APPENDIX B

REPORT ON CARCINOGENS, ELEVENTH EDITION

Appendix B

Agents, Substances, Mixtures, or

Exposure Circumstances Delisted

from Report on Carcinogens 

The agents, substances, mixtures or exposure circumstances contained

in this appendix had been previously listed in the Report on

Carcinogens as either known or reasonably anticipated to be human

carcinogens. Those substances delisted from the Report prior to the

1996 establishment of a formal review procedure for delisting listings

from the Report are contained in the following table with the reason

for delisting. The reason for delisting is, for some, a lack of exposure to

residents of the United States to these chemicals/ substances (since they

are no longer produced or used), or for others, because there has been a

revision in the rulings/findings as to the carcinogenic potential of these

entries (due to new studies, etc.). The last Report on Carcinogens in

which these chemicals/substances appeared, and to which reference can

be made for all information available, is also given in this table.

Those previously listed substances that have been delisted from the

Report as a result of a formal review for delisting (Eighth Edition

forward) are also contained in this table. A profile for those substances

delisted from the Report as a result of a formal review for delisting is

included in this appendix. These profiles summarize the reviews for

delisting and include the relevant information and the issues identified

by the scientific review groups that led to the substance’s delisting

from the Report on Carcinogens. Background documents outlining in

more detail the issues considered during the reviews for delisting these

substances can be obtained by contacting the National Toxicology

Program at the following address: National Toxicology Program,

Report on Carcinogens, P.O. Box 12233, MD EC-14, Research

Triangle Park, NC 27709. 

Substance Name CAS Number Last Listing Reason for Delisting

Aramite® 140-57-8 reasonably anticipated carcinogen No U.S. residents 

Fourth Report (1985) exposed

N,N-bis(2-Chloroethyl)- 494-03-1 known carcinogen No U.S. residents 

2-naphthylamine Fourth Report (1985) exposed

(Chlornaphazine)

Cycasin 14901-08-7 reasonably anticipated carcinogen No U.S. residents 

Fourth Report (1985) exposed

Methyl iodide 78-88-4 reasonably anticipated carcinogen Re-evaluated by IARC; 

Fourth Report (1985) now considered 

“equivocal”

5-Nitro-o-anisidine 99-59-2 reasonably anticipated carcinogen Insufficient evidence 

Fifth Report (1989) of carcinogenicity

p-Nitrosodiphenylamine 156-10-5 reasonably anticipated carcinogen Insufficient evidence 

Fifth Report (1989) of carcinogenicity

Ethyl acrylate 140-88-5 reasonably anticipated carcinogen See following profile

Eighth Report (1998)

Saccharin 81-07-2 reasonably anticipated carcinogen See following profile

Eighth Report (1998)
APPENDIX B

Summary

Actions on the Nomination of Ethyl

Acrylate for Delisting from the

Report on Carcinogens

Ethyl Acrylate

CAS No. 140-88-5

Ethyl acrylate is used in various industries as an intermediate in the

production of emulsion-based polymers which are then used in paint

formulations, industrial coatings, and latex products. It is also used as

a synthetic flavoring substance and fragrance adjuvant in consumer

products. Human exposure to ethyl acrylate occurs mostly through

inhalation of ethyl acrylate vapors, but it may also result from skin

contact or ingestion as a food additive or by drinking contaminated

water. The Report on Carcinogens review groups considered the data

underlying the nomination to remove ethyl acrylate from the Report

on Carcinogens where it has been listed as reasonably anticipated to be

a human carcinogen since 1989. The basis for this listing was a gavage

study which resulted in dose-related benign and malignant

forestomach neoplasms in rats and mice. The Basic Acrylic Monomer

Manufacturers, Inc. (BAMM), submitted a nomination to remove

ethyl acrylate from the Report on Carcinogens based upon the

following: 1) negative tumorigenicity results from chronic studies

using routes other than gavage in corn oil; 2) research results

suggesting that the forestomach carcinogenicity observed in the gavage

studies was secondary to a site-specific and concentration-dependent

irritating effect of ethyl acrylate; and 3) that significant human

exposure to ethyl acrylate monomer is unlikely in light of current

manufacturing practices and patterns of usage (see summary of ethyl

acrylate carcinogenicity data below). 

The majority opinion of the Report on Carcinogens review

groups1 was to recommend that ethyl acrylate be removed from the

Report on Carcinogens. This was based on the facts that 1) the

forestomach tumors induced in animal studies were seen only when

ethyl acrylate was administered by gavage at high concentrations that

induced marked local irritation and cellular proliferation, 2) animal

studies by other routes of administration including inhalation were

negative, and 3) because significant chronic human oral exposure to

high concentrations of ethyl acrylate monomer is unlikely. Therefore

ethyl acrylate does not meet the criteria to be listed in the Report on

Carcinogens as reasonably anticipated to be a human carcinogen. 

Summary of Available Carcinogenicity Data and

Other Relevant Information2

Animal Studies

Although mutagenic in some in vitro tests, ethyl acrylate is not

genotoxic under in vivo physiological conditions perhaps due to its

rapid metabolism to acrylic acid and ethanol by carboxyesterases and

detoxification through binding to non-protein sulfhydryls. Target

tissue toxicity comprised of irritation has been observed in the skin in

a lifetime mouse skin painting study, in the nasal olfactory mucosa in

27-month inhalation studies in rats and mice, and in the forestomach

in two-year corn oil gavage studies in rats and mice. Only body weight

reduction was observed in a two-year dosed-water study in rats. The

forestomach carcinogenicity observed in the corn oil gavage studies

represents the only treatment-related tumorigenic response in the

various animal studies. The irritation, hyperplasia, and tumor

responses in the forestomach were related more to target tissue

concentration of ethyl acrylate than to delivered dose in the chronic

gavage study. Based upon stop-exposure studies, gavage doses of ethyl

acrylate in corn oil sufficient to induce sustained mucosal hyperplasia

in the forestomach must be administered for longer than six months

to induce forestomach neoplasia.

Human Exposure and Cancer Studies

Prolonged consumer exposure to high levels of ethyl acrylate

monomer by the oral route is unlikely. Potential significant exposures

would most likely occur in an occupational setting where the routes of

exposure would be dermal and/or inhalation. Ethyl acrylate has a

strong acrid odor (odor threshold ~ 0.5 ppb) and is a known irritant

to the skin, eyes, and mucous membranes, making it unlikely that

humans would be chronically exposed to high concentrations. Data

provided in the BAMM nomination on worker exposure show

occupational exposure well below the threshold limit value (TLV=5

ppm for an eight-hour time-weighted average) and the short-term

exposure limit (STEL=15 ppm), although exposure of painters in an

unventilated room has been reported as high as 8 ppm in the painter’s

breathing zone.

An epidemiology study reported on mortality from cancer of the

colon and rectum in three separate cohorts of workers from two plants

manufacturing and polymerizing acrylate monomers. Workers were

exposed to ethyl acrylate and methyl methacrylate monomer between

1933 and 1982. Risks for both types of cancer were associated with

exposure in the earliest cohort, although the rectal cancer results are

imprecise because of the small number of cases involved. The greatest

relative risk was found in workers with the highest level of exposure

and a 20 year latency. The other two cohorts, with later dates of hire,

showed no excess risk, but very few cases were available for

observation. This study, by itself, can neither establish nor rule out a

causal relationship of ethyl acrylate with cancer.

Action on Nomination 

Ethyl acrylate will be delisted from the Report on Carcinogens because

the relevant data are not sufficient to meet the current criteria to list this

chemical as reasonably anticipated to be a human carcinogen. This is based

on the fact that the forestomach tumors induced in animal studies were

seen only when the chemical was administered by gavage at high

concentrations of ethyl acrylate, that induced marked local irritation

and cellular proliferation, and because significant chronic human

exposure to high concentrations of ethyl acrylate monomer is unlikely. 

1 Review groups for the Report on Carcinogens include the following:

The NIEHS Review Committee for the Report on Carcinogens (RG1)

The NTP Executive Committee* Interagency Working Group for the Report on Carcinogens (RG2) *

Agencies represented on the NTP Executive Committee include: Agency for Toxic Substances and

Disease Registry (ATSDR), Consumer Product Safety Commission (CPSC), Environmental Protection

Agency (EPA), Food and Drug Administration (FDA), National Center for Toxicological Research

(NCTR), National Institute for Occupational Safety and Health (NIOSH), Occupational Safety and

Health Administration (OSHA), Department of Health and Human Services (DHHS), National

Institutes of Health (NIH), National Cancer Institute (NCI), and National Institute of Environmental

Health Sciences/NTP (NIEHS/NTP)

The NTP Board of Scientific Counselors Report on Carcinogens Subcommittee (the External Peer

Review Group) 2 Summary of data contained in December, 1998 Ethyl Acrylate Background Document

REPORT ON CARCINOGENS, ELEVENTH EDITION
APPENDIX B

REPORT ON CARCINOGENS, ELEVENTH EDITION

Summary

Actions on the Nomination of

Saccharin for Delisting from the

Report on Carcinogens

Saccharin

CAS No. 81-07-2

Saccharin and its sodium and potassium salts have been produced

commercially in the United States for over 80 years. It is primarily

used as a nonnutritive sweetening agent. Potential exposure to

saccharin occurs through the consumption of dietetic foods and

drinks and by use of some personal hygiene products. Potential

exposure to saccharin also occurs in the workplace, specifically in

occupations, industries, or facilities that produce and deal with

saccharin and its salts. The Report on Carcinogens review groups

considered the data underlying the nomination to remove saccharin

from the Report on Carcinogens where it has been listed as reasonably

anticipated to be a human carcinogen since 1981. The basis for this

listing was sufficient evidence of carcinogenicity in experimental

animals. The Calorie Control Council submitted a nomination to the

NTP to consider removing saccharin from the Report on Carcinogens

based upon mechanistic data related to development of urinary

bladder cancers in rats (see summary of saccharin carcinogenicity data

below). 

The majority opinion of the review groups1 was to recommend

that saccharin be delisted from the Report on Carcinogens. There is

evidence for the carcinogenicity of saccharin in rats but less

convincing evidence in mice. Studies indicate that the observed

urinary bladder cancers in rats are related to the physiology of the rat

urinary system including urinary pH, osmolality, volume, and the

presence of precipitate, and urothelial damage with attendant

hyperplasia following consumption of diets containing sodium

saccharin at concentrations of 3% or higher with inconsistent findings

at lower dietary concentrations. The factors thought to contribute to

tumor induction by sodium saccharin in rats would not be expected to

occur in humans. The mouse data are inconsistent and require

verification by additional studies. Results of several epidemiology

studies indicate no clear association between saccharin consumption

and urinary bladder cancer. Although it is impossible to absolutely

conclude that it poses no threat to human health, sodium saccharin is

not reasonably anticipated to be a human carcinogen under conditions

of general usage as an artificial sweetener. 

Summary of Available Carcinogenicity Data and

Other Relevant Information2

Animal Studies

In four studies of up to 30 months duration, sodium saccharin was

carcinogenic in Charles River CD and Sprague-Dawley male rats as

evidenced by a dose-related increased incidence of benign or

malignant urinary bladder neoplasms at dietary concentrations greater

than 1% (Tisdel et al. 1974, Arnold et al. 1980, Taylor et al. 1980,

Schoenig et al. 1985). Non-statistically significant increases in urinary

bladder cancer have also been seen in saccharin-treated female rats

from studies showing a positive effect in males (Arnold et al. 1980,

Taylor et al. 1980). Furthermore, several initiation/promotion studies

in different rat strains have shown a reduced latency and/or increased

incidence of similar urinary bladder cancers in male and female rats

fed sodium saccharin subsequent to treatment with different urinary

bladder initiators (e.g., Hicks and Chowaniec 1977, Cohen et al.

1979, Nakanishi et al. 1980a, West et al. 1986, Fukushima et al.

1990). Several additional rat studies in which sodium saccharin was

administered either in the diet or in drinking water were negative for

tumorigenicity (Fitzhugh et al. 1951, Lessel 1971, Schmähl 1973,

Chowaniec and Hicks 1979, Hooson et al. 1980, Schmähl and Habs

1984). 

Three mouse studies have reported positive carcinogenicity

following exposure to saccharin. Two of these studies involved surgical

implantation of saccharin-containing cholesterol pellets into the

urinary bladders and resulted in development of malignant urothelial

neoplasms (Allen et al. 1957, Bryan et al. 1970). In the third study,

dietary sodium saccharin resulted in increased incidences of malignant

thyroid neoplasms (Prasad and Rai 1986). While the mouse data

cannot be discounted, some of these studies had methodological flaws,

provided limited information, did not show a dose-response, or had

unexpected outcomes that may be species or strain-specific and should

be verified by additional studies. Four studies in mice were judged

negative for tumorigenesis (Roe et al. 1970, Kroes et al. 1977,

Homberger 1978, Frederick et al. 1989) as were limited studies in

nonhuman primates (McChesney et al. 1977 abstr., Sieber and

Adamson 1978, Thorgiersson et al. 1994, Cohen et al. 1996 abstr.)

and a single hamster study (Althoff et al. 1975).

Human Cancer Studies

Most of the relevant human epidemiology studies have examined

associations between urinary bladder cancer and artificial sweeteners,

rather than saccharin per se. The time trend data for bladder cancer

show no clear indication that the increased use of saccharin or artificial

sweeteners commencing in the 1940s is associated with a general

increase in bladder cancer when controlled for confounding factors,

chiefly smoking. Risks of bladder cancer in diabetics, who presumably

consume greater amounts of artificial sweeteners compared to the

general population, are not greater than risks in the general population

(Armstrong and Doll 1975). Based upon several case-control studies

there is no overall association of use of artificial sweeteners and

bladder cancer (reviewed by IARC 1980, 1987b, JEFCA 1993).

However, an association between use of artificial sweeteners and

bladder cancer cannot be ruled out in some case-control subgroups,

albeit involving small numbers (Howe et al. 1980, Hoover and

Strasser 1980, Cartwright et al. 1981, Morrison et al. 1982,

Mommsen et al. 1983). Taken together, while the available

epidemiology data show no consistent evidence that saccharin is

associated with increased bladder cancer in general, a small increased

risk in some subgroups, such as heavy users of artificial sweeteners,

cannot be unequivocally excluded. With regard to the general

population, if sodium saccharin is a risk factor, it is weak and cannot

be proven or disproved due to lack of actual exposure data and

intrinsic limitations of existing epidemiology studies.

Additional Information Relevant to Carcinogenesis or

Possible Mechanisms of Carcinogenesis

Extensive studies of the mutagenicity and genotoxicity of saccharin

have shown generally negative but occasionally conflicting results.

Sodium saccharin is essentially nonmutagenic in conventional

bacterial systems (reviewed by Ashby 1985, IARC 1987a,b, Whysner

and Williams 1996) but is weakly clastogenic or genotoxic in shortterm in vitro and in some in vivo test systems (reviewed by Ashby

1985, IARC 1987a,b, Whysner and Williams 1996). Urine from mice

treated with sodium saccharin was mutagenic in the Ames test in one

study (Batzinger et al. 1977). Saccharin does not covalently bind to

DNA and does not induce unscheduled DNA synthesis in bladder

urothelium. 

Saccharin-induced carcinogenesis in rats shows a sex predilection for

males (Tisdel et al. 1974, Arnold et al. 1980, Taylor et al. 1980), an

organ specificity for urinary bladder (Tisdel et al. 1974, Arnold et al.

1980, Taylor et al. 1980, Fukushima et al. 1983, Schoenig et al. 1985),
APPENDIX B

and a dose-response when exposure to dietary concentrations of 1 to

7.5% of the sodium salt of saccharin was begun early in life (beginning

at birth or immediately at weaning) and continued for approximately

two years (Schoenig et al. 1985). The results of mechanistic studies have

shown that certain physiological conditions must be simultaneously or

sequentially present for induction of urinary bladder tumorigenesis.

These conditions include a urinary pH greater than 6.5, increased

urinary sodium concentration, increased urine volume, decreased urine

osmolality, presence of urinary crystals or precipitate, with resulting

damage to the urothelium prompting a proliferative (hyperplastic)

response of the urinary bladder epithelium. All of these conditions have

been studied extensively in male rats but less so in females or in mice.

The high levels of urinary protein characteristically produced by male

rats may partially explain the sex predilection. The high intrinsic rate of

urothelial proliferation at about the time of weaning is also believed to

contribute to the observed tumorigenic effects. The urinary milieu in

rats, especially male rats, is sufficiently different from that in humans or

other species to support the contention that these observations are ratspecific. Pharmacokinetic and metabolism data on sodium saccharin do

not explain the male rat sensitivity for induction of urinary bladder

neoplasms (Sweatman and Renwick 1979, 1980). 

Action on Nomination 

Saccharin will be delisted from the Report on Carcinogens, because

the rodent cancer data are not sufficient to meet the current criteria to

list this chemical as reasonably anticipated to be a human carcinogen.

This is based on the perception that the observed bladder tumors in

rats arise by mechanisms not relevant to humans, and the lack of data

in humans suggesting a carcinogenic hazard.

1 Review groups for the Report on Carcinogens include the following:

The NIEHS Review Committee for the Report on Carcinogens (RG1)

The NTP Executive Committee* Interagency Working Group for the Report on Carcinogens (RG2) *

Agencies represented on the NTP Executive Committee include: Agency for Toxic Substances and

Disease Registry (ATSDR), Consumer Product Safety Commission (CPSC), Environmental Protection

Agency (EPA), Food and Drug Administration (FDA), National Center for Toxicological Research

(NCTR), National Institute for Occupational Safety and Health (NIOSH), Occupational Safety and

Health Administration (OSHA), Department of Health and Human Services (DHHS), National

Institutes of Health (NIH), National Cancer Institute (NCI), and National Institute of Environmental

Health Sciences/NTP (NIEHS/NTP)

The NTP Board of Scientific Counselors Report on Carcinogens Subcommittee (the External Peer

Review Group)

2 Summary of data contained in the October, 1997, Saccharin Background Document.

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REPORT ON CARCINOGENS, ELEVENTH EDITION