. An 

increase in tumour incidence was observed after repeated subcutaneous injections to mice and rats 

[ref: 9]. 

When reserpine was administered either prior to and concurrently with or following treatment with 3-

methylcholanthrene orally, it had a protective effect against the induction of mammary tumours in 

rats [ref: 10]. Concurrent subcutaneous administration of reserpine reduced mammary tumour 

multiplicity and increased the percentage of well-differentiated tumours induced in rats by N-methylN-nitrosourea given intravenously [ref: 11]; its intravenous administration decreased skin tumour 

growth in 3-methylcholanthrene-treated mice [ref: 12]. 

C. Other relevant data

No data were available on the genetic and related effects of reserpine in humans. 

Reserpine did not induce dominant lethal mutations in mice in vivo. In human cells in vitro, it did not 

induce chromosomal aberrations or sister chromatid exchanges. It did not induce chromosomal 

aberrations in cultured rodent cells or unscheduled DNA synthesis in rat hepatocytes. Reserpine was 

not mutagenic to bacteria [ref: 13]. 

Overall evaluation

Reserpine is not classifiable as to its carcinogenicity to humans (Group 3).
For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 10 (1976); Vol. 24 (1980)

References

1. IARC Monographs, 24, 211-241, 1980 

2. Labarthe, D.R. & O'Fallon, W.M. (1980) Reserpine and breast cancer. A community-based 

longitudinal study of 2000 hypertensive women. J. Am. med. Assoc., 243, 2304-2310 

3. Kewitz, H., Jesdinksy, H.-J., Kreutz, G. & Schulz, R. (1980) Reserpine and breast cancer. Arch. 

int. Pharmacodynam. Ther., Suppl., 22-24 

4. Danielson, D.A., Jick, H., Hunter, J.R., Stergachis, A. & Madsen, S. (1982) Nonestrogenic drugs 

and breast cancer. Am. J. Epidemiol., 116, 329-332 

5. Curb, J.D., Hardy, R.J., Labarthe, D.R., Borhani, N.O. & Taylor, J.O. (1982) Reserpine and breast 

cancer in the hypertension detection and follow-up program. Hypertension, 4, 307-311 

6. Horwitz, R.I. & Feinstein, A.R. (1985) Exclusion bias and the false relationship of reserpine and 

breast cancer. Arch. intern. Med., 145, 1873-1875 

7. Stanford, J.L., Martin, E.J., Brinton, L.A. & Hoover, R.N. (1986) Rauwolfia use and breast cancer: 

a case-control study. J. natl Cancer Inst., 76, 817-822 

8. Ross, R.K., Paganini-Hill, A., Krailo, M.D., Gerkins, V.R., Henderson, B.E. & Pike, M.C. (1984) 

Effects of reserpine on prolactin levels and incidence of breast cancer in postmenopausal women. 

Cancer Res., 44, 3106-3108 

9. Muradyan, R.Y. (1986) A study of possible carcinogenicity of reserpine (Russ.). Vopr. Onkol., 32, 

76-81 

10. Gerard, S.S., Gardner, B., Patti, J., Husain, V., Shouten, J. & Alfonso, A.E. (1980) Effects of 

triiodothyronine and reserpine on induction and growth of mammary tumors in rats by 3-

methylcholanthrene. J. surg. Oncol., 14, 213-218 

11. Verdeal, K., Ertürk, E. & Rose, D.P. (1983) Effects of reserpine administration on rat mammary 

tumors and uterine disease induced by N-nitrosomethylurea. Eur. J. Cancer clin. Oncol., 19, 825-834 

12. Lupulescu, A. (1983) Reserpine and carcinogenesis: inhibition of carcinoma formation in mice. J. 

natl Cancer Inst., 71, 1077-1083 

13. IARC Monographs, Suppl. 6, 485-487, 1987 

Synonyms

● Abesta 

● Abicol 

● Adelfan 

● Adelphane 

● Adelphin 

● Adelphin-esidrex-K 

● Alkarau 

● Alkaserp 
● Alserin 

● Anquil 

● Apoplon 

● Apresoline 

● Apsical 

● Arcum R-S 

● Ascoserp 

● Austrapine 

● Banasil 

● Banisil 

● Bendigon 

● Bioserpine 

● Brinderdin 

● Briserine 

● Broserpine 

● Butiserpazide-25 

● Butiserpazide-50 

● Butiserpine 

● Cardioserpin 

● Carditivo 

● Carrserp 

● Crystoserpine 

● Darebon 

● Deserpine 

● 11,17α-Dimethoxy-18β[(3,4,5-trimethoxybenzoyl)oxy]-3β, 20α-yohimban-16β-carboxylic 

acid methyl ester 

● Diutensen-R 

● Drenusil-R 

● Dypertane compound 

● Ebserpine 

● Elfanex 

● Elserpine 

● ENT 50146 

● Eserpine 

● Diupres 

● Eskaserp 

● Gamaserpin 

● Gilucard 

● Hexaplin 

● Hiposerpil 

● Hiserpia 

● Hydromox R 

● Hydropres 

● Hydropres KA 

● 18β-Hydroxy-11,17α-dimethoxy-3β, 20α-yohimban-16β-carboxylic acid methyl ester 3,4,5-

trimethoxybenzoate (ester) 

● Hygroton-reserpine 

● Hypercal B 

● Hypertane forte 

● Hypertensan 

● Idoserp 

● Interpina 

● Key-Serpine 

● Kitine 

● Klimanosid 

● Lemiserp 

● Loweserp 

● Marnitension simple 

● Maviserpin 

● Mayserpine 

● Mephaserpin 

● Metatensin 

● Mio-pressin 

● Modenol 

● Methyl-1α,2α,3α,4,4aα,5,7,8,13,13bβ,14,14aβ-dodecahydro-2α,11-dimethoxy-3β-(3,4,5-
trimethoxybenzoyloxy)benz[g]indolo(2,3α)quinolizine-1β-carboxylate 

● Methyl reserpate 3,4,5-trimethoxybenzoic acid ester 

● Methyl 11, 17alpha-dimethoxy-18β(3,4,5-trimethoxy-benzoyloxy)-3β,20α-yohimbane-16βcarboxylate 

● Naquival 

● Nembu-Serpin 

● Neo-antitersol 

● Neo-serfin 

● Neo-Serp 

● Neoslowten 

● Ondasil 

● Orthoserpina 

● Perskleran 

● Pressimedin 

● Purserpine 

● Quiescin 

● Raucap 

● Raudixin 

● Raudixoid 

● Raugal 

● Raulen 

● Rauloycin 

● Rauloydin 

● Raunervil 

● Raunormin 'orzan' 

● Raupasil 

● Raurine 

● Rausan 

● Rau-Sed 

● Rausedan 

● Rausedil 

● Rausedyl 

● Rauserpen-alk 

● Rauserpin 

● Rausingle 

● Rautrin 

● Rauvilid 

● Rauwasedin 

● Rauwilid 

● Rauwiloid 

● Rauwiloid + 

● Rauwipur 

● Rauwita 

● Rauwoleaf 

● Rauwopur 'byk' 

● Recipin 

● Regroton 

● Renese R 

● Resaltex 

● Resedrex 

● Resedril 

● Rese-lar 

● Reser-ar 

● Reserbal 

● Resercaps 

● Resercen 

● Resercrine 

● Reserfia 

● Reserjen 

● Reserlor 

● Reserpamed 

● Reserpanca 

● Reserpene 

● Reserpex 

● Reserpidefe 
● Reserpil 

● Reserpin 

● Reserpka 

● Reserpoid 

● Reserpur 

● Reserp 'wander' 

● Resersana 

● Reserutin 

● Resiatric 

● Resine 

● Resocalm 

● Resomine 

● Respital 

● Restran 

● Rezerpin 

● Riserpa 

● Rivased 

● Rivasin 

● Rolserp 

● Roxel 

● Roxinoid 

● Salupres 

● Salutensin 

● Sandril 

● Sarpagen 

● Sedaraupin 

● Seda-recipin 

● Seda-salurepin 

● Sedserp 

● Seominal 

● Serfin 

● Serolfia 

● Serp 

● Serp-AFD 

● Serpalan 

● Serpaloid 

● Serpanray 

● Serpasil 

● Serpasil Apresoline 

● Serpasil-Esidrex 

● Serpasil-Esidrex No. 1 

● Serpasil-Esidrex No. 2 

● Serpasil-Esidrex K 

● Serpasil premix 

● Serpasol 

● Serpate 

● Serpatone 

● Serpax 

● Serpedin 

● Serpen 

● Serpena 

● Serpentil 

● Serpentina 

● Serpentine 'pharbil' 

● Serpicon 

● Serpiloid 

● Serpilum 

● Serpine 

● Serpipur 

● Serpivite 

● Serplex K 

● Serpoid 

● Serpone 

● Serpresan 

● Serpyrit 
● Sertabs 

● Sertens 

● Sertensin 

● Sertina 

● Sinesalin composition 

● Solfo serpine 

● Supergan 

● Temposerpine 

● Tendoscen-compr. 

● Tensanyl 

● Tenserlix 

● Tenserp 

● Tenserpine 'assia

● Tensional 

● Tensionorme 

● Terbolan 

● Transerpin 

● 3,4,5-Trimethoxybenzoic acid ester with methyl 18β-hydroxy-11,17α-dimethoxy-3β,20αyohimban-16β-carboxylate 

● 3,4,5-Trimethoxybenzoyl methyl reserpate 

● Triserpin 

● T-Serp 

● Tylandril 

● Unilord 

● Unitensen 

● Vio-serpine 

● Vioserpine 

● Veriloid 

● V-Serp 

● Yohimban-16-carboxylic acid derivative of benz[g]indolo(2,3α)quinolizine 

● 3β,16β,17α,18β,20α-Yohimban-16-carboxylic acid-11,17-dimethoxy-18-[(3,4,5-

trimethoxybenzoyl)oxy] methyl ester 

Last updated: 11 March 1998 
THE RUBBER INDUSTRY

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p.332) 

A. Evidence for carcinogenicity to humans (sufficient)

A large number of studies have been conducted on the rubber industries in Canada, China, Finland, 

Norway, Sweden, Switzerland, the UK and the USA [ref: 1-19]. Workers employed in the industry 

before 1950 have a high risk of bladder cancer, probably associated with exposure to aromatic 

amines. Leukaemias have been associated with exposure to solvents and with employment in back 

processing, tyre curing, synthetic rubber production and vulcanization. Excess mortality from 

lymphomas has been noted among workers exposed to solvents in such departments as footwear 

and in tyre plants [ref: 20]. Other cancers, including those of the lung, renal tract, stomach, 

pancreas, oesophagus, liver, skin, colon, larynx and brain, have been reported as occurring in 

excess in various product areas and departments, but no consistent excess of any of these cancers 

is seen across the various studies. 

B. Evidence for carcinogenicity to animals (inadequate)

In one inadequately reported experiment, three groups of rats were kept either in the compounding 

room, in the mixing area of a Banbury mill or in the mastication area of a Banbury mill at a tyre 

factory. Increased incidences of respiratory and digestive carcinomas were found in rats maintained 

for two years at the latter two locations when compared with control rats maintained in the institute 

laboratory [ref: 17]. 

C. Other relevant data

No increase in the incidence of chromosomal aberrations was observed among 55 rubber workers as 

compared to 35 control subjects, with the exception of a small group of nonsmokers involved in 

weighing rubber chemicals. Increased frequencies of sister chromatid exchanges were observed 

both in smoking and nonsmoking weighers and in mixers who smoked, compared with unexposed 

controls; the frequency of sister chromatid exchanges in vulcanizers was not statistically 

significantly increased. Negative results for chromosomal aberrations and sister chromatid 

exchanges were also obtained in another study of vulcanizers [ref: 21].

Urine samples from 55 workers in two rubber factories and from 35 controls were analysed for 

mutagenicity in bacteria in the presence of an exogenous metabolic system. Mutagenic activity was 

observed in the urine of workers involved in weighing and mixing rubber components and in the 

urine of some vulcanizers (Sorsa et al., 1983b). Similar results were reported by Falck (1983) in an 

extension of this study. No increase in bacterial mutagenicity was observed in urine samples from 

72 tyre builders in a rubber factory and from 23 controls [ref: 21]. 

Overall evaluation

Working in the Rubber industry entails exposures that are carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 28 (1982)

References
1. IARC Monographs, 28, 1982

2. Delzell, E. & Monson, R.R. (1981) Mortality among rubber workers. IV. General mortality 

patterns. J. occup. Med., 23, 850-856

3. Delzell, E. & Monson, R.R. (1982) Mortality among rubber workers. V. Processing workers. J. 

occup. Med., 24, 539-545

4. Delzell, E. & Monson, R.R. (1982) Mortality among rubber workers. VI. Men with potential 

exposure to acrylonitrile. J. occup. Med., 24, 767-769

5. Delzell, E. & Monson, R.R. (1984) Mortality among rubber workers. VIII. Industrial products 

workers. Am. J. ind. Med., 6, 273-279

6. Delzell, E. & Monson, R.R. (1985) Mortality among rubber workers. IX. Curing workers. Am. J. 

ind. Med., 8, 537-544

7. Delzell, E. & Monson, R.R. (1985) Mortality among rubber workers. X. Reclaim workers. Am. J. 

ind. Med., 7, 307-313

8. Delzell, E., Andjelkovich, D. & Tyroler, H.A. (1982) A case-control study of employment 

experience and lung cancer among rubber workers. Am. J. ind. Med., 3, 393-404

9. Holmberg, B., Westerholm, P., Maasing, R., Kestrup, L., Gumaelius, K., Holmlund, L. & Englund, 

A. (1983) Retrospective cohort study of two plants in the Swedish rubber industry. Scand. J. work 

Environ. Health, 9 (Suppl. 2), 59-68

10. Holmes, T.M., Buffler, P.A., Holguin, A.H. & Hsi, B.P. (1986) A mortality study of employees at a 

synthetic rubber manufacturing plant. Am. J. ind. Med., 9, 355-362

11. Kilpikari, I. (1982) Mortality among male rubber workers in Finland. Arch. environ. Health, 37, 

295-299

12. Kilpikari, I., Pukkala, E., Lehtonen, M. & Hakama, M. (1982) Cancer incidence among Finnish 

rubber workers. Int. Arch. occup. environ. Health, 51, 65-71

13. Meinhardt, T.J., Lemen, R.A., Crandall, M.S. & Young, R.J. (1982) Environmental epidemiologic 

investigation of the styrene-butadiene rubber industry. Scand. J. Work Environ. Health, 8, 250-259

14. Norell, S., Ahlbom, A., Lipping, H. & Osterblom, L. (1983) Oesophageal cancer and vulcanisation 

work. Lancet, i, 462-463

15. Norseth, T., Andersen, A. & Giltvedt, J. (1983) Cancer incidence in the rubber industry in 

Norway. Scand. J. Work Environ. Health, 9 (Suppl. 2), 69-71

16. Wilcosky, T.C., Checkoway, H., Marshall, E.G. & Tyroler, H.A. (1984) Cancer mortality and 

solvent exposures in the rubber industry. Am. ind. Hyg. Assoc. J., 45, 809-811

17. Wang, H.-W., You, X.-J., Qu, Y.-H., Wang, W.-F., Long, Y.-M. & Ni, J.A. (1984) Investigation of 

cancer epidemiology and study of carcinogenic agents in the Shanghai rubber industry. Cancer Res., 

44, 3101-3105

18. Arp, E.W., Jr, Wolf, P.H. & Checkoway, H. (1983) Lymphocytic leukemia and exposures to 

benzene and other solvents in the rubber industry. J. occup. Med., 25, 598-602
19. Gustavsson, P., Hogstedt, C. & Holmberg, B. (1986) Mortality and incidence of cancer among 

Swedish rubber workers. Scand. J. Work Environ. Health, 12, 538-544

20. Veys, C. (1982) The rubber industry: reflections on health risks. In: Gardner, A.W., ed., Current 

Approaches to Occupational Health, Vol. 2, Bristol, Wright PSG, pp. 1-29

21. IARC Monographs, Suppl. 6, 488, 1987 

Last updated: 10 February 1998 
SACCHARIN

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 334) 

Saccharin

CAS No.: 81-07-2

Chem. Abstr. Name: 1,2-Benzisothiazo1-3(2H)-one, l,l-dioxide

Sodium Saccharin

CAS No.: 128-44-9

Chem. Abstr. Name: 1,2-Benzisothiazo1-3(2H)-one, 1,1-dioxide, sodium salt

Calcium Saccharin

CAS No.: 6485-34-3

Chem. Abstr. Name: 1,2-Benzisothiazo1-3(2H)-one, 1,1-dioxide, calcium salt

ortho-Toluenesulphonamide

CAS No.: 88-19-7

Chem. Abstr. Name: 2-Methylbenzenesulfonamide

A. Evidence for carcinogenicity to humans (inadequate) 

The evidence that the risk of cancer is increased among users of artificial sweeteners is inconsistent 

[ref: 1]. Since the positive report of Howe et al. [ref: 2], reports have become available on seven 

case-control studies and on one population study of bladder cancer.

The largest was a population-based study in ten areas of the USA, with 3010 bladder cancer cases 

and 5783 controls. The relative risk for bladder cancer associated with use of artificial sweeteners 

was 1.0 (95% confidence interval, 0.9-1.1) among men and 1.1 (0.9-1.3) among women. 

Significant trends of increasing risk with increasing average daily consumption were found in certain 

subgroups examined a priori on the basis of the results of animal experiments; these subgroups 

were female nonsmokers and male heavy smokers [ref: 3]. Subsequent, independent re-analysis of 

the same data by a different statistical technique (multiple logistic regression) confirmed the original 

findings overall but cast doubt on the significance of the findings in the two subgroups because of 

inconsistent dose-response trends, especially among the male heavy smokers [ref: 4]. In response, 

the original investigators noted that the inconsistency derived from the development of risk scores 

which, in their opinion, were not correctly derived, as two relevant variables had been omitted [ref: 

5]. In a subsequent report on data from one of the areas participating in this study, the use of 

hospital and population controls was compared. A higher proportion of hospital controls was found to 

have used artificial sweeteners than population controls [ref: 6]. This had been postulated earlier 

[ref: 2] as a possible reason for the negative findings of a hospital-based case-control study [ref: 7]. 

Bias resulting from use of prevalent rather than incident cases [ref: 8] has been suggested as a 

possible reason for the negative findings of another hospital-based case-control study [ref: 9].

Three other case-control studies have also shown increased risks among subgroups. In one, 

conducted simultaneously in Japan, the UK and the USA, the relative risks among women in the US 

component of the study associated with 'any' use of diet drinks and of sugar substitutes were 1.6 

and 1.5, respectively, and 2.6 and 2.1, respectively, for nonsmokers [ref: 10]. In the other two 

areas, however, a history of the use of sugar substitutes, primarily saccharin, was not associated 

with an elevated bladder cancer risk [ref: 11]. In a second study, conducted in West Yorkshire, UK, 

elevated risks were found for saccharin takers who were nonsmokers. In men, the relative risk was 

2.2 (95% confidence interval, 1.3-3.8); that in women was 1.6 (0.8-3.2) [ref: 12]. In a third study, 

conducted in a rural district of Denmark, a relative risk of 2.5 (1.0-6.6) was reported for saccharin 

consumption in men and women combined. This risk was not reduced after controlling for tobacco 

use and industrial work [ref: 13].
Two studies in Denmark [ref: 14,15], one in the USA [ref: 16] and a further case-control study in 

Canada [ref: 17], however, gave negative results. In one of the Danish studies, incidence of bladder 

cancer at ages 20-34 among people born 1941-1945 (when use of saccharin was high in Denmark) 

was compared with that among those born 1931-1940. The risk for men was 1.0 (0.7-1.6) and that 

for women 0.3 (0.1-1.0). This study indirectly assessed intrauterine exposure to saccharin [ref: 14]. 

The other two studies were population-based case-control studies of bladder cancer. In Denmark, 

the relative risk for people of the two sexes combined was 0.8 (0.6-1.1) [ref: 15]. In a study in the 

USA of bladder cancer in women aged 20-49, the odds ratio for regular use of artificially sweetened 

beverages, table-top sweetener or both was 1.0 (0.7-1.7) [ref: 16]. In Canada, the odds ratio for 

use of saccharin was 1.0 (0.9-1.2) in men and 1.0 (0.8-1.2) in women [ref: 17]. The increased risks 

seen in subgroups in other studies were not replicated in either study.

In the USA, in a study of 1862 patients hospitalized for cancer and of 10 874 control patients, a 

greater proportion of artificial sweetener users was found among women with cancer of the 

stomach. Little information was available on urinary-tract cancer. No overall association was found 

between artificial sweetener use and cancer [ref: 18]. 

B. Evidence for carcinogenicity to animals (sufficient

Saccharin (unspecified or commercial) has been tested for carcinogenicity by oral administration to 

mice, rats and hamsters. In mice, saccharin produced no difference in tumour incidence between 

treated and control animals in one single and in one multigeneration study. Two further studies by 

oral administration in mice and three in rats were considered to be inadequate for evaluation. A 

study in hamsters by oral administration and one study in mice by skin application could not be 

evaluated. A study in mice by bladder insertion provided evidence for the induction of bladder 

carcinomas [ref: 1]. Oral administration to mice produced thyroid tumours [ref: 19].

Sodium saccharin has been tested for carcinogenicity by oral administration to mice, rats and 

monkeys. One study in mice was inadequate for evaluation [ref: 1]. One single-generation study in 

rats showed an increased incidence of bladder tumours in males; two further studies showed a few 

bladder tumours; another study showed no difference in tumour incidence between treated and 

control animals; and two others were inadequate for evaluation [ref: 1]. In four two-generation 

studies in rats, sodium saccharin produced a statistically significant increase in the incidence of 

bladder tumours in F1 males fed either 5% or 7.5% sodium saccharin [ref: 1,20]. In a further twogeneration study of rats, a dose-related increase in the incidences of benign, malignant and/or 

combined bladder neoplasms was observed in males treated with doses ranging from 4-7.5% in the 

diet, while no tumorigenic effect was observed with 1% [ref: 21,22]. Transplacental exposure of rats 

to sodium saccharin and to saccharin (commercial) did not produce any treatment-related neoplasm 

[ref: 21,23]. Sodium saccharin has also been tested in mice by bladder insertion: it increased the 

incidence of bladder carcinomas. Expreiments in which it was tested by oral administration to 

monkeys and by intraperitoneal administration to mice were considered to be inadequate for 

evaluation [ref: 1].

The combination of sodium saccharin with sodium cyclamate in a ratio of 1:10 has been tested by 

oral administration in a multigeneration experiment in mice and in single experiments in rats. In one 

study in rats, transitional-cell carcinomas in the bladder were produced in male animals given the 

highest dose; in two further studies in rats and in the study in mice, there was no difference in 

tumour incidence between treated and control animals [ref: 1,24]. Another study in rats was 

inadequate for evaluation [ref: 1].

Pretreatment with a single instillation into the bladder of a low dose of N-methyl-N-nitrosourea or 

feeding of N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide and subsequent oral administration of 

sodium saccharin for long periods increased the incidence of bladder neoplasms in rats over than 

induced by the nitrosourea or the amide alone [ref: 1]. Simultaneous administration of N-nitroso-N-

(4-hydroxybutyl)butylamine and sodium saccharin significantly enhanced the induction of bladder 

papillomas compared to treatment with the nitrosamine alone [ref: 25]. Commercial saccharin 

preparations enhanced lung tumour induction in mice when given before or during intraperitoneal 

urethane administration [ref: 26]. In rats, oral administration sodium saccharin significantly 

increased the incidence of bladder neoplasms induced by ulceration of bladder mucosa [ref: 27,28]. 

Other studies of simultaneous or consecutive treatment with saccharin and known carcinogens were 

inadequate for evaluation [ref: 1].
ortho-Toluenesulphonamide was tested for carcinogenicity by oral administration in rats in a twogeneration study: no increase in bladder tumour incidence was noted in animals of either 

generation. In one of two single-generation studies in rats, benign and malignant bladder tumours 

were found [ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of saccharin, sodium saccharin or orthotoluenesulphonamide in humans [ref: 29].

It should be noted that many studies do not differentiate between saccharin ('insoluble' form) and 

sodium saccharin. Additionally, when it is reported that 'saccharin' (presumably sodium saccharin) 

causes a positive response, primarily in assays for chromosomal effects, the effect is seen only with 

very high concentrations, at which simple salts also give responses [ref: 29].

Treatment of mice with saccharin did not induce micronuclei or chromosomal aberrations in bonemarrow cells or spermatocytes; conflicting results were obtained for the induction of dominant lethal 

mutations. A commercial preparation (of unknown purity) caused somatic mutations in the mouse 

spot test. Injection of radioactive saccharin into rats revealed no DNA binding in the liver or bladder, 

nor did treatment of rats result in DNA damage in bladder tissue. Saccharin did not induce sister 

chromatid exchanges in cultured human lymphocytes. Negative results were obtained in assays for 

transformation in cultured rodent cells, but saccharin enhanced transformation of virus-infected rat 

embryo cells and of C3H 10T1/2 mouse embryo cells initiated with 3-methylcholanthrene in twostage transformation assays. Results obtained with rodent cell systems were inconclusive with 

regard to inhibition of intercellular communication. It caused DNA strand breaks in rat hepatocytes 

but no chromosomal aberration in Chinese hamster cells. Saccharin induced aneuploidy but not 

recombination or gene conversion in yeast. It was not mutagenic and did not induce prophage in 

bacteria [ref: 29].

Treatment of mice with sodium saccharin did not induce micronuclei, somatic mutations (in the spot 

test) or sperm abnormalities. Treatment of Chinese hamsters did not induce chromosomal 

aberrations in bone-marrow cells or spermatogonia but induced sister chromatid exchanges in bonemarrow cells. Treatment of mice with commercial sodium saccharin resulted in the induction of 

dominant lethal mutations, but treatment with a preparation 'purified' by undefined criteria did not. 

Sodium saccharin induced chromosomal aberrations and sister chromatid exchanges in cultured 

human lymphocytes and induced sister chromatid exchanges and chromosomal aberrations in 

cultured Chinese hamster cells but no mutation in mouse lymphoma cells. It did not induce 

tranformation of BALB/c 3T3 cells. Contradictory results have been reported concerning the ability of 

sodium saccharin to induce sex-linked recessive lethal mutations in Drosophila, and it did not cause 

a significant increase in heritable translocations. Sodium saccharin induced mutation, gene 

conversion and recombination in yeast, but was not mutagenic to bacteria [ref: 29].

ortho-Toluenesulphonamide did not induce micronuclei or somatic mutation (in the spot test) in mice 

treated in vivo. Contradictory results have been obtained for the induction of sex-linked recessive 

lethal mutations in Drosophila. It was not mutagenic to bacteria [ref: 29]. 

Overall evaluation

Saccharin is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Subsequent evaluation: Vol. 73 (1999)

Also see previous evaluation: Vol. 22 (1980)

References
1. IARC Monographs, 22, 55-109, 171-185, 1980

2. Howe, G.R., Burch, J.D., Miller, A.B., Cook, G.M., Estève, J., Morrison, B., Gordon, P., Chambers, 

L.W., Fodor, G. & Winsor, G.M. (1980) Tobacco use, occupation, coffee, various nutrients and 

bladder cancer. J. natl Cancer Inst., 64, 701-713

3. Hoover, R.M. & Strasser, P.H. (1980) Artificial sweeteners and human bladder cancer. Preliminary 

results. Lancet, i, 837-840

4. Walker, A.M., Dreyer, N.A., Friedlander, E., Loughlin, J., Rothman, K.J. & Kohn, H.I. (1982) An 

independent analysis of the National Cancer Institute study on non-nutritive sweeteners and bladder 

cancer. Am. J. publ. Health, 72, 376-381

5. Hoover, R. & Hartge, P. (1982) Non-nutritive sweeteners and bladder cancer. Am. J. publ. Health, 

72, 382-383

6. Silverman, D.T., Hoover, R.N. & Swanson, G.M. (1983) Artificial sweeteners and lower urinary 

tract cancer: hospital vs. population controls. Am. J. Epidemiol., 117, 326-334

7. Wynder, E.L. & Stellman, S.D. (1980) Artificial sweetener use and bladder cancer: a case-control 

study. Science, 207, 1214-1216

8. Goldsmith, D.F. (1982) Calculation of potential bias in the odds ratio illustrated by a study of 

saccharin use and bladder cancer. Environ. Res., 27, 298-306

9. Kessler, I.I. & Clark, J.P. (1978) Saccharin, cyclamate, and human bladder cancer. No evidence of 

an association. J. Am. med. Assoc., 240, 349-355

10. Morrison, A.S. & Buring, J.E. (1980) Artificial sweeteners and cancer of the lower urinary tract. 

New Engl. J. Med., 302, 537-541

11. Morrison, A.S., Verhoek, W.G., Leck, I., Aoki, K., Ohno, Y. & Obata, K. (1982) Artificial 

sweeteners and bladder cancer in Manchester, UK, and Nagoya, Japan. Br. J. Cancer, 45, 332-336

12. Cartwright, R.A., Adib, R., Glashan, R. & Gray, B.K. (1981) The epidemiology of bladder cancer 

in West Yorkshire. A preliminary report on non-occupational aetiologies. Carcinogenesis, 2, 343-347

13. Mommsen, S., Aagaard, J. & Sell, A. (1983) An epidemiological study of bladder cancer in a 

predominantly rural district. Scand. J. Urol. Nephrol., 17, 307-312

14. Jensen, O.M. & Kamby, C. (1982) Intra-uterine exposure to saccharin and risk of bladder cancer 

in man. Int. J. Cancer, 29, 507-509

15. Møller-Jensen, O., Knudsen, J.B., Sørensen, B.L. & Clemmesen, J. (1983) Artificial sweeteners 

and absence of bladder cancer risk in Copenhagen. Int. J. Cancer, 32, 557-582

16. Piper, J.M., Matanoski, G.M. & Tonascia, J. (1986) Bladder cancer in young women. Am. J. 

Epidemiol., 123, 1033-1042

17. Risch, H.A., Burch, J.D., Miller, A.B., Hill, G.B., Steele, R. & Howe, G.R. (1987) Dietary factors 

and the incidence of cancer of the urinary bladder. Am. J. Epidemiol. (in press)

18. Morrison, A.S. (1979) Use of artificial sweeteners by cancer patients. J. natl Cancer Inst., 62, 

1397-1399
19. Prasad, O. & Rai, G. (1986) Induction of papillary adenocarcinoma of thyroid in albino mice by 

saccharin feeding. Indian J. exp. Biol., 24, 197-199

20. Taylor, J.M., Weinberger, M.A. & Friedman, L. (1980) Chronic toxicity and carcinogenicity of the 

urinary bladder of sodium saccharin in the in utero-exposed rat. Toxicol. appl. Pharmacol., 54, 57-75

21. Schoenig, G.P., Goldenthal, E.I., Geil, R.G., Frith, C.H., Richter, W.R. & Carlborg, F.W. (1985) 

Evaluation of the dose response and in utero exposure to saccharin in the rat. Food chem. Toxicol., 

23, 475-490

22. Squire, R.A. (1985) Histopathological evaluation of rat urinary bladders from the IRDC twogeneration bioassay of sodium saccharin. Food chem. Toxicol., 23, 491-497

23. Schmähl, D. & Habs, M. (1980) Absence of a carcinogenic response to cyclamate and saccharin 

in Sprague-Dawley rats after transplacental application. Arzneimittelforsch., 30, 1905-1906

24. Schmähl, D. & Habs, M. (1984) Investigations on the carcinogenicity of the artificial sweeteners 

sodium cyclamate and sodium saccharin in rats in a two-generation experiment. Arzneimittelforsch., 

34, 604-606

25. Nakanishi, K., Hirose, M., Ogiso, T., Hasegawa, R., Arai, M. & Ito, N. (1980) Effects of sodium 

saccharin and caffeine on the urinary bladder of rats treated with N-butyl-N-(4-

hydroxybutyl)nitrosamine. Gann, 71, 490-500

26. Theiss, J.C., Arnold, L.J. & Shimkin, M.B. (1980) Effect of commercial saccharin preparations on 

urethan-induced lung tumorigenesis in strain A mice. Cancer Res., 40, 4322-4324

27. Cohen, S.M., Murasaki, G., Fukushima, S. & Greenfield, R.E. (1982) Effect of regenerative 

hyperplasia on the urinary bladder: carcinogenicity of sodium saccharin and N-[4-(5-nitro-2-furyl)-2-

thiazolyl]formamide. Cancer Res., 42, 65-71

28. Hasegawa, R., Greenfield, R.E., Murasaki, G., Suzuki, T. & Cohen, S.M. (1985) Initiation of 

urinary bladder carcinogenesis in rats by freeze ulceration with sodium saccharin promotion. Cancer 

Res., 45, 1469-1473

29. IARC Monographs, Suppl. 6, 488-493, 520-522, 1987 

Synonyms for Saccharin

● Anhydro-o-sulphaminebenzoic acid 

● Assugrin vollsuss [also contains sodium cyclamate] 

● 3-Benzisothiazolinone 1,1-dioxide 

● 1,2-Benzisothiazolin-3-one, 1,1-dioxide 

● 1,2-Benzisothiazolinone, 1,1-dioxide 

● Benzoic sulphimide 

● o-Benzoic sulphimide 

● Benzoic sulphinide 

● Benzosulphimide 

● Benzo-2-sulphimide 

● o-Benzosulphimide 

● o-Benzoyl sulphimide 

● Benzo-sulphinide 

● 1,2-Dihydro-2-ketobenzisosulphonazole 

● 2,3-Dihydro-3-oxobenzisosulphonazole 

● Edulcor 

● Garantose 

● Glucid 
● Gluside 

● Hermesetas 

● 3-Hydroxybenzisothiazole-S,S-dioxide 

● Insoluble saccharin 

● Kandiset 

● Natreen [also contains sodium cyclamate] 

● Sacarina 

● Saccharimide 

● Saccharin acid 

● Saccharin insoluble 

● Saccharina 

● Saccharine 

● Saccharinol 

● Saccharinose 

● Saccharol 

● Saxin 

● Sucre 

● Sucrette 

● o-Sulphobenzimide 

● o-Sulphobenzoic acid imide 

● 2-Sulphobenzoic imide 

● Sykose 

● Zaharina 

Synonyms for Sodium saccharin

● 1,2-Benzisothiazolin-3-one,l,l-dioxide, sodium salt 

● Cristallose 

● Crystallose 

● Dagutan 

● Kristallose 

● ODA 

● Saccharinriatrium 

● Saccharin sodium 

● Saccharin soluble 

● Saccharoidum Natricum 

● Saxin 

● Sodium benzosulphimide 

● Sodium 2-benzosulphimide 

● Sodium ortho-benzosulphimide 

● Sodium saccharide 

● Sodium saccharinate 

● Sodium saccharine 

● Soluble saccharin 

● Soluble Gluside 

● Succaril (also contains sodium cyclamate) 

● Sucra 

● 2-Sulphobenzoic imide, sodium salt 

● Sweeta 

● Sykose 

● Willosetten 

Synonyms for Calcium saccharin

● 1,2-Benzisothiazolin-3-one,l,l-dioxide, calcium salt 

● Calcium benzosulphimide 

● Calcium 2-benzosulphimide 

● Calcium-ortho-benzosulphimide 

● Calcium saccharina 

● Calcium saccharinate 

● Calcium saccharine 

● Daramin 

● Saccharin calcium 
● 2-Sulphobenzoic imide, calcium salt 

Synonym for ortho-Toluenesulphonamide

● 2-Methylbenzenesulfonamide 

Last updated: 30 September 1999 
SHALE-OILS

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 339) 

CAS No.: 68308-34-9

A. Evidence for carcinogenicity to humans (sufficient)

The association between shale-oils and skin cancers, particularly of the scrotum, was demonstrated 

by analyses of 65 cases of skin cancer, including 31 of the scrotum, from the Scottish shale-oil 

industry. In the UK, over 2000 cases of skin cancer ('mule-spinners' cancer') were recorded among 

cotton-textile workers and others exposed to lubricating oils (many of which are believed to have 

been shale-derived). The occupational etiology of these cases is supported by occupational mortality 

statistics for the UK and by an occupational comparison with fatal cases of penile cancer. In 

contrast, one study showed very few scrotal cancers among US cotton-textile workers employed in 

mills where shale-derived lubricants were not used. A cohort study of shale-oil workers in western 

USA showed statistically significant excesses of all cancers and of colon cancer, although data on 

duration and time since first exposure were not available. A cohort study of shale-oil workers in 

Estonia showed a significant excess of skin cancer but not of cancers at other sites [ref: 1]. A followup of 6064 men who had worked in the Scottish oil-shale industry between 1950 and 1962 showed 

a significant excess of skin cancer [ref: 2]. A case-control study of lung cancer in the shale area 

showed no association with work in the shale industry [ref: 2].

Two basal- and two squamous-cell carcinomas were found among 325 workers employed at an oilshale demonstration facility during 1948-1969 in Utah, USA. The incidence was about that expected 

[ref: 3]. 

B. Evidence for carcinogenicity to animals (sufficient)

Inhalation of either raw oil shale or spent oil shale produced lung tumours in rats. Application of an 

extract of spent oil shale produced skin tumours in mice [ref: 1].

Skin application of crude oils from both low- and high-temperature retorting induced skin tumours in 

mice and rabbits; the high-temperature retorted oils had greater carcinogenic activity. A lowtemperature crude oil produced lung tumours in mice after intratracheal instillation [ref: 1].

Various fractions of shale-oils were carcinogenic when applied to the skin of mice and rabbits [ref: 

1].

Shale-oil distillates, residues, blends, and commercial products of the oil-shale industry were tested 

in mice by skin application, producing skin tumours. Distillation fractions from less highly refined 

shale-oils were more carcinogenic than the more highly refined products [ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of shale-oils in humans.

All shale-derived materials assayed in tests for genetic and related effects came from sources in the 

USA and were therefore all produced by low-temperature processes [ref: 4].

Chromosomal aberrations were induced in bone-marrow cells of rats following administration by 

gavage of a suspension of raw oil-shale. In-vitro tests of extracts of raw oil-shale in cultured rodent 

cells, yeast and bacteria gave negative results [ref: 4].
Preparations of spent oil-shale yielded negative results in an assay for chromosomal aberrations in 

vivo and in mutation assays with eukaryotic cells in vitro; contradictory results were obtained in 

bacterial mutation assays [ref: 4].

Preparations of shale-derived crude oils from various sources and retort processes gave both 

positive and negative results in assays for chromosomal effects in rodents in vivo. Two crude shaleoil preparations induced sister chromatid exchanges in cultured human lymphocytes; three others 

did not induce mitotic gene conversion in yeast. Shale-derived crude oils were mutagenic to cultured 

rodent cells, yeast and bacteria following metabolic or photoinduced activation [ref: 4].

As compared with the corresponding crude shale-oils, preparations of hydrotreated oils showed less 

activity or gave negative results in various short-term tests [ref: 4].

Oil-shale retort process-waters induced chromosomal aberrations, but not sister chromatid 

exchanges, in cells of mice treated in vivo, chromosomal aberrations in cultured rodent cells and 

mutation and DNA damage in cultured rodent cells and bacteria following metabolic activation or 

photoactivation [ref: 4].

Extracts of oil-shale ash were not mutagenic to fungi but were mutagenic to bacteria in the absence 

of a metabolic system [ref: 4]. 

Overall evaluation

Shale-oils are carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 35 (1985)

References

1. IARC Monographs, 35, 161-217, 243-247, 1985

2. Miller, B.G., Cowie, H.A., Middleton, W.G. & Seaton, A. (1986) Epidemiologic studies of Scottish 

oil shale workers. III. Causes of death. Am. J. ind. med., 9, 433-446

3. Rom, W.N., Krueger, G., Zone, J., Attfield, M.D., Costello, J., Burkart, J. & Turner, E.R. (1985) 

Morbidity survey of US oil shale workers employed during 1948-1969. Arch. environ. Health, 40, 58-

62

4. IARC Monographs, Suppl. 6, 494, 1987 

Last updated: 10 February 1998 
SODIUM ortho-PHENYLPHENATE

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 392) 

CAS No.: 132-27-4

Chem. Abstr. Name: (1,1'-Biphenyl)-2-ol, sodium salt 

B. Evidence for carcinogenicity to animals (sufficient) 

Sodium ortho-phenylphenate produced urinary bladder carcinomas in rats following its oral 

administration [ref: 1-3]. It increased the incidences of haemangiosarcomas of the liver and of 

hepatocellular carcinomas in male mice after its oral administration [ref: 4]. When given in the diet 

to rats, it enhanced the incidence of bladder cancer induced by oral administration of N-nitroso-N-(4-

hydroxybutyl)-N-butylamine [ref: 5]. 

Overall evaluation

Sodium ortho-phenylphenate is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Subsequent evaluation: Vol. 73 (1999)

Also see previous evaluation: Vol. 30 (1983)

References

1. IARC Monographs, 30, 329-344, 1983

2. Fujii, T. & Hiraga, K. (1985) Carcinogenicity testing of sodium ortho-phenylphenate in F344 rats 

(Jpn.). J. Saitama med. School,12, 277-287

3. Fujii, T., Mikuriya, H., Kamiya, N. & Hiraga, K. (1986) Enhancing effect of thiabendazole on 

urinary bladder carcinogenesis induced by sodium o-phenylphenate in F344 rats. Foodchem. 

Toxicol., 24, 207-211

4. Hagiwara, A., Shibata, M., Hirose, M., Fukushima, S. & Ito, N. (1984) Long-term toxicity and 

carcinogenicity study of sodium o-phenylphenate in B6C3F1 mice. Food chem. Toxicol., 22, 809-814

5. Fukushima, S., Kurata, Y., Shibata, M., Ikawa, E. & Ito, N. (1983) Promoting effect of sodium ophenylphenate and o-phenylphenol on two-stage urinary bladder carcinogenesis in rats. Gann, 74, 

625-632 

Synonyms

● 2-Biphenylol, sodium salt 

● Biphenyl-2-ol, sodium salt 

● Dowicide 

● Dowicide A & A flakes 

● Dowizid A 

● 2-Hydroxybiphenyl sodium salt 
● 2-Hydroxydiphenyl sodium 

● Mystox WFA 

● Natriphene 

● 2-Phenylphenol sodium salt 

● ortho-Phenylphenol sodium salt 

● Preventol ON & ON extra 

● Sodium [1,1'-biphenyl]-2-olate 

● Sodium 2-biphenylolate 

● Sodium 2-hydroxydiphenyl 

● Sodium 2-phenylphenate 

● Sodium ortho-phenylphenol 

● Sodium ortho-phenylphenolate 

● Sodium ortho-phenylphenoxide 

● Sodium ortho-phenylphenylolate 

● Sodium phenylphenate 

● SOPP 

● Stopmold B 

● Topane 

Last updated: 30 September 1999 
SOOTS

(Group 1)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p.343) 

A. Evidence for carcinogenicity to humans (sufficient)

The carcinogenicity of soot is demonstrated by numerous case reports, dating back over 200 years, 

of skin cancer, particularly of the scrotum, among chimney-sweeps. More recent cohort studies of 

mortality among chimney-sweeps in Sweden and Denmark have shown a significantly increased risk 

of lung cancer. Supporting evidence for an association with lung cancer was provided by two earlier 

epidemiological studies in the German Democratic Republic and the UK. The potentially confounding 

and interactive effects of smoking could not be evaluated; however, cigarette smoking is not 

believed to have seriously biased these estimates. In addition to lung cancer, statistically significant 

excess mortality from oesophageal cancer, primary liver cancer and leukaemia was found among 

chimney-sweeps in one study [ref: 1]. 

B. Evidence for carcinogenicity to animals (inadequate for soots; sufficient for soot extracts)

Coal soot was tested in two experiments in mice by whole-body exposure, but the studies were 

inadequate for evaluation. Coal-soot extracts applied to the skin of mice produced skin tumours in 

two studies. A wood-soot extract applied to the skin of mice was inadequately tested. In limited 

studies, subcutaneous implants of wood soot in female rats produced a few local sarcomas; similar 

implants in the scrotal sac of rats did not. An extract of fuel-oil soot was inadequately tested by 

application to the skin of mice. Extracts of soot from the combustion of oil shale produced skin 

tumours in mice after dermal application and lung tumours in rats after intratracheal instillation. 

Extracts of soot from the combustion of a heating oil produced from shale-oil produced skin tumours 

in mice in two experiments when applied to the skin [ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of soots in humans.

Extracts of soot samples from domestic sources were mutagenic to Salmonella typhimurium both in 

the presence and absence of an exogenous metabolic system. Extracts of experimentally-derived 

soots were mutagenic in forward mutation assays in S. typhimurium and in cultured human 

lymphoblasts in the presence of an exogenous metabolic system. Extracts of particulate emissions 

from wood combustion were shown to induce sister chromatid exchanges in Chinese hamster ovary 

cells, transformation of Syrian hamster embryo cells and mutation in S. typhimurium. An 

experimentally-derived, intact particulate soot and an extract of this material were mutagenic in a 

human lymphoblastoid cell line [ref: 2]. 

Overall evaluation

Soots are carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 35 (1985)

References

1. IARC Monographs, 35, 219-246, 1985
2. IARC Monographs, Suppl. 6, 497, 1987 

Synonym

● Primary carbonaceous particulate emissions 

Last updated: 10 February 1998 
SPIRONOLACTONE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 344) 

CAS No.: 52-01-7

Chem. Abstr. Name: Pregn-4-ene-21-carboxylic acid,7-(acetylthio)-17-hydroxy-3-oxo-, γlactone,(7α, 17α) 

A. Evidence for carcinogenicity to humans (inadequate) 

Cases of breast cancer have been reported in women who had used spironolactone. Four analytical 

studies, however, showed no consistent evidence of an assocation [ref: 1]. 

B. Evidence for carcinogenicity to animals (limited) 

Spironolactone was tested by oral administration in two experiments in rats. Increased incidences of 

thyroid and testicular tumours were reported in one experiment but not in another experiment of 

longer duration with lower doses [ref: 1]. 

C. Other relevant data

No data were available to the Working Group. 

Overall evaluation

Spironolactone is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Subsequent evaluation: Vol. 79 (2001)

Also see previous evaluation: Vol. 24 (1980)

Reference

1. IARC Monographs, 24, 259-273, 1980 

Synonyms

● 7α-Acetylthio-17β-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone 

● 7α-Acetylthio-3-oxo-17α-pregn-4-ene-21,17β-carbolactone 

● 7α-Acetylthio-3-oxo-17β-pregn-4-ene-21, 17β-carbolactone 

● Aldactazide 

● Aldactide 

● Aldactone 

● Aldactone A 

● β-(7α-Acetylthio-17β-hydroxy)-3-oxoandrost-4-en-17α-yl)propionic acid, lactone 

● 17-Hydroxy-7α-mercapto-3-oxo-17α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γlactone 7-acetate 

● 3-(3-Keto-7α-acetylthio-17β-hydroxy-4-androsten-17α-yl) propionic acid lactone 
● Osiren 

● Osyrol 

● 3'-(3-Oxo-7α-acetylthio-17β-hydroxyandrost-4-en-17β-yl)propionic acid lactone 

● 3-(3-Oxo-7α-acetylthio-17β-hydroxy-4-androsten-17α-yl)propionic acid gamma-lactone 

● S-Ester with 17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid, γ-lactone 

● SC 15983 

● SC 9420 

● Spiresis 

● Spiridon 

● Spiro[17H-cyclopenta[a]phenanthrene-17,2'(5'H)furan], pregn-4-ene-21-carboxylic acid 

deriv. 

● Spiroctanie 

● Spirolactone 

● Spirolakton 

● Spirolang 

● Spirone 

● Spironolactone A 

● Uractone 

● Verospiron 

● Verospirone 

Last updated: 11 March 1998 
SULFAFURAZOLE (SULPHISOXAZOLE)

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 347) 

CAS No.: 127-69-5 

Chem. Abstr. Name: Benzenesulfonamide, 4-amino-N-(3,4-dimethyl-5-isoxazolyl)- 

A. Evidence for carcinogenicity to humans (inadequate) 

No significant association with cancer at any site was oberved during 1969-1976 among 11 659 

members of a prepaid health plan prescribed sulfafurazole during 1969-1973 [ref: 1]. 

B. Evidence for carcinogenicity to animals (inadequate) 

Sulfafurazole was tested in mice and rats by oral administration; no increase in tumour incidence 

was observed [ref: 2]. 

C. Other relevant data

No data were available to the Working Group. 

Overall evaluation

Sulfafurazole (sulphisoxazole) is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 24 (1980)

References

1. Friedman, G.D. & Ury, H.K. (1980) Initial screening for carcinogenicity of commonly used drugs. 

J. natl Cancer Inst., 65, 723-733 

2. IARC Monographs, 24, 275-285, 1980 

Synonyms

● Accuzole 

● Alphazole 

● Amidoxal 

● 5-(p-Aminobenzenesulphonamide)-3,4-dimethylisoxazole 

● 4-Amino-N-(3,4-dimethyl-5-isoxazolyl)benzenesulphonamide 

● 5-(4-Aminophenylsulphonamido)-3,4-dimethylisoxazole 

● Astrazolo 

● Azo gantrisin 

● Azosulfizin 

● Bactesulf 

● Barazae 
● Chemouag 

● 3,4-Dimethylisoxazole-5-sulphanilamide 

● N'-(3,4)Dimethylisoxazol-5-yl-sulphanilamide 

● N1-(3,4-Dimethyl-5-isoxazolyl)sulphanilamide 

● 3,4-Dimethyl-5-sulphanilamidoisoxazole 

● 3,4-Dimethyl-5-sulphonamidoisoxazole 

● Dorsulfan 

● Entusil 

● Entusul 

● Ganda 

● Gantrisin 

● Gantrisine 

● Gantrisona 

● Gantrosan 

● Isoxamin 

● J-Sul 

● Koro-Sulf 

● Neazolin 

● Neoxazol 

● Norilgan-S 

● Novazolo 

● Novosaxazole 

● NU 445 

● Pancid 

● Renosulfan 

● Resoxol 

● Roxosul 

● Roxoxol 

● Saxosozine 

● Sodizole 

● Sosol 

● Soxamide 

● SK-soxazole 

● Soxisol 

● Soxitabs 

● Soxo 

● Soxomide 

● Stansin 

● Sulbio 

● Sulfagan 

● Sulfagen 

● Sulfalar 

● Sulfapolar 

● Sulfasan 

● Sulfasol 

● Sulfazin 

● Sulfazole 

● Sulfisin 

● Sulfizin 

● Sulfizol 

● Sulfizole 

● Sulfoxol 

● Suloxsol 

● Sulphadimethylisoxazole 

● Sulphafuraz 

● Sulphafurazol 

● Sulphafurazole 

● Sulphafurazolum 

● Sulphaisoxazole 

● 5-Sulphanilamido-3,4-dimethyl-isoxazole 

● Sulphisoxazol 

● Sulphisoxazole 

● Sulphofurazole 

● Sulsoxin 

● Thiasin 
● TL-azole 

● Unisulf 

● Urisoxin 

● Uritrisin 

● Urogan 

● U.S.-67 

● Vagilia 

● V-Sul 

Last updated: 11 March 1998 
SULFAMETHOXAZOLE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 348) 

CAS No.: 723-46-6

Chem. Abstr. Name: Benzenesulfonamide, 4-amino-N-(5-methyl-3-isoxazolyl)- 

A. Evidence for carcinogenicity to humans (inadequate) 

Although no increase in the incidence of cancer at all sites combined was noted during 1969-1976 

among 1709 members of a prepaid health plan prescribed sulfamethoxazole during 1969-1973, 

significant increases in the incidence of nasopharyngeal carcinoma (3 observed, 0.1 expected; 

relative risk, 30.0 [95% confidence interval, 23.7-36.3]) and of cancer of the cervix after a two-year 

lag period (7 observed, 2.2 expected; relative risk, 3.2 [1.8-4.5]) were observed. However, a 

significant deficit of colon cancer was also seen (none observed, 4.7 expected) [ref: 1]. 

B. Evidence for carcinogenicity to animals (limited) 

Sulfamethoxazole produced thyroid tumours in rats following its oral administration; no information 

on other tumour types was reported [ref: 2]. 

C. Other relevant data

In a single study, sulfamethoxazole did not induce chromosomal aberrations in human lymphocytes 

in vivo or in vitro. It was not mutagenic to bacteria [ref: 3]. 

Overall evaluation

Sulfamethoxazole is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Subsequent evaluation: Vol. 79 (2001)

Also see previous evaluation: Vol. 24 (1980)

References

1. Friedman, G.D. & Ury, H.K. (1980) Initial screening for carcinogenicity of commonly used drugs. 

J. natl Cancer Inst., 65, 723-733 

2. IARC Monographs, 24, 285-295, 1980 

3. IARC Monographs, Suppl. 6, 502-503, 1987 

Synonyms

● N1-(5-Methylisoxazol-3-yl)sulphanilamide 

● 3-p-Aminobenzenesulphonamido-5-methylisoxazole 
● 4-Amino-N-(5-methyl-3-isoxazolyl)benzene sulphonamide 

● 3-(p-Aminophenylsulphonamido)-5-methylisoxazole 

● Azo-gantanol 

● Bactrim 

● Co-trimoxazole 

● Eusaprim 

● Fectrim 

● Gantanol 

● Metoxal 

● N1-(5-Methyl-3-isoxazolyl)sulphanilamide 

● 5-Methyl-3-sulphanilamidoisoxazole 

● MS 53 

● Radonil 

● Ro 4-2130 

● Septra 

● Septran 

● Septrin 

● Sinomin 

● Sulphamethalazole 

● Sulphamethoxazol 

● Sulphamethoxazole 

● Sulphamethoxizole 

● Sulphamethylisoxazole 

● 3-Sulphanilamido-5-methylisoxazole 

● Sulphisomezole 

● Trib 

● Trimetoprim-sulfa 

Last updated: 11 March 1998 
TALC NOT CONTAINING ASBESTIFORM FIBRES 

(Group 3)

TALC CONTAINING ASBESTIFORM FIBRES 

(Group 1) 

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p.349) 

Talc

CAS No.: 14807-96-6

A. Evidence for carcinogenicity to humans (inadequate for talc not containing asbestiform 

fibres; sufficient for talc containing asbestiform fibres)

Evaluation of the effects of talc is confused by the fact that talc deposits may be contaminated with 

various other minerals, including carbonates, quartz, serpentines and amphiboles (asbestiform and 

nonasbestiform) [ref: 1].

Case studies have suggested an association between mesothelioma and exposure to talc containing 

asbestiform fibres [ref: 1].

A proportionate mortality study of miners and millers of talc containing asbestiform tremolite has 

shown an excess of lung cancer and one case of mesothelioma. Another cohort study of workers 

mining and milling talc containing tremolite, anthophyllite and serpentine minerals revealed 

significant excess mortality from lung cancer and from nonmalignant respiratory disease. Mortality 

from lung cancer increased with latency [ref: 1].

Several mortality studies have assessed cancer risk among miners and millers of talc that was 

reported to contain no more than trace amounts of asbestos. A cohort mortality study of talc miners 

and millers showed an excess of lung cancer among underground miners but not among millers; a 

contributory etiological role of radon daughters to the lung cancer risk in miners could not be 

excluded. The three other studies published suffered from methodological limitations and could not 

be interpreted [ref: 1].

A cohort study of pottery workers exposed to silica and talc showed an excess risk of lung cancer 

(standardized mortality ratio [SMR], 143; 52 observed, 36.3 expected). Among those exposed to 

high levels of silica, an SMR of 254 (21 observed, 8.3 expected; p < 0.05) occurred among those 

with exposure to nonfibrous talc in contrast to an SMR of 137 (18 observed, 13.2 expected; p > 

0.05) among those without talc exposure. Mortality from lung cancer increased with duration of 

exposure to talc (SMR, 364 for those with 15 years or more of exposure), but not with duration of 

exposure to silica [ref: 2].

A case-control study has suggested an approximate doubling in relative risk for ovarian cancer 

among women with perineal use of talc, but the possibility of recall bias cannot be ruled out [ref: 1]. 

B. Evidence for carcinogenicity to animals (inadequate; for talc not containing asbestiform 

fibres and for talc containing asbestiform fibres)

Talc of different grades was tested in mice, rats and hamsters by various routes of administration, 

including intraperitoneal, intrathoracic and intrapleural routes. Most of these studies were 

inadequate. No tumour was induced in rats following either a single intrapleural administration or 

four intraperitoneal injections of talc, or following administration of talc in the diet. No local tumour 

developed in mice following a single subcutaneous injection of talc [ref: 1]. 
C. Other relevant data

No data were available on the genetic and related effects of talc in humans.

Talc did not induce dominant lethal mutations or chromosomal aberrations in bone-marrow cells of 

rats treated in vivo, or chromosomal aberrations in human cells in vitro. Talc was not mutagenic to 

yeast or to bacteria in a host-mediated assay [ref: 3]. 

Overall evaluation

Talc not containing asbestiform fibres is not classifiable as to its carcinogenicity to humans (Group 

3).

Talc containing asbestiform fibres is carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 42 (1987)

References

1. IARC Monographs, 42, 185-224, 1987

2. Thomas, T.L. & Stewart, P.A. (1987) Mortality from lung cancer and respiratory disease among 

pottery workers exposed to silica and talc. Am. J. Epidemiol., 125, 35-43

3. IARC Monographs, Suppl. 6, 504-5-5, 1987 

Synonyms for Talc

● Agalite 

● Asbestine 

● B9 finntalc P40 

● B13 

● Beaver white 200 

● CP 10-40 

● CP 38-33 

● Crystalite 

● CR 6002 

● Desertalc 57 

● Emtal 500 

● Emtal 549 

● Emtal 596 

● Emtal 599 

● Fibrene C 400 

● French chalk 

● FW-XO 

● HSDB 830 

● IT Extra 

● LMR 100 

● Microneeca K 1 

● Micro white 5000A 

● Microtalco IT extra 

● Mistron 

● MP 25-38 

● MP 40-27 

● MP 45-26 
● MST 

● MT 12-50 

● Mussolinite 

● NCI CO6018 

● Nytal 200 

● Nytal 400 

● Pk-C 

● Pk-N 

● Polytal 4641 

● Polytal 4725 

● Potstone 

● Snowgoose 

● Soapstone 

● Steatite 

● Steawhite 

● Supreme 

● Supreme dense 

● Talcan PK-P 

● Talcron CP 44-31 

● Talcum 

Last updated: 10 February 1998 
TOBACCO PRODUCTS, SMOKELESS

(Group 1) 

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 357) 

A. Evidence for carcinogenicity to humans (sufficient)

In North America and western Europe, case reports indicate an association between tobacco 

chewing and oral cancer at the site where the quid was placed habitually. In those case-control 

studies in which an association between tobacco chewing and cancer of the oral cavity, pharynx and 

larynx has been observed, confounding by tobacco smoking or alcohol consumption could not be 

excluded. A slight increase in the incidence of oesophageal cancer related to tobacco chewing has 

been seen in four case-control studies [ref: 1].

Case reports indicate an association between oral use of snuff and oral cancer. Four case-control 

studies imply a causal association between snuff use and oral, and possibly pharyngeal, cancer. 

That oral use of snuff increases the risk of nasal-sinus cancer was suggested in one case-control 

study [ref: 1].

Three case series also show a high relative frequency of smokeless-tobacco use (chewing tobacco or 

oral snuff, unspecified) among oral cancer patients. Four case-control studies have shown the 

association between smokeless-tobacco use and the risk of oral cancer. Two cohort mortality studies 

provide evidence of a positive association with oesophageal cancer, and one suggests an increased 

risk for oral and pharyngeal cancer [ref: 1].

Two large case-control studies from Pakistan and India reported substantial increases in the risk for 

oral cancer related to tobacco-lime (khaini) chewing [ref: 1]. In addition, evidence is available from 

various studies in which cancer risks were studied in relation to unspecified habits of betel-tobaccolime chewing [ref: 2].

Case series have indicated an association between use of shammah and nass and oral cancer. Oral 

cancer was found to develop at the site at which nass was placed habitually. Two case-control 

studies showed substantial increases in the risk of oral cancer associated with nass use and one with 

naswar use; however, in these studies positive confounding by smoking and other factors could not 

be excluded. Oral cancer in users of mishri and gudakhu was studied in a prevalence survey; no 

case was found [ref: 1]. A study of 64 patients with squamous-cell carcinoma of the head and neck 

in Saudi Arabia showed that 81% were alshammah users and 34% were alqat users, but only 14% 

were cigarette smokers; none used alcohol to excess [ref: 3]. 

No association has been seen between nasal use of snuff and oral cancer. In two case-control 

studies, an association between snuff inhaling and nasal-sinus cancer has been reported. One casecontrol study reported snuff inhaling to be more common among patients with cancers of the 

oesophagus, hypopharynx or oropharynx than among controls [ref: 1]. 

B. Evidence for carcinogenicity to animals (inadequate)

Various chewing tobaccos and unburnt cigarette tobaccos and their extracts were tested for 

carcinogenicity by oral administration in mice, by topical application to the oral mucosa of mice, rats 

and hamsters, and by subcutaneous administration, skin application, inhalation, intravesicular 

implantation and intravaginal application to mice. All of these studies suffered from certain 

deficiencies [ref: 1].

In a two-stage mouse-skin assay, applications of tobacco extract followed by treatment with croton 

oil induced papillomas and squamous-cell carcinomas of the skin. In further two-stage mouse-skin 

assays, application of tobacco extracts following initiation by 7,12-dimethylbenz[a]anthracene 
resulted in papillomas [ref: 1].

A commercial Swedish snuff was tested for carcinogenicity in rats by topical administration in a 

surgically-created oral canal, alone or in combination with herpes simplex type 1 infection. Two 

squamous-cell carcinomas of the oral cavity were observed in the group receiving both treatments, 

but this result was not statistically significant [ref: 1]. A commercial North American snuff was 

tested in rats by the same route. One squamous-cell carcinoma and two papillomas of the oral 

cavity were found, but this result was not statistically significant [ref: 4].

An aqueous extract of a commercial North American snuff was also tested by topical application to 

the oral mucosa in rats, alone or enriched with the tobacco-specific nitrosamines, N'-

nitrosonornicotine and 4-(nitrosomethylamino)-1-(3-pyridyl)-1-butanone. Some papillomas of the 

oral cavity were observed in rats treated with the enriched snuff extract, but this result was not 

statistically significant [ref: 4].

Snuff was tested by oral administration in hamsters, alone and in combination with calcium 

hydroxide, but the data were insufficient for evaluation. Several studies in hamsters in which snuff 

was administered as single or repeated applications into the cheek pouch or fed in the diet yielded 

insufficient data for evaluation. Subcutaneous injection of ethanol extracts of snuff to rats did not 

produce an increase in tumour incidence [ref: 1].

Nass was tested for carcinogenicity in hamsters by administration into the cheek pouch or by skin 

application. No tumour was found at the site of application. Although nass administration was 

associated with an apparent excess of liver tumours in various groups receiving cheek-pouch 

administration, which may be indicative of carcinogenicity, deficiencies in reporting do not allow an 

evaluation to be made [ref: 1]. 

C. Other relevant data

An increased incidence of micronuclei was observed in exfoliated epithelial cells from users of khaini

and nass. Saliva collected from chewers of Indian tobacco induced chromosomal aberrations in 

Chinese hamster ovary cells in vitro [ref: 5].

Ethanol extracts of Indian chewing tobacco induced micronuclei in bone-marrow cells of Swiss mice 

treated in vivo and were mutagenic to Chinese hamster V79 cells in vitro, both in the presence and 

absence of an exogenous metabolic system, and to Salmonella typhimurium. Both ethanol and ethyl 

acetate extracts of Sri Lankan chewing tobacco induced transformation of Syrian hamster embryo 

cells. Ethyl acetate extracts induced sister chromatid exchanges in cultured human cells, but not 

mutation in Chinese hamster V79 cells when tested in the absence of an exogenous metabolic 

system [ref: 5].

Aqueous extracts of nass and khaini induced chromosomal aberrations in Chinese hamster ovary 

cells. Powdered tobacco fed to larvae of Drosophila did not induce sex-linked recessivel lethal 

mutations, autosomal translocations or sex-chromosome loss [ref: 5].

Chloroform extracts of shammah induced transformation in mouse C3H 10T1/2 cells. The same 

extracts also induced aberrant colonies and gene conversion in yeast and were mutagenic to S. 

typhimurium, both in the presence and absence of an exogenous metabolic system [ref: 5].

Extracts of North American oral snuff (at pH 3.0) and extracts of North American chewing tobacco 

treated with sodium nitrite under acidic conditions were mutagenic to S. typhimurium in the 

presence and absence of a metabolic system. Organic solvent extracts of snuff induced a doserelated increase in the frequency of sister chromatid exchanges in human peripheral lymphocytes in 

vitro in the absence of a metabolic system [ref: 5]. 

Overall evaluation

Smokeless tobacco products are carcinogenic to humans (Group 1).
For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 37 (1985)

References

1. IARC Monographs, 37, 37-136, 1985

2. IARC Monographs, 37, 141-209, 1985

3. Ibrahim, E.M., Satti, M.B., Al Idrissi, H.Y., Higazi, M.M., Magbool, G.M. & Al Quorain, A. (1986) 

Oral cancer in Saudi Arabia: The role of alqat and alshammah. Cancer Detect. Prev., 9, 215-218

4. Hecht, S.S., Rivenson, A., Braley, J., DiBello, J., Adams, J.D. & Hoffmann, D. (1986) Induction of 

oral cavity tumors in F344 rats by tobacco-specific nitrosamines and snuff. Cancer Res., 46, 4162-

4166

5. IARC Monographs, Suppl. 6, 519, 1987 

Last updated: 10 February 1998 
TOBACCO SMOKE

(Group 1) 

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p.359) 

A. Evidence for carcinogenicity to humans (sufficient)

Cigarette smoking has been shown to cause lung cancer, bladder cancer, cancer of the renal pelvis 

(and possibly renal adenocarcinoma), cancer of the lip, and oropharyngeal, hypopharyngeal, 

laryngeal, oesophageal and pancreatic cancers. In some studies, increased risks of cancers of the 

stomach, liver and cervix have been noted, but the data were inadequate to decide whether the 

association is causal or not. The risk for lung cancer due to cigarette smoking is substantially 

increased in conjunction with exposure to radon daughters or asbestos. An increase in the incidence 

of lung cancer also results from smoking other forms of tobacco, i.e., pipe, cigars and bidis. Pipe 

and cigar smoking probably increase the risk of bladder cancer, but at lower levels than that caused 

by cigarette smoking. They also increase the risks of oral, oropharyngeal, hypopharyngeal, 

laryngeal and oesophageal cancers to approximately the same extent as cigarette smoking, and, as 

with cigarette smoking, the risk is substantially augmented in conjunction with high-dose exposure 

to alcohol [ref: 1].

Tobacco smoke affects not only people who smoke but also those who are exposed to the 

combustion products of other people's tobacco (passive smokers). The most numerous observations 

hitherto available concern lung cancer, and the results of most of the 13 main epidemiological 

studies [ref: 2] carried out so far are compatible with either an increased risk from passive smoking 

or an absence of risk. However, the aggregate evidence from these studies, taken together with 

knowledge of the nature of sidestream and mainstream smoke, of the materials absorbed during 

passive smoking and of the quantitative relationships between dose and effect that are commonly 

observed after exposure to carcinogens, leads to the conclusion that passive smoking does carry 

some risk for lung cancer. 

B. Evidence for carcinogenicity to animals (sufficient)

Cigarette smoke has been tested for carcinogenicity by inhalation in mice, rats, hamsters and dogs. 

Exposure of hamsters and rats to whole smoke produced malignant respiratory-tract tumours [ref: 

1]. In mice, inhalation of whole tobacco smoke resulted in a slightly increased incidence of 

alveologenic lung tumours, but this was not statistically significant in some of the studies [ref: 1,3]. 

An increased incidence of lung tumours has also been reported in dogs exposed to cigarette smoke, 

but the data were insufficient for evaluation. More tumours of the respiratory tract occurred in 

rodents exposed to both cigarette smoke and 7,12-dimethylbenz[a]anthracene than to either one 

alone; the same is true for concomitant exposure to benzo[a]pyrene or radon daughters [ref: 1].

Cigarette-smoke condensate induced benign and malignant skin tumours in mice and rabbits after 

application to the skin. Following its topical administration to oral mucosa, it resulted in an 

increased incidence of lung tumours and tumours of other organs, primarily lymphomas, in one 

strain of mice. In rats, cigarette-smoke condensate produced lung cancer after intrapulmonary 

injection. In two-stage mouse-skin assays, a single topical administration of cigarette-smoke 

condensate induced changes resulting in benign and malignant skin tumours after additional 

application of croton oil. Skin tumours were also produced when cigarette-smoke condensate was 

applied chronically subsequent to a single treatment with other agents, such as 7,12-

dimethylbenz[a]anthracene [ref: 1]. 

C. Other relevant data

Structural chromosomal aberrations, sister chromatid exchanges and micronuclei have been 

observed in peripheral blood lymphocytes of tobacco smokers. Although in some studies there was 

no increase in the incidence of sister chromatid exchanges, in several others a dose-response 

relationship was reported between the amount and duration of cigarette smoking and the frequency 
of sister chromatid exchange. Long-term heavy smokers generally also had higher frequencies of 

chromosomal aberrations in peripheral blood lymphocytes. In a large study, a significant doseresponse relationship was found between the frequency of structural chromosomal aberrations and 

the estimated daily uptake of condensate. In a single study, it was reported that DNA adducts 

associated with cigarette smoke were detected in the bronchus of one smoker and in the larynx of 

another, but not in the bronchus of a nonsmoker. In another study, one of several DNA adducts 

detected in 16/17 placentas from smokers and 3/14 placentas from nonsmokers was claimed to be 

related to maternal smoking. Antigenicity against polycyclic aromatic hydrocarbon DNA adducts has 

been demonstrated in peripheral lymphocytes and lung samples from cigarette smokers, although 

the occurrence of these adducts could not be correlated with cigarette smoking [ref: 4].

Extracts of urine from smokers induced chromosomal aberrations in Chinese hamster ovary cells 

and were mutagenic to bacteria in the presence of an exogenous metabolic system. Passive 

exposure to tobacco smoke has also been reported to increase urinary mutagenicity. In studies of 

amniotic fluid samples from smoking and nonsmoking mothers, more mutagenicity to Salmonella 

typhimurium was reported in samples taken at term from heavy smokers as compared to 

nonsmokers, but not in samples taken at 16 weeks by amniocentesis. One study of the mutagenicity 

of cervical mucus from smoking and nonsmoking women was difficult to interpret due to inadequate 

reporting [ref: 4].

Tobacco smoke inhibited DNA repair capacity in mice and increased the frequency of sister 

chromatid exchanges in bone-marrow cells of mice exposed in vivo and in human lymphocytes in 

vitro; it also induced single-strand breaks in cultured human cells. It induced sex-linked recessive 

lethal mutations in Drosophila and mitotic recombination, gene conversion and mutation in yeast. 

The urine of rats and baboons exposed to cigarette smoke was mutagenic to bacteria [ref: 4].

Tobacco smoke and extracts of particulate matter collected on filters in rooms containing cigarette 

smoke were mutagenic to bacteria. The extracts also induced sister chromatid exchanges in cultured 

Chinese hamster ovary cells [ref: 4].

Tobacco condensates induced mutation, sister chromatid exchanges and transformation in rodent 

cells in culture, sex-linked recessive lethal mutations in Drosophila and mutation and gene 

conversion in fungi. Tobacco-smoke condensate inhibited intercellular communication of Chinese 

hamster V79 cells. All tobacco-smoke condensates tested were mutagenic to bacteria [ref: 4]. 

Overall evaluation

Tobacco smoke is carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 38 (1986)

References

1. IARC Monographs, 38, 1986

2. Wald, N.J., Nanchahal, K., Thompson, S.G. & Cuckle, H.S. (1986) Does breathing other people's 

tobacco smoke cause lung cancer? Br. med. J., 293, 1217-1222

3. Henry, C.J. & Kouri, R.E. (1986) Chronic inhalation studies in mice. II. Effects of long-term 

exposure to 2R1 cigarette smoke on (C57BL/Cum x C3H/AnfCum)F1 mice. J. natl Cancer Inst., 77, 

203-212

4. IARC Monographs, Suppl. 6, 519-520, 1987 
Last updated: 9 February 1998 
ortho-TOLUIDINE

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 362) 

CAS No.: 95-53-4 

Chem. Abstr. Name: Benzenamine, 2-methylA. Evidence for carcinogenicity to humans (inadequate)

There are numerous studies of dyestuffs workers, dating back to the classical cohort studies in 1954. 

Although an excess of bladder tumours has often been found in workers exposed to varying 

combinations of dyestuffs and dyestuff intermediates, no population of workers exposed to orthotoluidine alone has been described [ref: 1]. Occasional cases of bladder tumours have been reported 

in workers classified as being exposed primarily to ortho-toluidine, but either insufficient data or 

insufficient follow-up time have prevented a clear association being made with the exposure. An 

excess of bladder tumours was noted in workers exposed to toluene, ortho-nitrotoluene, orthotoluidine and 4,4'-methylene bis(2-methylaniline) during the manufacture of new fuchsin ('new' 

magenta) and safranine-T [ref: 1,2]. 

B. Evidence for carcinogenicity to animals (sufficient)

ortho-Toluidine hydrochloride was tested for carcinogenicity in mice and rats by oral administration, 

producing neoplasms at various sites in both species; in particular, vascular tumours were induced, 

including tumours of the spleen and other abdominal haemangiosarcomas [ref: 1,3]. Following 

subcutaneous injection in a limited study in hamsters, no treatment-related neoplasm was observed 

[ref: 4]. Experiments in rabbits and guinea-pigs by subcutaneous administration were inadequate for 

evaluation [ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of ortho-toluidine in humans.

ortho-Toluidine did not induce micronuclei in mice treated in vivo; equivocal results were obtained 

for sister chromatid exchanges in Chinese hamsters. It induced sister chromatid exchanges, mutation 

and unscheduled DNA synthesis in human cells in vitro. It induced transformation, aneuploidy and 

chromosomal aberrations in cultured rodent cells; conflicting results were obtained for sister 

chromatid exchanges, mutation and DNA damage. ortho-Toluidine caused somatic mutation in 

Drosophila. Conflicting results were obtained for mutagenicity to yeast; it induced aneuploidy, but 

not mitotic recombination. ortho-Toluidine was mutagenic to bacteria when higher amounts of an 

exogenous metabolic system were used than in the standard assay [ref: 5]. 

Overall evaluation

ortho-Toluidine is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluations: Vol. 16 (1978); Vol. 27 (1982); Vol. 77 (2000)

References

1. IARC Monographs, 27, 155-175, 1982
2. Rubino, G.F., Scansetti, G., Piolatto, G. & Pira, E. (1982) The carcinogenic effect of aromatic 

amines: an epidemiological study of the role of o-toluidine and 4,4'-methylene bis(2-methylaniline) 

in inducing bladder cancer in man. Environ. Res., 27, 241-254

3. Hecht, S.S., El-Bayoumy, K., Rivenson, A. & Fiala, E. (1982) Comparative carcinogenicity of otoluidine hydrochloride and o-nitrosotoluene in F-344 rats. Cancer Lett., 16, 103-108

4. Hecht, S.S., El-Bayoumy, K., Rivenson, A. & Fiala, E.S. (1983) Bioassay for carcinogenicity of 3,2'-

dimethyl-4-nitrosobiphenyl, o-nitrosotoluene, nitrosobenzene and the corresponding amines in 

Syrian golden hamsters. Cancer Lett., 20, 349-354

5. IARC Monographs, Suppl. 6, 523-527, 1987 

Synonyms

● 1-Amino-2-methylbenzene 

● 2-Amino-1-methylbenzene 

● 2-Aminotoluene 

● o-Aminotoluene 

● Azoic brown 29 [component] 

● 1-Methyl-2-aminobenzene 

● 2-Methyl-1-aminobenzene 

● o-Methylaniline 

● 2-Methylaniline 

● 2-Methylbenzenamine 

● o-Methylbenzenamine 

● 2-Toluidine 

● o-Toluidin 

● o-Tolylamine 

Last updated: 3 March 1998 
TREOSULPHAN 

(Group 1) 

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 363) 

CAS No.: 299-75-2

Chem. Abstr. Name: 1,2,3,4-Butanetetrol, 1,4-dimethanesulfonate, [S-(R*,R*)]-

A. Evidence for carcinogenicity to humans (sufficient)

In one epidemiological study of 553 patients with ovarian cancer treated only with treosulphan and 

followed for nine years (over 1700 person-years) after treatment, 13 patients developed acute 

nonlymphocytic leukaemia, mostly within five years after the start of chemotherapy; the expected 

number of cases among the patients was less than 0.1, giving a relative risk in excess of 100. There 

was a significant correlation between cumulative dose of treosulphan and risk of leukaemia [ref: 

1,2]. 

B. Evidence for carcinogenicity to animals

No data were available to the Working Group. 

C. Other relevant data

Treosulphan is a bifunctional alkylating agent. No data were available on the genetic and related 

effects of this compound in humans. It induced chromosomal aberrations in plant cells [ref: 3]. 

Overall evaluation

Treosulphan is carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 26 (1981)

References

1. IARC Monographs, 26, 341-349, 1981

2. Pedersen-Bjergaard, J., Ersböll, J., Sorensen, H.M., Keiding, N., Larsen, S.O., Philip, P., Larsen, 

M.S., Schultz, H. & Nissen, N.I. (1985) Risk of acute nonlymphocytic leukemia and preleukemia in 

patients treated with cyclophosphamide for non-Hodgkin's lymphomas. Comparison with results 

obtained in patients treated for Hodgkin's disease and ovarian carcinoma with other alkylating 

agents. Ann. intern. Med., 103, 195-200

3. IARC Monographs, Suppl. 6, 528-529, 1987 

Synonyms

● 1,4-Bis-O-methanesulphonyl-L-threitol 

● Dihydroxybusulphan 

● 1,4-Di-O-methanesulfonylbutan-1,2,3,4-tetrole 
● 1,4-Dimethanesulphonate-(L-threitol) 

● NSC 39069 

● 1-Threitol-1,4-bis(methanesulphonate 

● (2S,3S)-Threitol 1,4-bismethanesulphonate 

● L-Threitol 1,4-dimethanesulfonate 

● L-(+)Threitol 1,4-dimethanesulphonate 

● L-Threitol dimethanesulphonate 

● Treosulfan 

● Tresulphan 

● Treosulphan leo 

Last updated: 10 February 1998 
4,5',8-TRIMETHYLPSORALEN

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 366)

CAS No.: 3902-71-4

Chem. Abstr. Name: 2,5,9-Trimethyl-7H-furo[3,2-g][1]benzopyran-7-one 

A. Evidence for carcinogenicity to humans (inadequate) 

Malignant melanoma was diagnosed in a 30-year-old male shortly after commencement of 

treatment with 4,5',8-trimethylpsoralen for vitiligo. No skin cancer was observed during two to 14 

months of follow-up in 57 patients with psoriasis treated for one to 23 months with 4,5',8-

trimethylpsoralen [ref: 1]. 

B. Evidence for carcinogenicity to animals (inadequate) 

No skin tumour was observed in mice given thrice-weekly skin applications of 4,5',8-

trimethylpsoralen followed by low doses of ultraviolet A irradiation for nine months [ref: 1,2]. 

C. Other relevant data

No data were available on the genetic and related effects of 4,5',8-trimethylpsoralen in humans. 

In combination with ultra-violet A radiation, 4,5',8-trimethylpsoralen bound covalently to DNA in 

guinea-pig skin in vivo. It induced sister chromatid exchanges and unscheduled DNA synthesis in 

human cells in vitro, and DNA cross-links in human and rodent cells in vitro. It induced mutation in 

yeast and DNA damage in bacteria. Results on the induction of mutation in bacteria were 

inconclusive [ref: 3]. 

In the absence of ultra-violet A radiation, 4,5',8-trimethylpsoralen did not induce sister chromatid 

exchanges in human lymphocytes in vitro; results for induction of unscheduled DNA synthesis were 

equivocal. Mutagenicity studies in bacteria were inconclusive [ref: 3]. 

4,5,8'-Trimethylpsoralen is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 40 (1986)

References

1. IARC Monographs, 40, 357-371, 1986 

2. Hannuksela, M., Stenbäck, F. & Lahti, A. (1986) The carcinogenic properties of topical PUVA. A 

lifelong study in mice. Arch. Dermatol. Res., 278, 347-351 

3. IARC Monographs, Suppl. 6, 541-544, 1987 

Synonyms
● 6-Hydroxy-β,2,7-trimethyl-5-benzofuranacrylic acid, δ-lactone 

● NSC 71047 

● TMP 

● Trimethylpsoralen 

● 2',4,8-Trimethylpsoralen 

● Trioxalen 

● Trioxsalen 

● Trioxysalen 

● Trisoralen 

Last updated: 11 March 1998 
TRIS(AZIRIDINYL)-para-BENZOQUINONE (TRIAZIQUONE)

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 367) 

CAS No.: 68-76-8

Chem. Abstr. Name: 2,3,5-Tris(1-aziridinyl)-2,5-cyclohexadiene-1,4-dione 

A. Evidence for carcinogenicity to humans (inadequate) 

No epidemiological study of triaziquone as a single agent was available to the Working Group. 

Occasional case reports of exposure to triaziquone, especially in the presence of concurrent therapy 

with other putative carcinogens, such as ionizing radiation, alkylating agents and other potent 

oncotherapeutic drugs, do not constitute evidence of carcinogenesis [ref: 1]. 

B. Evidence for carcinogenicity to animals (limited) 

Triaziquone produced a small number of different types of malignant tumours in rats after repeated 

intravenous injections or after repeated intravenous injections followed by repeated intraperitoneal 

injections [ref: 1]. 

C. Other relevant data

Triaziquone is an alkylating agent [ref: 2]. No data were available on its genetic and related effects 

in humans. 

Triaziquone induced dominant lethal mutations, heritable translocations, chromosomal aberrations 

and micronuclei in bone-marrow cells of mice and chromosomal aberrations in oocytes of mice and 

hamsters treated in vivo. In human cells in vitro, it induced chromosomal aberrations and sister 

chromatid exchanges. In Chinese hamster cells in vitro, triaziquone induced chromosomal 

aberrations, micronuclei and sister chromatid exchanges; it induced unscheduled DNA synthesis in 

mouse testicular cells. It induced aneuploidy, chromosomal aberrations and sex-linked recessive 

lethal mutations in Drosophila, mutation in plant cells, gene conversion in yeast and mutation and 

DNA damage in bacteria [ref: 2]. 

Tris(aziridinyl)-para-benzoquinone (triaziquone) is not classifiable as to its carcinogenicity to 

humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 9 (1975)

References

1. IARC Monographs, 9, 67-73, 1975 

2. IARC Monographs, Suppl. 6, 545-548, 1987 

Synonyms

● Bayer 3231 

● 1,1'1''-(3,6-Dioxo-1,4-cyclohexadiene-1,2,4-triyl)trisaziridine 
● Oncovedex 

● Prenimon 

● Riker 601 

● TEIB 

● Trenimon 

● Triaziquinone 

● Triaziquone 

● Triethyleneiminobenzoquinone 

● Triethyleniminobenzoquinone 

● 2,3,5-Triethylenimino-1,4-benzoquinone 

● 2,3,5-Tris(aziridino)-1,4-benzoquinone 

● 2,3,5-Tris(aziridinyl)-1,4-benzoquinone 

● 2,3,5-Tris(1-aziridinyl)-p-benzoquinone 

● Tris-(ethyleneimino)benzoquinone 

● 2,3,5-Trisethyleneiminobenzoquinone 

● Trisethyleneiminoquinone 

● 2,3,5-Tris(ethylenimino)benzoquinone 

● 2,3,5-Tris(ethylenimino)-1,4-benzoquinone 

● 2,3,5-Tris(ethylenimino)-p-benzoquinone 

Last updated: 11 March 1998 
URACIL MUSTARD 

(Group 2B)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 370) 

CAS No.: 66-75-1

Chem. Abstr. Name: 5-[Bis(2-chloroethyl)amino]-2,4(1H,3H)pyrimidinedione 

A. Evidence for carcinogenicity to humans (inadequate)

No epidemiological study of uracil mustard as a single agent was available to the Working Group. 

Occasional case reports of treatment with uracil mustard, especially in the presence of concurrent 

therapy with other putative carcinogens, such as ionizing radiation, alkylating agents and other 

potent oncotherapeutic drugs, do not constitute evidence of carcinogenesis [ref: 1-5].

B. Evidence for carcinogenicity to animals (sufficient) 

Intraperitoneal administration of uracil mustard to mice of three strains induced lung adenomas and 

adenocarcinomas in a dose-dependent incidence; in one of the strains, liver, ovarian and lymphatic 

tumours were also observed. In rats, intraperitoneal administration induced peritoneal sarcomas and 

lymphomas and tumours in the pancreas, ovary and mammary gland [ref: 6]. 

C. Other relevant data

Uracil mustard is an alkylating agent [ref: 7]. No data were available on its genetic and related 

effects in humans.

Uracil mustard did not induce dominant lethal mutations in mice in one study using low doses. It 

induced mutation in mouse lymphoma cells in vitro, aneuploidy and sex-linked recessive lethal 

mutations in Drosophila and mitotic recombination in yeast. It caused DNA damage and was 

mutagenic in bacteria [ref: 7].

Overall evaluation

Uracil mustard is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 9 (1975)

References

1. Reimer, R.R., Hoover, R., Fraumeni, J.F., Jr & Young, R.C. (1977) Acute leukemia after alkylatingagent therapy of ovarian cancer. New Engl. J. Med., 297, 177-181

2. Zarrabi, M.H. & Rosner, F. (1979) Acute myeloblastic leukemia following treatment for nonhematopoietic cancers. Report of 19 cases and review of the literature. Am. J. Hematol., 7, 357-367

3. McKenna, R.W., Parkin, J.L., Foucar, K. & Brunning, R.D. (1981) Ultrastructural characteristics of 

therapy-related acute nonlymphocytic leukemia: evidence for a panmyelosis. Cancer, 48, 725-737
4. Rosner, F. (1976) Acute leukemia as a delayed consequence of cancer chemotherapy. Cancer, 37, 

1033-1036

5. Zarrabi, M.H. (1980) Association of non-Hodgkin's lymphoma (NHL) and second neoplasms. 

Semin. Oncol., 7, 340-351

6. IARC Monographs, 9, 235-241, 1975

7. IARC Monographs, Suppl. 6, 558-560, 1987 

Synonyms

● 5-Aminouracil mustard 

● 5-[Bis(2-chloroethyl)amino]uracil 

● 5-N,N-Bis(2-chloroethyl)aminouracil 

● CB 4835 

● Demethyldopan 

● Desmethyldopan 

● 5-[Di(β-chloroethyl)amino]uracil 

● 2,6-Dihydroxy-5-bis(2-chloroethyl)aminopyrimidine 

● ENT 50439 

● NSC 34462 

● SK 19849 

● U-8344 

● Uramustine 

Last updated: 3 March 1998 
VINBLASTINE SULPHATE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 371) 

CAS No.: 143-67-9

Chem. Abstr. Name: Vincaleukoblastine, sulfate (1:1) (salt) 

A. Evidence for carcinogenicity to humans (inadequate) 

No epidemiological study of vinblastine sulphate as a single agent was available to the Working 

Group. Occasional case reports of exposure to vinblastine sulphate, especially in the presence of 

concurrent therapy with other putative carcinogens, such as ionizing radiation, alkylating agents and 

other potent oncotherapeutic drugs, do not constitute evidence of carcinogenesis [ref: 1]. 

In a large systematic follow-up of patients with Hodgkin's disease treated with an intensive 

chemotherapeutic combination including vinblastine (plus adriamycin, bleomycin and dacarbazine) 

but no alkylating agent, preliminary evidence suggests no excess of acute nonlymphocytic 

leukaemia in the first decade after therapy [ref: 2,3]. 

B. Evidence for carcinogenicity to animals (inadequate) 

No evidence of carcinogenicity was found after intraperitoneal administration of vinblastine sulphate 

to mice and rats or after its intravenous administration to rats, but it has not been adequately 

tested at high doses [ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of vinblastine sulphate in humans. 

Vinblastine sulphate weakly induced micronuclei in a single study using low doses, but it did not 

induce dominant lethal mutations in mice treated in vivo. It induced chromosomal aberrations but 

not mutation in Chinese hamster cells in vitro and was not mutagenic to bacteria [ref: 4]. 

Overall evaluation

Vinblastine sulphate is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 26 (1981)

References

1. IARC Monographs, 26, 349-363, 1981 

2. Santoro, A., Viviani, S., Villarreal, C.J.R., Bonfante, V., Delfino, A., Valagussa, P. & Bonadonna, 

G. (1986) Salvage chemotherapy in Hodgkin's disease irradiation failures: superiority of doxorubicin 

containing regimens over MOPP. Cancer Treat. Rep., 70, 343-348 

3. Valagussa, P., Santoro, A., Fossati Bellani, F., Franchi, F., Banfi, A. & Bonadonna, G. (1982) 
Absence of treatment-induced second neoplasms after ABVD in Hodgkin's disease. Blood, 59, 488-

494 

4. IARC Monographs, Suppl. 6, 561-562, 1987 

Synonyms

● Exal 

● LE 29060 

● NSC 49842 

● Velban 

● Velbe 

● Vincaleucoblastine sulfate 

● Vincaleukoblastine sulfate 

● VLB sulfate 

Last updated: 11 March 1998 
VINCRISTINE SULPHATE

(Group 3)

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 372) 

CAS No.: 2068-78-2

Chem. Abstr. Name: Vincaleukoblastine, 22-oxo, sulfate (1:1) (salt) 

A. Evidence for carcinogenicity to humans (inadequate) 

No epidemiological study of vincristine sulphate as a single agent was available to the Working 

Group. Intensive combination chemotherapy with regimens including vincristine has been shown to 

result in increased risks for acute nonlymphatic leukaemia (ANLL). (See also the summary of data 

on MOPP and other combined chemotherapy including alkylating agents) Such combinations usually 

include procarbazine together with an alkylating agent such as nitrogen mustard (see p. 269), both 

of which are potent animal carcinogens, suggesting more plausible explanations for the association 

between combination chemotherapy and ANLL. In the presence of concurrent therapy with other 

putative carcinogens, including ionizing radiation and other potent drugs, occasional case reports of 

exposure to vincristine sulphate do not constitute evidence of carcinogenesis [ref: 1]. 

B. Evidence for carcinogenicity to animals (inadequate) 

In limited studies in mice and rats, no evidence of carcinogenicity was found after intraperitoneal 

administration of vincristine sulphate [ref: 1]. 

C. Other relevant data

No data were available on the genetic and related effects of vincristine sulphate in humans. 

Vincristine sulphate induced micronuclei in bone-marrow cells of mice and hamsters treated in vivo. 

Conflicting results were obtained for induction of sister chromatid exchanges in human lymphocytes 

in vitro. It induced aneuploidy in and transformation of Syrian hamster embryo cells, but it did not 

transform mouse C3H 10T1/2 cells. It did not induce chromosomal aberrations, sister chromatid 

exchanges or unscheduled DNA synthesis in rodent cells in vitro. It induced mutation in mouse 

lymphoma cells but not in other rodent cells. It did not induce sex-linked recessive lethal mutations 

in Drosophila and was not mutagenic to bacteria [ref: 2]. 

Overall evaluation

Vincristine sulphate is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 26 (1981)

References

1. IARC Monographs, 26, 365-384, 1981 

2. IARC Monographs, Suppl. 6, 563-565, 1987 

Synonyms
● Des-Na-methyl-Na-formylvinblastine sulfate 

● LCR sulfate 

● Leurocristine sulfate (1:1) (salt) 

● Leurocristine sulfate 

● Leurocristine sulfate (1:1) (salt) 

● NSC 67574 

● Oncovin 

● Onkovin 

● VCR sulfate 

● Vincristin 

● Vincrisul 

Last updated: 11 March 1998 
VINYL CHLORIDE 

(Group 1) 

For definition of Groups, see Preamble Evaluation. 

Supplement 7: (1987) (p. 373) 

CAS No.: 75-01-4

Chem. Abstr. Name: Chloroethene 

A. Evidence for carcinogenicity to humans (sufficient)

Vinyl chloride has been associated with tumours of the liver, brain, lung and haematolymphopoietic 

system [ref: 1]. A large number of epidemiological studies [ref: 2-12] and case reports [ref: 13-25] 

have substantiated the causal association between vinyl chloride and angiosarcoma of the liver. 

Several studies also confirm that exposure to vinyl chloride causes other forms of cancer, i.e., 

hepatocellular carcinoma [ref: 13,19,23,26], brain tumours [ref: 11,27], lung tumours [ref: 12,28-

30] and malignancies of the lymphatic and haematopoietic system [ref: 11,29,31]. Exposure to 

polyvinyl chloride dust was associated with an increased incidence of lung tumours in one study; the 

authors suggested that trapped vinyl chloride monomer was responsible [ref: 30]. Melanoma 

occurred in excess in one study [ref: 12] but has not been mentioned in others. Slightly elevated 

risks for gastric [ref: 29] and gastrointestinal cancer (other than liver cancer) [ref: 32] were 

indicated in some studies, but these were not confirmed in others. 

B. Evidence for carcinogenicity to animals (sufficient)

Vinyl chloride administered orally or by inhalation to mice, rats and hamsters produced tumours in 

the mammary gland, lung, Zymbal gland and skin and angiosarcomas of the liver [ref: 1]. Similar 

findings were made in more recent studies [ref: 33-39]. In one, a combination of oral administration 

of ethanol and inhalation of vinyl chloride resulted in more liver tumours (including angiosarcomas) 

than after treatment with vinyl chloride alone [ref: 40]. 

C. Other relevant data

Chromosomal aberrations were induced in peripheral blood lymphocytes of workers exposed to vinyl 

chloride at levels of 5-500 ppm (13-1300 mg/m3). Two studies reported negative results for sister 

chromatid exchanges in exposed workers, while in another study a weakly positive response was 

found [ref: 41].

Vinyl chloride induced chromosomal aberrations, sister chromatid exchanges and micronuclei in 

rodents exposed in vivo but did not induce mutation in the mouse spot test or dominant lethal 

mutations in rats or mice. It alkylated DNA in several tissues of mice and rats exposed in vivo. Vinyl 

chloride induced sister chromatid exchanges in human lymphocytes in vitro. It induced mutation in 

Chinese hamster cells and unscheduled DNA synthesis in rat hepatocytes in vitro and induced 

transformation in BALB/c 3T3 cells and virus-infected Syrian hamster cells. It induced sex-linked 

recessive lethal mutations, but not aneuploidy, heritable translocations or dominant lethal mutations 

in Drosophila. It was mutagenic to plants and to Schizosaccharomyces pombe but not to other 

fungi; it induced gene conversion in yeast. It caused DNA damage and mutation in bacteria. Vinyl 

chloride bound covalently to isolated DNA in the presence of a metabolic system [ref: 41]. 

Overall evaluation

Vinyl chloride is carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.
Also see previous evaluations: Vol. 7 (1974); Vol. 19 (1979)

References

1. IARC Monographs, 19, 377-438, 1979

2. Baxter, P.J., Anthony, P.P., MacSween, R.N.M. & Scheuer, P.J. (1977) Angiosarcoma of the liver 

in Great Britain. 1963-73. Br. med. J., ii, 919-921

3. Brady, J., Liberatore, F., Harper, P., Greenwald, P., Burnett, W., Davies, J.N.P., Bishop, M., Polan, 

A. & Viana, N. (1977) Angiosarcoma of the liver: an epidemiologic survey. J. natl Cancer Inst., 59, 

1383-1385

4. Baxter, P.J., Anthony, P.P., MacSween, R.N.M. & Scheuer, P.J. (1980) Angiosarcoma of the liver: 

annual occurrence and aetiology in Great Britain. Br. J. ind. Med., 37, 213-221

5. Baxter, P.J. (1981) The British hepatic angiosarcoma register. Environ. Health Perspect., 41, 115-

116

6. Falk, H., Herbert, J., Crowley, S., Ishak, K.G., Thomas, L.B., Popper, H. & Caldwell, G.G. (1981) 

Epidemiology of hepatic angiosarcoma in the United States, 1964-1974. Environ. Health Perspect., 

41, 107-113

7. Thériault, G. & Allard, P. (1981) Cancer mortality of a group of Canadian workers exposed to 

vinyl chloride monomer. J. occup. Med., 23, 671-676

8. Vianna, N.J., Brady, J.A. & Cardamone, A.T. (1981) Epidemiology of angiosarcoma of liver in New 

York State. N.Y. State J. Med., 6, 895-899

9. Weber, H., Reinl, W. & Greiser, E. (1981) German investigations on morbidity and mortality of 

workers exposed to vinyl chloride. Environ. Health Perspect., 41, 95-99

10. Forman, D., Bennett, B., Stafford, J. & Doll, R. (1985) Exposure to vinyl chloride and 

angiosarcoma of the liver: a report of the register of cases. Br. J. ind. Med., 42, 750-753

11. von Greiser, E., Reinl, W. & Weber, H. (1982) Vinyl chloride exposure and mortality of German 

chemical workers in comparison to mortality of non-exposed chemical workers and PVC workers 

(Ger.). Zbl. Arbeitsmed., 32, 44-62

12. Heldaas, S.S., Langard, S.L. & Andersen, A. (1984) Incidence of cancer among vinyl chloride 

and polyvinyl chloride workers. Br. J. ind. Med., 41, 25-30

13. Gokel, J.M., Liebezeit, E. & Eder, M. (1976) Hemangiosarcoma and hepatocellular carcinoma of 

the liver following vinyl chloride exposure. A report of two cases. Virchows Arch. Pathol. Anat. 

Histol., 372, 195-203

14. Bonneton, G., Champetier, J., Fournet, J., Guidicelli, H., Legrand, J., Dupre, A., Hostein, M., 

Marty, F. & Pahn, M. (1977) Angiosarcoma of the liver and portal fibrosis in vinyl chloride workers. 

Two cases (Fr.). Nouv. Presse méd., 6, 735-742

15. Puech, A.-M., Fournet, A., Laulhere, L., Faure, J., Cau, G. & Mallion, J.-M. (1977) Study of 

hepatic lesions seen in 5 subjects exposed to vinyl chloride, including 3 cases of angiosarcoma of 

the liver (Fr.). Arch. Mal. prof., 38, 787-795

16. Réty, J., Lambert, R. & Pialat, J. (1981) Medical surveillance of persons exposed to occupational 
toxic compounds with late or carcinogenic effects. The 11th French case of angiosarcoma of the liver 

in a PVC worker (Fr.). Arch. Mal. prof., 42, 405-406

17. Pialat, J., Pasquier, B., Pahn, M. & Kopp, N. (1979) Hepatic lesions cuased by vinyl chloride 

monomer. Study of eight clinicopathological cases (Fr.). Arch. Anat. Cytol. pathol., 27, 361-375

18. Ghandur-Mnaymneh, L. & Gonzalez, M.S. (1981) Angiosarcoma of the penis with hepatic 

angiomas in a patient with low vinyl chloride exposure. Cancer, 47, 1318-1324

19. Koischwitz, D., Lelbach, W.K., Lackner, K. & Hermanutz, D. (1981) Angiosarcoma of the liver 

and hepatocellular carcinomas induced by vinyl chloride (Ger.). Fortschr. Rontgenstr., 134, 283-290

20. Vianna, N.J, Brady, J. & Harper, P. (1981) Angiosarcoma of the liver: a signal lesion of vinyl 

chloride exposure. Environ. Health Perspect., 41, 207-210

21. Chiappino, G., Bertazzi, P.A., Baroni, M. & Masini, T. (1982) Hepatic angiosarcoma from vinyl 

chloride. Report of a new Italian case. Med. Lav., 6, 555-563

22. Jones, D.B. & Smith, P.M. (1982) Progression of vinyl chloride induced hepatic fibrosis to 

angiosarcoma of the liver. Br. J. ind. Med., 39, 306-307

23. Evans, D.M.D., Williams, W.J. & Kung, I.T.M. (1983) Angiosarcoma and hepatocellular 

carcinoma in vinyl chloride workers. Histopathology, 7, 377-388

24. Maltoni, C., Clini, C., Vicini, F. & Masina, A. (1984) Two cases of liver angiosarcoma among 

polyvinyl chloride (PVC) extruders of an Italian factory producing PVC bags and other containers. 

Am. J. ind. Med., 5, 297-302

25. Louagie, Y.A., Gianello, P., Kestens, P.J., Bonbled, F. & Haot, J.G. (1984) Vinyl chloride induced 

hepatic angiosarcoma. Br. J. Surg., 71, 322-323

26. Langbein, G., Permanetter, W. & Dietz, A. (1983) Hepatocellular carcinoma after vinyl chloride 

exposure (Ger.). Dtsch. med. Wochenschr., 108, 741-745

27. Cooper, W.C. (1981) Epidemiologic study of vinyl chloride workers: Mortality through December 

31, 1972. Environ. Health Perspect., 41, 101-106

28. Buffler, P.A., Wood, S., Eifler, C., Suarez, L. & Kilian, D.J. (1979) Mortality experience of 

workers in a vinyl chloride monomer production plant. J. occup. Med., 21, 195-203

29. Fedotova, I.V. (1983) The incidence of malignant tumors among workers engaged in the 

manufacture of vinyl chloride and polyvinyl chloride (Russ.). Gig. Tr. prof. Zabol., 4, 30-32

30. Waxweiler, R.J., Smith, A.H., Falk, H. & Tyroler, H.A. (1981) Excess lung cancer risk in a 

synthetic chemicals plant. Environ. Health Perspect., 41, 159-165

31. Filatova, V.S., Antonyuzhenko, V.A., Smulevich, V.B., Fedotova, I.V., Kryzhanovskaya, N.A., 

Bochkareva, T.V., Goryacheva, L.A. & Bulbulyan, N.A. (1982) Blastomogenic hazard of vinyl chloride 

(clinico-hygienic and epidemiologic study) (Russ.). Gig. Tr. prof. Zabol., 1, 28-31

32. Molina, G., Holmberg, B., Elofsson, S., Holmlund, L., Moosing, R. & Westerholm, P. (1981) 

Mortality and cancer rates among workers in the Swedish PVC processing industry. Environ. Health 

Perspect., 41, 145-151

33. Hong, C.B., Winston, J.M., Thornburg, L.P., Lee, C.C. & Woods, J.S. (1981) Follow-up study on 
the carcinogenicity of vinyl chloride and vinylidene chloride in rats and mice: tumor incidence and 

mortality subsequent to exposure. J. Toxicol. environ. Health, 7, 909-924

34. Feron, V.J., Hendriksen, C.F.M., Speek, A.J., Til, H.P. & Spit, B.J. (1981) Lifespan oral toxicity 

study of vinyl chloride in rats. Food Cosmet. Toxicol., 19, 317-333

35. Hehir, R.M., McNamara, B.P., McLaughlin, J., Jr, Willigan, D.A., Bierbower, G. & Hardisty, J.F. 

(1981) Cancer induction following single and multiple exposures to a constant amount of vinyl 

chloride monomer. Environ. Health Perspect., 41, 63-72

36. Maltoni, C., Lefemine, G., Ciliberti, A., Cotti, G. & Carretti, D. (1981) Carcinogenicity bioassays 

of vinyl chloride monomer: a model of risk assessment on an experimental basis. Environ. Health 

Perspect., 41, 3-29

37. Drew, R.T., Boorman, G.A., Haseman, J.K., McConnell, E.E., Busey, W.M. & Moore, J.A. (1983) 

The effect of age and exposure duration on cancer induction by a known carcinogen in rats, mice 

and hamsters. Toxicol. appl. Pharmacol., 68, 120-130

38. Suzuki, Y. (1983) Neoplastic effect of vinyl chloride in mouse lung - lower doses and short-term 

exposure. Environ. Res., 32, 91-103

39. Groth, D.H., Coate, W.B., Ulland, B.M. & Hornung, R.W. (1981) Effects of aging on the induction 

of angiosarcoma. Environ. Health Perspect., 41, 53-57

40. Radike, M.J., Stemmer, K.L. & Bingham, E. (1981) Effect of ethanol on vinyl chloride 

carcinogenesis. Environ. Health Perspect., 44, 59-62

41. IARC Monographs, Suppl. 6, 566-569, 1987 

Synonyms

● Chloroethylene 

● Monochloroethylene 

● VC 

● VCM 

● Vinyl C monomer 

Last updated: 10 February 1998