NlaSM 

e~ 9~ 8tdtetue ~~-B~ 19tAwe3() In 1978 

CONTENTS 

NO. TITLE 

19 - Z,4-DIAMINOANISOLE 

(4-Methoxy-m-Phenylenediamine) 

IN HAIR AND FUR DYES 

2.0 - TETRACHLOROETHYLENE 

(perchloroethylene) 

ZI - TRlMELUTIC ANHYDRIDE (TMA) 

ZZ - ETHYLENE THIOUREA 

Z3 - ETHYLENE DIBROMIDE AND DISULFIRAM 

TOXIC INTERACTION 

Z4 - DIRECT BLUE 6, DIRECT BLACK 38, 

DIRECT BROWN 95 

Benzidine Derived Dyes 

Z5 - ETHYLENE DICHLORIDE 

(l,Z-dichloroethane) 

Z6 - NIAX· Catalyst ESN ••• a mixture of 

Dimethylaminopropionitrile and 

Bis[Z-(dimethylamino)ethylj ether 

27 - CHLOROETHANES: REVIEW OF TOXICITY 

28 - VINYL HALIDES CARCINOGENICITY 

Vinyl Bromide, Vinyl Chloride, 

Vinylidene Chloride 

29 - GL YCIDYL ETHERS 

30 - EPICHLOROHYDRIN 

Cumulative List of NIOSH Current Intelligence Bulletins 

#l through ;¥o30 for 1975 through 1978 

----------.---------

DATE 

January 13, 1978 

January 20, 1978 

February 3, 1978 

April 11, 1978 

April 11, 1978 

April 17, 1978 

April 19, 1978 

May 22,1978 

August 21, 1978 

September 21,1978 

October lZ, 1978 

October 12, 1978 

«( » 

( 4: 1) 

(1 _:"_ :3) 

(1 ~7) 

1~1) 

U. S. DEPARTMENT OF HEALTH, EDUCATION" A /IYID WELFARE 

Public Health Ser"ice 

Center tor Disease Control 

National Institute tor Occupational Satety and Heallf:hiJ 
/ 

/ 
NIOSH CURRENT INTELLIGENCE BULLETIN 

REPRINTS - BULLETINS 19 thru 30 for 1978 

Leonard J. Bah1man, Editor 

Technical Evaluation and Review Branch 

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE 

Public Health Service 

Center for Disease Control 

National Institute for Occupational Safety and Health 

Office of Extramural Coordination and Special Projects 

Rockville, Maryland 20857 

September 1979 
DISCLAIMER 

Mention of company names or products does not constitute 

endorsement by the National Institute for Occupational 

Safety and Health. 

DHEW (NIOSH) Publication No. 79-146 

ii 
PREFACE 

In January 1975, the National Institute for Occupational Safety and Health (NIOSH) 

developed a Current Intelligence System. Through this system, persons concerned 

with occupational health are informed of health and safety hazards that have gone 

unrecognized or are greater hazards than generally known. Since the inception of 

the NIOSH Current Intelligence System, over 30 Current Intelligence Bulletins have 

been issued as part of the information dissemination process. The 1978 Bulletins 

have been reprinted in this publication. It is important to note that the Bulletins 

have been reprinted essentially as originally published and do not contain 

information that may have become available since date of publication. Also, for 

some of the substances, NIOSH may have since issued Criteria Documents with 

recommended occupational health standards. 

Bulletins #1 through #18 have been previously reprinted as a NIOSH publication 

#78-127. Copies of all Bulletins and reprints are available from NIOSH 

Publications Dissemination, Division of Technical Services, 4676 Columbia 

Parkway, Cincinnati, Ohio 45226. 

iii 

(1) 

NlaSM 

January 13,1978 

2 ,4 - DIAMINOANISOLE 

(4-METHOXY-m -PHENYLENEDIAMINE) 

IN HAIR AND FUR DYES 

U. s. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE 

Public Health Service 

Center for Disease Control 

National Institute for Occupational Safety and Health 
(2) 

The Current Intelligence Bulletin is the primary product of the 

Current Intelligence System. The purpose of the Current Intelligence 

System is to promptly review, evaluate, and supplement new information 

received by NIOSH on occupational hazards that are either unrecognized 

or are greater than generally known. 

As warranted by this evaluation, the information is capsulized and 

disseminated to NIOSH staff, other government agencies, and the 

occupational health community, including labor, industry, academia, 

and public interest groups. With respect to currently known hazard 

information this system also serves to advise appropriate members of 

the above groups of recently acquired specific knowledge which may 

have an impact on their programs or perception of the hazard. Above 

all, the Current Intelligence System is designed to protect the health 

of American workers and to allow them to work in the safest possible 

environment. 

SYNONY!'1S 

2,4-Diaminoanisole 2,4-Diaminoanisole Sulfate 

Chemical Abstract Service Number 615-05-4 

CI. 76050 

CI. oxidation Base 12 

1,3-Diamino-4-methoxybenzene 

Furro L 

4-Methoxy-l,3-benzenediamine 

4-Methoxy-m-phenylenediamine 

Pelagol DA 

Pelagol Grey L 

Pelagol L 

Chemical Abstract Service Number 39156-41- 7 

CI. 76051 

l,3-Diamino-4-methoxybenzene Sulfate 

4-Methoxy-l,3-benzenediaJTline Sulfate 

4-HethoxY-'m-phenylenediamine Sulfate 

DHEW (NIOSH) Publication No. 78-111 

ii 
CURRENT INTELLIGENCE BULLETIN: 

2,4-Diaminoanisole in Hair and Fur Dyes 

January 13, 1978 

The National Institute for Occupational Safety and Health (NIOSH) 

recommends that 2,4-diaminoanisole (4-methoxy-m-phenylenediamine) and 

its salts* be handled in the workplace as if they were human ' carcinogens. 

This recommendation is based primarily upon a preliminary analysis of 

National Cancer Institute data indicating laboratory rats and mice fed 2,4-

diaminoanisole sulfate experienced a statistically significant excess of sitespecific malignant tumors as compared to controls. Caution is also 

indicated by NIOSH epidemiologic studies which suggest an elevated 

incidence of cancer among cosmetologists. As an interim measure, pending 

further evaluation of the carcinogenic potential of 2,4-diaminoanisole in the 

workplace, NIOSH believes it would be prudent to minimize occupational 

exposure to 2,4-diaminoanisole. 

This Bulletin summarizes the results of the National Cancer Institute animal 

study, the NIOSH epidemiologic studies, other pertinent data, their 

implications for occupational health, and precautions for handling products 

containing 2,4-diaminoanisole in the workplace. 

Background 

The principal use of 2,4-diaminoanisole is as a component of oxidation 

("permanent") hair and fur dye formulations. Approximately three-quarters 

of the current oxidation hair dye formulations contain 2,4-diaminoanisole in 

concentrations ranging from approximately 0.05% to approximately 2%. The 

concentration is determined by the shade of the dye. Oxidation hair dyes 

are very common among professional as well as over-the-counter products 

and account for approximately $200 million of the $280 million annual retail 

expenditure for hair dyes. NIOSH is unaware of any current domestic 

production of 2,4-diaminoanisole. Imports of 2,4-diaminoanisole are on the 

order of 25,000 pounds per year. 

* In this Bulletin, the phrase, "2,4-diaminoanisole," will be used to signify 

2,4-diaminoanisole as well as its salts, such as 2,4-diaminoanisole sulfate 

(4-methoxy-m-phenylenediamine sulfate). 

1 

(3) 
(4) 

Potential Occupational Exposures 

NIOSH estimates that approximately 400,000 workers have potential 

occupational exposure to 2.,4-diaminoanisole. Hairdressers and 

cosmetologists comprise the largest portion of workers with potential 

exposure. (Gloves are usually worn by hairdressers when applying hair dyes). 

A relatively small number of fur dyers are probably exposed to higher levels 

of 2.,4-diaminoanisole. 

Epidemiologic Studies 

NIOSH has conducted two epidemiologic studies which suggest excess cancer 

among cosmetologists. 

A report 1 based on data from a case-control study of 2.5,416 hospital 

admissions between 1956 and 1965 at Roswell Park Memorial Institute 

suggests an excess of cancer of specific genital sites (corpus uteri, ovaries) 

among hairdressers and cosmetologists. 

Another study currently being conducted by NIOSH is also suggestive of 

excess cancer among cosmetologists. This study involves a sample of 53,183 

records which are representative of the 417,795 Social Security disability 

awards made to female workers between 1969 and 1972.. Age and race 

adjusted proportional morbidity ratios* (PMbR's) have been constructed for 

2.4 selected occupational groups. Among cosmetologists, elevated PMbR's 

were observed for' cancer of the digestive organs, respiratory system, 

trachea, bronchus and lung, breast, and genital organs. Cosmetologists had a 

greater number of elevated PMbR's for specific primary malignant 

neoplasms than any other tabulated occupational group. Thus, the 

preliminary analysis of the Social Security Administration disability data is 

consistent with the hypothesis that persons employed in occupations 

classified within the broad category of cosmetology may be at elevated risks 

of developing a neoplasm due to exposures of occupational origin. 

Other relevant epidemiologic studies with conflicting results have been 

reported. 2- 6 These studies do not clearly demonstrate an association 

between hair dyes and cancer. NIOSH believes that its studies do suggest an 

association between cancer and employment as cosmetologists and 

hairdressers. However, it is recognized that cosmetologists and hairdressers 

are exposed to a large variety of substances, and it is difficult at this time 

to attribute any excess incidence of cancer to either hair dyes in general or 

2.,4-diaminoanisole in particular. 

* Each proportional morbidity ratio compares the observed number of 

women within an occupational category granted an award for a particular 

disability with the expected number of women (derived from all 

occupations in the entire sample) granted an award for the same 

disability. 
Laboratory Studies 

Preliminary analyses of National Cancer Institute data indicate that male 

and female laboratory rats and mice fed 2,4-diaminoanisole sulfate in their 

diets for seventy-eight weeks experienced a statistically significant excess 

of site-specific malignant tumors as compared to controls. 

Groups of fifty male and fifty female Fisher 344 rats and B6C3Fl mice were 

used in the test. Feed containing 0.05% or 0.12% technical grade 2,4-

diaminoanisole sulfate was administered to each group of treated rats; each 

group of treated mice received feed containing 0.12% or 0.24% technical 

grade 2,4-diaminoanisole sulfate. Fifty animals of each sex of each species 

served as controls. After the seventy-eight week treatment period, 

observation of the mice continued for an additional thirteen weeks and 

observation of the rats continued for an additional twenty-six weeks. 

Significant excess cancer was observed in the thyroid gland and 

integumentary system (skin) of high dose exposed rats of both sexes, as well 

as in the thyroid gland of high dose exposed mice, and in the lymphatic 

system of low dose exposed mice. 

In other studies, 2,4-diaminoanisole was tested by skin application to 

laboratory rodents. Testing by skin application has considerable merit since 

this route of administration approximates that resulting from the use of hair 

dyes. Laboratory mice and rats painted with 2,4-diaminoanisole have been 

reported to experience no statistically significant excess of cancer. 7,8 

Kinkle and Holzman, for example, reported applying a mixture containing 

0.4% 2,4-diaminoanisole to the shaved backs of Sprague-Dawley rats twice 

weekly for two years, and then continuing to observe the surviving animals 

for an additional six months.8 However, the interpretation of the reported 

data is complicated by experimental design9 and these experiments do not 

convincingly establish the safety of 2,4-diaminoanisole applied to skin. 

NIOSH understands that recent and still unpublished data acquired by the 

Food and Drug Administration indicate that 2,4-diaminoanisole penetrates 

the skin and thereby enters the system of both man and rhesus monkey. This 

indicates that skin contact with 2,4-diaminoanisole must be avoided in the 

workplace. 

There are reports indicating that 2,4-diaminoanisole is mutagenic in 

bacterial systems9 and in drosophila.10 Mutagenic activity per se should 

be considered an important liability. In addition, empirical correlations have 

suggested a relationship between mutagenicity, especially in bacterial 

strains, and carcinogenicity in higher animals. 

3 

(5) 
(6) 

NIOSH Recommendation 

Animal studies are valuable in helping identify human carcinogens. 

Substances that cause cancer in experimental animals must be considered to 

pose a potential cancer risk in man. Although safe levels of exposure to 

carcinogens have not yet been demonstrated, decreasing exposure to 

carcinogens does reduce their probability of initiating cancer development. 

While the carcinogenicity of Z,4-diaminoanisole is being further evaluated, 

the National Institute for Occupational Safety and Health recommends, as 

an interim and prudent measure, that occupational exposure to Z,4-

diaminoanisole and its salts be minimized. Exposures should be limited to as 

few employees as possible, while minimizing workplace exposure levels with 

engineering and work practice controls. In particular, skin exposures should 

be avoided. Although substitution is a possible control measure, NIOSH 

recommends that caution be exercised in selecting a substitute for hair and 

fur dye formulations containing Z,4-diaminoanisole. Alternatives should be 

fully evaluated with regard to possible human health effects. This is 

particularly important in view of the many questions which have been raised 

recently regarding the safety of numerous components of hair dye 

formulations. 

4 

Edward J. Baier 

Deputy Director 
References 

1. A Retrospective Survey of Cancer in Relation to Occupation, DHEW 

(NIOSH) Publication No. 77-178, U.S. Department of Health, Education, 

and Welfare, Public Health Service, Center for Disease Control, National 

Institute for Occupational Safety and Health, Cincinnati, Ohio, 1977. 

2. Garfinkel J., Selvin, S. and Brown, S. M., "Possible Increased Risk of 

Lung Cancer Among Beauticians," J. National Cancer Institute, 58, 141, 

1977. 

3. Hammond, E. C., "Some Negative Findings (Polio, Small Pox, Tetanus and 

Diptheria-Vaccines; Beauticians) and Evaluation of Risks," Presented at 

the American Cancer Society's Nineteenth Science Writers' Seminar, 

Sarasota, Florida, April 1977. 

4. Kinlen, L. J. et al., "Use of Hair Dyes by Patients with Breast Cancer: A 

Case-ControIStudy," British Medical Journal, 2, 366, 1977. 

5. Menck, H. R. et al., "Lung Cancer Risk Among Beauticians and Other 

Female Workers,"J. National Cancer Institute, 59, 1423, 1977. 

6. Shafer, N., and Shafer, R. W., "Potential of Carcinogenic Effects of Hair 

Dyes, " Nevv York State Journal of Medicine, 76, 394, 1976. 

7. Burnett, C. et al., "Long-Term Toxicity Studies on Oxidation Hair Dyes," 

Food and Cosmetics Toxicology, 13, 353, 1975. 

8. Kinkel, H. J., and Holzmann, S., "Study of Long-Term Percutaneous 

Toxicity and Carcinogenicity of Hair Dyes (Oxidizing Dyes) in Rats," 

Food and Cosmetics Toxicology, 11, 641, 1973. 

9. Ames, B.N. et al., "Hair Dyes Are Mutagenic: Identification of a Variety 

of MutagenicIngredients," Proceedings National Academy of Sciences 

USA, 72, 2423, 1975. 

10. Blijleven, W. G •• H, "Mutagenicity of Four Hair Dyes in DrosCJphila 

Melanogaster," Mutation Research, 48, 181, 1977. 

5 

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·NIDSH 

JANUARY 20,1978 

TETRACHLOROETHYLENE 

( perchloroethylene) 

U. S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE 

Public Health Se,,,ice 

Cente, to, Diae.ae Cont,ol 

natlona"nafifufe to, Occupational S.'ety and Health 

(9) 
(10) 

The Current Intelligence Bulletin is the primary product of the 

Current Intelligence System. The purpose of the Current Intelligence 

System is to promptly review, evaluate, and supplement new information 

received by NIOSH on occupational hazards that are either unrecognized 

or are greater than generally known. 

As warranted by this evaluation, the information is capsulized and 

disseminated to NIOSH staff, other government agencies, and the 

occupational health community, including labor, industry, academia, 

and public interest groups. with respect to currently known hazard 

information this system also serves to advise appropriate members of 

the above groups of recently acquired specific knowledge which may 

have an impact on their programs or perception of the hazard. Above 

all, the Current Intelligence System is designed to protect the health 

of American workers and to allow them to work in the safest possible 

environment. 

Ankilostin 

Antisal 1 

CAS 127-18-4 

Didakene 

Ethylene tetrachloride 

Pedal-Un 

Nema 

Perclene 

PerSec 

Synonyms 

NIOSH-RTECS KX38500 

Tetracap 

Tetrachlorethylene 

Tetrachloroethene 

Tetraguer 

Tetraleno 

Tetropil 

Tetlen 

l,l, 2 ,2-Tetrachloroethylene 

DHEW (NIOSH) Publication No. 78-112 

ii 
TETRACHLOROETHYLENE (PERCHLOROETHYLENE) 

The National Institute for Occupational Safety and Health (NIOSH) recommends that it is prudent to handle tetrachloroethylene (perchloroethylene) 

in the workplace as if it were a human carcinogen. The recommendation 

is based on a recent study by the National Cancer Institute (NCI) indicating 

that tetrachloroethylene causes liver cancer in laboratory mice (1). This 

Bulletin is to advise you of the findings of the NCI study, other pertinent 

data, their implications for occupational health, and precautions for handling 

tetrachloroethylene. 

Animal studies are valuable in helping identify human carcinogens. Substances 

that cause cancer in experimental animals must be considered to pose a 

potential cancer risk in man. Safe levels of exposure to carcinogens ~ave 

not been demonstrated, but the probability of cancer development is lowered 

with decreasing exposure to carcinogens. Thus NIOSH recommends that 

occupational exposure to tetrachloroethylene be minimized, and is providing 

suggested industrial hygiene practices. This is an interim recommendation, 

while the carcinogenic potential of tetrachloroethylene in the workplace 

is being further evaluated. 

The current Occupational Safety and Health Administration (OSHA) standard 

for occupational exposure to tetrachloroethylene is 100 ppm, (8-hour timeweighted average). In July 1976 NIOSH (3) recommended an exposure limit 

of 50 ppm (time-weighted average for up to a 10-hour workday, 40-hour 

workweek). Neither of these levels may provide adequate protection from 

potential carcinogenic effects because they were selected to prevent toxic 

effects other than cancer. 

Potential Occupational Exposures 

Tetrachloroethylene is a volatile liquid with an odor detectable at about 

50 ppm. It is a solvent widely used in dry cleaning, fabric finishing, metal 

degreasing, and other applications. NIOSH estimates that approximately 

500,000 workers are currently at risk of exposure to tetrachloroethylene 

in the United States. Over ZO,OOO dry cleaning establishments and a large 

number of other industries manufacture or use this substance. About 700 

million pounds of tetrachloroethylene are currently produced in the United 

States each year. 

Two-thirds of the domestically consumed tetrachloroethylene is used for 

dry cleaning and for the processing and finishing of textiles. Tetrachloroethylene is used by three-quarters of the dry cleaners in the United States 

because it. is an excellent cleaner of most fabrics, is easily recycled, and 

is not flammable. 

Metal cleaning accounts for approximately fifteen percent of the domestic 

consumption of tetrachloroethylene, where exposures can occur during 

degreasing and cold cleaning. Tetrachloroethylene also serves as a chemical 

(11 ) 
( 12) 

intermediate in the synthesis of trichlorotrifluoroethane (fluorocarbon 

113), dichlorotetrafluoroethane (fluorocarbon 114), chloropentafluoroethane 

(fluorocarbon 115), and hexafluoroethane (fluorocarbon 116). Tetrachloroethylene exposures may also occur in extraction processes, during its use 

as an industrial solvent, as a heat exchange fluid, and as a drug in treatment 

of internal parasite infestations. 

Laboratory Animal Studies for Carcinogenicity 

The long term animal study reported by NCI demonstrates tetrachloroethylene to be carcinogenic in laboratory mice. In the study, B6C3Fl mice 

were force fed tetrachloroethylene for 78 weeks. Male mice were treated 

at two dose levels (536 or 1072 mg/kg/day) and female mice were treated 

at two different dose levels (386 or 772 mg/kg/day). A significant increase 

of hepatocellular carcinoma (liver cancer) was observed in both sexes of 

treated mice when compared with control animals. At both dose levels 

more than 50% of the male mice and 40% of the female mice (each from 

groups of approximately 50 animals) developed liver cancer. By comparison, cancer developed in 12% or less of the groups of untreated or vehiclematched controls. This NCI report is the first definitive association of 

tetrachloroethylene with cancer. To relate some of the above information 

to the work envi: or.ment, a 70 kg man breathing a typical 10 cu m/day 

(over an 8-hour work shift) of air contaminated with 100 ppm of tetrachloroethylene would have an inhalation exposure of about 100 mg/kg/day. 

In t.i~e same NCI report, Osborne-Mendel rats showed no significant increase 

of liver cancer wtder the same experimental procedure. Because many 

of the lats died early in the study, this bioassay was considered inadequate 

for the cCU'cinogenicity testing of tetrachloroethylene. However there 

was a high incidence of kidney damage observed in both the rats and mice 

treated with tetrachloroethylene. 

A study by The Dow Chemical Company (2) found many tumors in SpragueDawley rats exposed by inhalation to 300 or 600 ppm tetrachloroethylene, 

but for most tumors there was no statistically significant difference in 

tumor incidence between exposed and control rats. Some tumors were 

found in higher incidence in control animals. The only tumor seen at higher 

incidence in exposed animals was adrenal pheochromocytoma in female 

rats at the lower exposure level only. Pheochromocytoma is a tumor which 

gives rise to high blood pressure and hyperglycemia due to release of adrenalin and noradrenalin into the blood. Increased mortality occurred in male 

rats exposed to 600 ppm tetrachloroethylene. 

Section references: 1,2 

Other Laboratory Animal Studies 

The liver is a principal target organ of tetrachloroethylene exposure in 
animals. Typical toxic effects are fatty liver, liver enlargement, and 

abnormal liver fWlction tests. Tetrachloroethylene has also been shown 

to cause kidney damage in mice following intraperitoneal injection and 

in rats and rabbits following inhalation. 

Neurophysiological effects of tetrachloroethylene are reflected in the 

distinct alterations of the electroencephalogram (EEG) in rats. Central 

nervous system (CNS) depression, including abnormal weakness, handling 

intolerance, intoxication, restlessness, irregular respiration, muscle incoordination, and Wlconsciousness have been observed in exposed animals. 

Tetrachloroethylene has been shown to be a primary eye and skin irritant 

in rabbits. Other effects of tetrachloroethylene exposure in laboratory 

animals include IWlg damage (excessive fluid accumulation, inflammation, 

congestion, or hemorrhage), cardiac depression, decreased blood pressure, 

depressed respiration, decreased oxygen consumption, and depression in 

growth rate. 

One study suggests the teratogenic potential of tetrachloroethylene. Fetal 

and maternal toxicity was observed in mice and rats exposed to tetrachloroethylene on days 615 of gestation. In this study a decrease in the maternal 

weight gain in rats, an increase in the relative weight of the liver in pregnant 

mice, an increase of fetal reabsorption in rats, a decrease in fetal body 

weight and an increase of subcutaneous edema in fetal mice, were all associated with exposure to tetrachloroethylene. Delayed ossification of skull 

bones and split sternebrae were possible teratogenic effects observed in 

mice. 

Section references: 3,5,6,7,8,13 

Human Toxicity 

Clinical evidence accumulated over the years clearly demonstrates that 

tetrachloroethylene is toxic to the liver and kidneys in humans. Liver 

impairment has been noted in cases of exposure to tetrachloroethylene 

as evidenced by abnormal liver function tests. Also, toxic chemical hepatitis, and enlargement of the liver and spleen have been associated with 

exposure to tetrachloroethylene. Tetrachloroethylene vapor is irritating 

to the eyes and upper respiratory tract, and may cause frontal sinus congestion and headache. Direct contact with skin can cause burns, blistering, 

and erythema due to the "degreasing" effect of tetrachloroethylene on 

the skin. Over a period of time this can result in extreme skin dryness 

with cracking and associated infection. 

Altered physiological and behavioral responses observed in subj~ts exposed 

to tetrachloroethylene include vague nonspecific complaints generally 

attributed to CNS depression. These symptoms include vertigo, impaired 

memory, confusion, fatigue, drowsiness, irritability, loss of appetite, nausea 

3 

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(14 ) 

and vomiting. Motor coordination following tetrachloroethylene exposure 

requires additional mental effort, which along with memory impairment 

and fatigue have important implications for worker safety. Various disturbances of the peripheral nervous system such as tremors and numbness 

have also been associated with exposure to tetrachloroethylene. Excessive 

absorption of tetrachloroethylene can cause severe depression of the eNS 

leading to coma; ultimately death may occur from respiratory paralysis 

or circulatory failure. 

Tetrachloroethylene is most commonly absorbed through the lungs and 

can be absorbed from the intestines if ingested. The skin is a less important absorption site. Physical exercise can significantly increase the amount 

of tetrachloroethylene absorbed through the lungs because of greater respiration and increased blood flow. 

Metabolism and elimination of tetrachloroethylene is relatively slow. It 

is deposited in body fat and the biologic halflife of tetrachloroethylene 

in man is estimated at six days. 

Section references: 3,4,8,9,10,11,12,14 

NIOSH Action on Tetrachloroethylene 

1. NIOSH has contracted for a retrospective mortality study of persons 

employed in dry cleaning establishments where there had been 

exposure to tetrachloroethylene. The contract will be monitored 

by the Biometry Section of the NIOSH Industry-wide Studies Branch. 

z. The NIOSH Industrial Hygiene Section of the Industry-wide Studies 

Branch plans an industrial hygiene assessment of dry cleaning workers 

exposed to tetrachloroethylene. 

3. The NIOSH Behavioral and Motivational Factors Branch is undertaking 

a tetrachloroethylene behavioral teratology study. The study 

results should be available in late 1978. 

4. NIOSH has contracted for a control technology assessment of the 

dry cleaning industry. The contract will be monitored by the NIOSH 

Control Technology Research Branch. 

5. NIOSH will coordinate research on tetrachloroethylene with the 

National Cancer Institute (NCr) which is also examining the mortality 

experience of persons employed in dry cleaning establishments. 

6. NIOSH has contracted for a study to evaluate the potential 

ter",togenicity and the mutagenicity of tetrachloroethylene. This 

contract will be monitored by the NIOSH Experimental Toxicology 

Branch. 

4 
7. Currently available NIOSH publications on tetrachlproethylene include: 

a) Criteria for a recommended standard •••• Occupational Exposure 

to Tetrachloroethylene (Perchloroethylene). HEW Publication 

No. (NIOSH) 76-185. 

b) Health and Safety Guide for Laundries and Dry Cleaners. HEW 

Publication No. (NIOSH) 75-151. 

c) Effects of Perchloroethylene/Drug Interaction on Behavior 

and Neurological Funct\on HEW Publication No. (NIOSH) 77-

191. 

d) A Behavioral and Neurological Evaluation of Dry Cleaners 

Exposed Perchloroethylene. HEW Publication No. (NIOSH) 

77-Z14. 

5 

Edward J. Baier 

Deputy Director 

(15) 
(1 6) 

BIBLIOGRAPHY 

1. Bioassay of Tetrachloroethylene for Possible Carcinogenicity. DHEW 

Publication No. (NIH) 77-813. U.S. Department of Health, 

Education, and Welfare, Public Health Service, National 

Institutes of Health, National Cancer Institute, October, 

1977. 

z. Rampy, L. W., J. F. Quast, B.K.J. Leong and P.J. Gehring, Results 

of longterm inhalation toxicity studies on rats of 1,1, 

trichloroethane and perchloroethylene formulations. 

Toxicology Research Laboratory, Dow Chemical, U.S.A., Poster 

presentation, International Congress of Toxicology, Toronto, 

Canada, April, 1977. 

3. Criteria for a recommended standard •••• Occupational Exposure to 

Tetrachloroethylene (Perchloroethylene). HEW Publication 

No. (NIOSH) 76-185. U.S. Department of Health, Education, 

and Welfare, Public Health Service, Center for Disease Control, 

National Institute for Occupational Safety and Health, July, 

1976. 

4. Fishbein, L., Industrial mutagens and potential mutagens I. 

Halogenated aliphatic derivatives. Mutat. Res., 32.: 2.67-308, 

1976. 

5. Fujii, T., Variation in the liver function of rabbits after 

administration of chlorinated hydrocarbons, Jap. J. Ind. 

Hlth., 17: 81-88, 1975. 

6. Duprat, P., L. Delsaut and D. Gradiski, Irritant potency of the 

principal aliphatic chloride solvents on the skin and ocular 

mucous membranes of rabbits. Europ. J. Toxicol., 3:171-177, 

1976. 

7. Brancaccio, A., V. Mazza and R. Di Paolo, Renal function in 

experimental tetrachloroethylene poisoning. Folia Med., 54: 

2.33-2.37, 1971. 

8. Mazza, V., Enzymatic changes in experimental tetrachloroethylene 

poisoning. Folia Med., 55:373-381, 1972.. 

9. Korn, J., How many more? Perchloroethylene intoxication in coin 

drycleaning establishments. Ugeskr. laeg., 139: 303-304, 

1977. 

6 
10. Weichardt, H., and J. Lindner, Health hazards due to 

perchloroethylene in chemical drycleaning enterprises, from 

the viewpoint of occupational medicine and toxicology. 

Staub Reinhalt Luft, 35: 416-420, 1975. 

II. Medek, V., and J. Kovarik, The effect of perchloroethylene on the 

health of workers. Pracovni lekarstvi, 25: 339-341, 1973. 

12. Larsen, N., B. Nielsen, and A. RaynNielsen, Perchloroethylene 

intoxication. A hazard in the use of coin laWldries. 

Ugeskr. Laeg., 139: 270-275, 1977. 

13. Schwetz, B.A., KJ. Leong and P.J. Gehring, The effect of 

maternally inhaled trichloroethylene, perchloroethylene, 

methyl chloroform and methylene chloride on embryonal and 

fetal development in mice and rats. Toxicol. Appl. 

Pharmacol., 32: 84-96, 1975. 

14. Ikeda, M., and T. Imamura, Biological halflife of trichloroethylene 

and tetrachloroethylene in human subjects. Int. Arch. Arbeitsmed., 

31: 209-224, 1973. 

7 

( l7) 
( 18) 

SUGGESTED PROCEDURES FOR MINIMIZING EMPLOYEE EXPOSURE 

TO TETRACHLOROETHYLENE {PERCHLOROETHYLENE} 

CONTROL OF OVEREXPOSURES 

NIOSH recommends that it is prudent to handle tetrachloroethylene in 

the workplace as if it were a human carcinogen and that occupational 

exposure to tetrachloroethylene be minimized. Exposure to tetrachloroethylene should be ·limited to as few employees as possible, while minimizing workplace exposure levels. The area in which it is used should be 

restricted to those employees necessary to the process or operation. 

Furthermore, consideration should be given to isolating the tetrachloroethylene exposure area so that adjacent workers are not also exposed. 

1. Exposure monitoring 

The NIOSH Occupational Exposure Sampling Strategy Manual, NIOSH publication :ff77-173, may be helpful in developing efficient programs to monitor employee exposures to tetrachloroethylene. The manual discusses 

determination of the need for exposure measurements, seiection of appropriate employees for sampling, and selection of sampling times. 

Employee exposure measurement samples can be obtained and analyzed 

using the guidelines in NIOSH method :ffP&CAM 127 in the second edition 

of the NIOSH Manual of Analytical Methods, NIOSH publication :ff77-157. 

Exposure measurements shOUld consist of 8-hour TWA exposure estimates 

calculated from personal or breathing zone samples (air that would most 

nearly represent that inhaled by the employees). 

2. Engineering controls 

Engineering and work practice controls should be used to minimize employee exposure to tetrachloroethylene. 

To ensure that ventilation equipment is working properly, it is advised 

that effectiveness be checked at least every three months {e.g., air velocity, 

static pressure or air volume}. System effectiveness should also be checked 

within five days of any change in production, process, or control which 

might result in significant increases in airborne exposures to tetrachloroethylene. 

3. Respiratory protection 

Exposure to tetrachloroethylene should not be controlled with the use of 

respirators except: 

8 
During the time period necessary to install or implement engineering or 

work practice controls; or 

In work situations in which engineering and work practice con troIs are 

technically not feasible; or 

To supplement engineering and work practice controls when such controls 

fail to adequately control exposure to tetrachloroethylene; or 

For operations which require entry into tanks or closed vessels; or 

In emergencies. 

Respirators should be approved by the National Institute for Occupational 

Safety and Health (NIOSH) or by the Mining Enforcement and Safety Administration (MESA). Refer to NIOSH Certified Equipment, December 15, 

1975, NIOSH publication #76-145 and Cumulative Supplement June 1977, 

NIOSH Certified Equipment, NIOSH Publication #77-195. The use of faceseal coverlets or socks with any respirator voids NIOSHjMESA approvals. 

Quantitative faceseal fit test equipment (such as sodium chloride or PDOP) 

should be used. Refer to A Guide to Industrial Respiratory Protection, 

NIOSH publication #76-189 for guidelines on appropriate respiratory protection programs. 

Where respirators are used under the preceding guidelines, NIOSH recommends that for routine use the employer provide either a) Self-contained 

breathing apparatus with a full facepiece operated in pressure-demand 

or other positive pressure mode (30 CFR 11.70(a)) or b) A combination 

respirator which includes a Type-C supplied-air respirator with a full facepiece operated in pressure-demand or other positive pressure or continuous 

flow mode and an auxiliary self-contained breathing apparatus operated 

in pressure-demand or positive pressure mode (30 CFR 11.70(b)). For firefighting, the employer should provide a) Self-contained breathing apparatus 

with a full facepiece operated in pressure-demand or other positive pressure 

mode (30 CFR 11.70(a)). For escape the employer should provide a) Any 

gas mask providing protection against organic vapors (30 CFR 11.90) or 

b) Any escape self-contained breathing apparatus (30 CFR 11.70(a)). 

PERSONAL PROTECTIVE EQUIPMENT 

Employers should provide impervious, gloves, face shields (8-inch minimum) 

and other appropriate clothing necessary to prevent repeated or prolonged 

skin contact with liquid tetrachloroethylene. 

Employers should see that employee clothing wet with liquid tetrachloroethylene is placed in closed containers for storage until it can be discarded 

or until the employer provides for the removal of tetrachloroethylene from 

the clothing. If the clothing is to be laundered or otherwise cleaned to 

remove the tetrachloroethylene, the employer should inform the person 

9 

(19 ) 
(20) 

performing the operation of the hazardous properties of tetrachloroethylene 

including the fact that it is a possible human carcinogen. 

Employers should see that permeable clothing which becomes contaminated 

with liquid tetrachloroethylene be removed promptly and not reworn until 

the tetrachloroethylene is removed from the clothing. 

PERSONAL HYGIENE 

Employers should see that employees who handle liquid tetrachloroethylene 

wash their hands thoroughly with soap or mild detergent before eating, 

smoking, or using toilet facilities. 

Employers should see that employees whose skin becomes contaminated 

with liquid tetrachloroethylene promptly wash or shower with soap and 

mild detergent and water to remove any tetrachloroethylene f.-om the 

skin. 

10 
(21) 

NlaSM . 

February 3 I 1978 

TRIMELLITIC Al'~I-IYDRIDE (TMA) 

U. S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE 

Public Health Service 

Center tor Disease Cont,ol 

National Institute for Occupational Safety and Health 
(22) 

The 

of 

the 

Current Intel l igence Bulletin i s the primary product 

the Current Intelligence Sys tem. The purpose of 

Current Intelligence System is to promptly reevaluate, and supplement new information reby NIOSH on occupational hazards that are 

unrecognized or are gre ater than generally 

view, 

ceived 

either 

known. 

As warranted by this evaluation. the information is 

capsulized and diss eminated to NIOSH staff, other 

government agencies, and the occupational health community, including labor, industry, academia, and public interest groups. With respect to currently known 

hazard information this system also serves to advise 

appropriate members of the above groups of recently acquired specific knowledge which may have an impact on their programs or perception of the hazards. Above all, the Current Intelligence Sy;stem 

is designed to protect the health of American workers and to allow them to work in the s afest 

possible environment. 

Synonyms 

ANHYDROTRIMELLITIC ACID 

1,2,4-BENZENETRICARBOXYLIC ACID ANHYDRIDE 

1,2,4-BENZENETRICARBOXYLIC ACID, CYCLIC 1,2-ANHYDRIDE 

1,2,4-BENZENETRICARBOXYLIC ANHYDRIDE 

4-CARBOXYP'HTHALIC ANHYDRIDE 

CHEMICAL ABSTRACTS SERVICE NUMBER: 552-30-7 

CHEMICAL FORMULA: CgH405 

1,3-DIHYDRO-l,3-DIOXO-5-ISOBENZOFURANCARBOXYLIC ACID 

1,3-DIOXO-5-PHTHALANCARBOXYLIC ACID 

DIPHENYLMETHANE-4,4'-DIISOCY AN ATE-TRIMELLIC 

ANHYDRIDE-ETHOMID HT POLYMER 

NIOSH - RTECS DC20500 

TMA* 

TMAN 

TRIMELLITIC ACID ANHYDRIDE 

TRIMELLITIC ACID 1,2-ANHYDRIDE 

TRIMELLITIC ACID CYCLIC 1,2-ANHYDRIDE 

*TMA is also an acronym for trimethylamine. 

Dt-IEW (NIOSH) Publication No. 78-121 
TRIMELLITIC ANHYDRIDE (TMA) 

The National Institute for Occupational Safety and Health (NIOSH) recommends that 

trimellitic anhydride (TMA) be handled as an extremely toxic agent in the workplace. 

Exposure to this compound may result in noncardiac pulmonary edema (apparently 

without benefit of a pulmonary irritation warning), immunological sensitization, and 

irritation of the pulmonary tract, eyes, nose, and skin, There is no current Occupational 

Safety and Health Administration (OSHA) exposure standard for trimellitic anhydride. 

The Amoco Chemicals Corporation, the sole domestic producer, suggests a limit of 

"0.05 mg/m 3 or less for susceptible individuals."(l) 

NIOSH has prepared this Current Intelligence Bulletin to advise you of recent findings 

of toxic effects of trimellitic anhydride and to provide some precautions for handling 

trimellitic anhydride in the workplace. Attached are "Suggested Procedures for 

Minimizing Employees' Exposure to Trimellitic Anhydride." 

Potential Occupational Exposures 

NIOSH estimates approximately 20,000 American workers are currently at risk of 

exposure to trimellitic anhydride in its various applications. TMA is used as a curing 

agent for epoxy and other resins, in vinyl plasticizers, paints and coatings, polymers, 

polyesters, agricultural chemicals, dyes and pigments, pharmaceuticals, surface active 

agents, modifiers, intermediates, and specialty chemicals. The sole domestic producer 

of trimellitic anhydride is Amoco Chemicals Corporation which has a 50 million poundper-year plant at Joliet, Illinois. 

Human Toxicity 

The ability for trimellitic anhydride to cause pulmonary edema (excessive fluid in the 

lungs) has been demonstrated by Rice et al.(2) Two workers had been employed by the 

same company for only a short period of time (3 and 6 weeks). They received multiple 

inhalation exposures to an epoxy resin containing trimellitic anhydride when it was 

(23) 
(24) 

sprayed on heated pipes. The levels of trimellitic anhydride were not available to the 

authors. No mention was made of severe irritation of the upper respiratory tract while 

they were receiving their exposures, suggesting little or no warning of subsequent 

damage to the lungs. The possibility that the pulmonary edema was the result of a 

hypersensitivity reaction must therefore be considered. Resins can be sensitizers (e.g., 

toluene diisocyanate or TDI), though most of the reported effects have been those of 

direct irritation. (3) 

Sensitization to trimellitic anhydride was reported by Zeiss et a1.(4) Respiratory 

symptoms were observed in fourteen workers employed in the synthesis of trimellitic 

anhydride. The authors suggest three distinct syndromes induced by inhalation of TMA. 

The first, rhinitis and/or asthma, developed over an industrial exposure period of weeks 

to years. After this period, the sensitized worker exhibited symptoms immediately 

following exposure to trimellitic anhydride dust or fume, which abated after the work 

exposure had stopped. The second syndrome, termed "TMA-flu" by the workers, also 

required a sensitization period of exposure and was characterized by delayed onset 

cough, wheezing, and labored breathing starting 4 to 8 hours after a work shift and 

peaking at night. These respiratory symptoms were usually accompanied by malaise, 

chills, fever, muscle and joint aches, and appeared to be associated with relatively high 

exposures to trimellitic anhydride during particular work shifts. The third syndrome, 

which followed initial high exposure to TMA, was primarily an irritant effect. It was 

characterized by a "running" nose without itching or sneezing, occasional nosebleed, 

cough, labored breathing, and occasional wheezing. Symptoms usually abated after 8 

hours and rarely lasted into the night. 

The above stUdies suggest harmful respiratory effects of trimellitic anhydride at 

relatively high concentrations, but even at lower concentrations some workers may 

develop an immunological sensitization over a period of time. 

Fawcett et ala (5) also observed sensitization in a worker exposed to trimellitic 

anhydride in the production of tubular steel shop fittings coated with an epoxy resin. 

The chemical agent responsible for asthma symptoms of six workers was identified by 

careful inhalation challenge testing, simulating work exposure. Typical attacks which 

began one year after onset of TMA exposure consisted of cough and breathlessness 

2 
lasting for 30 minutes, which subsided, only to be followed the same evening by sneezing 

which persisted for about 24 hours. Subsequent attacks were prevented by avoiding 

exposure. 

Data on occupational exposures to trimellitic anhydride were also obtained during a 

NIUSH Health Hazard Evaluation of a paint and varnish company during the 

manufacture of an epoxy paint.(6) The Health Hazard Evaluation was conducted at the 

request of employees who were concerned about possible harmful effects of trimellitic 

anhydride exposure during processing and decontamination operations. The occupational 

airborne exposure levels averaged 1.5 mg/m3 TMA (with a range from "none detected" 

to 4.0 mg/m3) during processing operations and 2.8 mg/m3 TMA (ranging from "none 

detected" to 7.5 mg/m3) during decontamination operations. A total of 13 employees (5 

present and 8 former employees) were interviewed and briefly examined. Employees' 

symptoms and complaints were: eye irritation, nasal irritation, shortness of breath, 

wheezing, cough, heartburn, mmsea, headache, skin irritation, and throat irritation. 

Three of the former workers stated that they had left that department for health 

reasons. Complaints subsided when non-TMA-containing products were being 

formulated. 

The Occupational Health and Safety Division, Department of Labour, Alberta, Canada, 

has reported to NIOSH that they are aware of employee reactions in two plants using 

TMA-epoxy powder pipe coatings. The one plant, started in 1971, had a number of 

employees with an immediate reaction. After instituting engineering and administrative controls, there has been no further incidence. In the second plant, began in 1974, 

the first adverse reaction occurred in 1975. There have been 9 cases of adverse 

reactions reported to date. Most of these employees were kept in intensive care while 

they recuperated and were advised by their physicians to seek new jobs. However, some 

returned to their previous jobs and became ill again. Due to the unavailability of a good 

analytical method for trimellitic anhydride occupational levels could not be documented 

until November of 1977. The TMA concentrations found ranged from 0.11 mg/m3 to 

3 0.27 mg/m . 

3 

(2S) 
(26) 

In view of the employer's responsibility, "to furnish to each of his employees 

employment and a place of employment which are free from recognized hazards that 

are causing or likely to cause death or serious physical harm to his employees ... ," 

occupational exposure to trimellitic anhydride should be minimized. It appears evident 

that trirnellitic anhydride, a known irritant, can 

immunological sensitization, and asthma symptoms. 

severe pulmonary edema, 

References 

\ 

J. Donald Millar, M.D. 

Assistant Surgeon General 

Acting Director 

1. Amoco-Industrial Hygiene Toxicology and Safety Data Sheet, Environmental 

Health Services, Medical and Health Services Department, July 8, 1976. 

2. Rice, D. L., Jenkins, D. E., Gray, J. M., and Greenberg, S. D., "Chemical 

Pneumonitis Secondary to Inhalation of Epoxy Pipe Coating," Archives of 

Environmental Health 32(4):173-8, july-August 1977. 

3. Patty, F. A., ed. Industrial Hygiene and Toxicology, Second Revised Edition, 

Volume II,. Fawcett, D. W., Irish, D. D., eds. John Wiley &: Sons, Inc., New York. 

4. Zeiss, C. R., Patterson, R., Pruzansky, J.J., Miller, M. M., Rosenberg, M., Levitz, 

D., "Trimellitic Anhydride-Induced Airway Syndromes: Chemical and Immunologic 

Studies", J. Allergy &: Clinical Immunology 60(2):96-103, August 1977. 

5. Fawcett, D. W., Taylor, A. J., Pepys, J. "Asthma Due to Inhaled Chemical AgentsEpoxy Resin Systems Containing Phthalic Acid Anhydride, Trimel-litic Acid 

Anhydride and Triethylene Tetramine", Clinical Allergy 7(1):-14, January 1977. 

6. National Institute for Occupational Safety and Health, Health Hazard Evaluation 

Determination Report No. 74-111-283. 

4 
SUGGESTED PROCEDURES FOR MINIMIZING EMPLOYEE EXPOSURE TO 

TRIMELLITIC ANHYDRIDE (TMA) 

CONTROL OF OVEREXPOSURES 

NIOSH recommends that trimellitic anhydride be handled in the workplace as an 

extremely toxic substance because it can cause noncardiac pulmonary edema, 

immunological sensitization, and severe respiratory irritation. Exposure to trimellitic 

anhydride should be limited to as few employees as possible, while minimizing 

workplace exposure levels. The area in which it is used should be restricted to those 

employees necessary to the process or operation. Furthermore, consideration should be 

given to isolating the trimellitic anhydride exposure area so that adjacent workers are 

not also exposed. 

1. Exposure Monitoring 

The NIOSH Occupational Exposure Sampling Strategy Manual, NIOSH Publication #77-

173, may be helpful in developing efficient programs to monitor employee exposures to 

trimellitic anhydride. The manual discusses determination of the need for exposure 

measurements, selection of appropriate employees for sampling, and selection of 

sampling times. 

Exposure measurements should consist of 8-hour TWA (time-weighted average) exposure 

estimates calculated from personal or breathing zone samples (air that would most 

nearly represent that inhaled by the employees). 

2. Engineering Controls 

Engineering and work practice controls should be used to minimize employee exposure 

to trimellitic anhydride. 

To ensure that ventilation equipment is working properly, effectiveness (e.g., air 

velocity, static pressure or air volume) should be checked at least every three months. 

5 

(27) 
{28} 

System effectiveness should also be checked within five days of any change in 

production, process, or control which might result in significant increases in airborne 

exposures to trimellitic anhydride. 

3. Respiratory Protection 

Exposure to trimellitic anhydride should not be controlled with the use of respirators 

except: 

o During the time period necessary to install or implement engineering or work 

practice controls; or 

o In work situations in which engineering and work practice controls are technically 

not feasible; or 

o To supplement engineering and work practice controls when such controls fail to 

adequately control exposure to trimellitic anhydride; or 

o For operations which require entry into tanks or closed vessels; or 

o In emergencies. 

Respirators should be approved by the National Institute for Occupational Safety and 

Health (NIOSH) or by the Mining Enforcement and Safety Administration (MESA). 

Refer to NIOSH Certified Equipment, December 15, 1975, NIOSH publication #76-145 

and Cumulative Supplement June 1977, NIOSH Certified Equipment, NIOSH publication 

#77-195. The use of face seal coverlets or socks with any respirator voids NIOSH/MESA 

approvals. 

Quantitative faceseal fit test equipment (such as sodium chloride, dioctyl phthalate, or 

equivalent) should be used. Refer to A Guide to Industrial Respiratory Protection, 

NIOSH publication #76-189 for guidelines on appropriate respiratory protection 

programs. 

6 
Where respirators are needed and NIOSH recommendations allow their use to reduce 

employee exposure, the following types of respirators may be used. They are listed in 

order of increasing protection factors. 

o Protection factor of 50: any chemical cartridge respirator with a full facepiece, 

organic vapor cartridge(s), and high efficiency filter(s) (30 CFR 11.150 and 

11.130); any gas mask with a chin-style organic vapor canister and high efficiency 

filter (30 CFR 11.90(a) and 11.130); any supplied-air respirator with a full 

facepiece, helmet, or hood (30 CFR 11. 110(a»; any self-contained breathing 

apparatus with a full facepiece (30 CFR 11.70(a». 

o Protection factor of 1000: any powered air purifying chemical cartridge 

respirator with full facepiece, organic vapor cartridge(s), and high efficiency 

particulate filter(s). 

o Protection factor of 2000: any type C supplied-air respirator with a full facepiece 

operated in positive pressure-demand or other positive pressure mode or with a 

full facepiece, hood, or helmet operated in continuous flow mode 

(30 CFR 11.110(a». 

o Protection factor of 10,000+: self-contained breathing apparatus with a full 

facepiece operated in positive pressure-demand or other positive pressure mode 

(30 CFR 11.70(a»; any combination respirator which includes a type C supplied-air 

respirator with a full facepiece operated in positive pressure-demand or other 

positive pressure or continuous flow mode and an auxilary self-contained breathing 

apparatus operated in positive pressure-demand or positive pressure mode (30 CFR 

11. 70(b». 

PERSONAL PROTECTIVE EQUIPMENT 

Employers should provide appropriate protective clothing and equipment necessary to 

prevent repeated or prolonged skin contact with trimellitic anhydride. 

7 

(29) 
(30) 

Employers should see that employees whose clothing may have become contaminated 

with trimellitic anhydride change into uncontaminated clothing before leaving the work 

premises. 

Employers should see that non-impervious clothing which becomes contaminated with 

trimellitic anhydride be promptly removed and not reworn until the trimellitic 

anhydride is removed from the clothing. 

Employers should see that clothing contaminated with trimellitic anhydride is placed in 

closed containers for storage until it can be discarded or removed from the clothing. If 

the clothing is to be laundered or otherwise cleaned to remove the trimellitic anhydride, 

the employer should tell the person performing the cleaning operation of the hazardous 

properties of trimellitic anhydride. 

Employers should provide dust-resistant safety goggles where there is any possibility of 

triinellitic anhydride dust contacting the eyes. 

8 
NlaSM 

ETHYLENE THIOUREA 

U. S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE 

Public Health Service 

Center 'or Disease Control 

National Institute for Occupational Sa'ety and Health 

(31) 

April 11,1978 
(32) 

The Current Intelligence Bulletin is the primary product of the 

Current Intelligence System. The purpose of the Current Intelligence 

System is to promptly review, evaluate, and supplement new information 

received by NIOSH on occupational hazards that are either unrecognized 

or are greater than generally known. 

As warranted by this evaluation, the information is capsulized and 

disseminated to NIOSH staff, other government agencies, and the 

occupational health community, including labor, industry, academia, 

and public interest groups, With respect to currently known hazard 

information this system also serves to advise appropriate members of 

the above groups of recently acquired specific knowledge which may 

have an impact on their programs or perception of the hazard. Above 

all, the Current Intelligence System is designed to protect the health 

of American workers and to allow them to work in the safest possible 

environment. 

IDENTIFIERS AND SYNONYMS FOR ETHYLENE THIOUREA 

Chemical Abstracts Service 

Registry Number 96-45-7 

NIOSH RTECS Number NI96Z50 

Chemical Formula C3H6NZS 

4,5-Dihydroimidazole-Z(3 H)-thione 

4,5-Dihydro-Z-mercaptoimidazole 

N,N'-(l,Z-Ethanediyl) thiourea 

Ethylene thiourea 

Ethylene thiour ea 

1,3-Ethylene-Z-thiourea 

1,3-Ethylenethiourea 

N,N'-Ethylenethiourea 

ETU 

Imidazolidinethione 

Imidazoline-2-thiol 

Z-Imidazolidinethione 

Z-Imidazoline-2-thiol 

Imidazoline-Z(3H)-thione 

Mercaptoimidazoline 

2-Mercaptoimidazoline 

2-Mercapto-2-imidazoline 

NA 2Z 

NA-2Z-D 

Pennac CRA 

Rhodanin S 6Z 

Sodium-ZZ Neoprene accelerator 

Tetrahydro-ZH-imidazole-Z-thione 

Z-Thiol-dihydroglyoxaline 

Warecure C 

DHEW (NIOSH) Publication No. 78-144 

ii 
CURRENT INTELLIGENCE BULLETIN: 

ETHYLENE THIOUREA (ETU) 

April 11, 1978 

The National Institute for Occupational Safety and Health (NIOSH) recommends that ethylene thiourea be handled in tbe workplace as if it were a 

human carcinogen and teratogen. During development of a NIOSH Special 

Occupational Hazard Review on ethylene thiourea (scheduled for issuance 

later in 1978) it became apparent that exposure to ethylene thiourea poses a 

risk of teratogenesis, particularly to the central nervous system, which is 

greater than has been generally recognized. The NIOSH literature review 

clearly shows ethylene thiourea to be a teratogen and a carcinogen in 

laboratory rats with supportive studies in other species. Pending completion 

of a NIOSH Special Occupational Hazard Review, this Current Intelligence 

Bulletin has been prepared to provide early dissemination of the informatioI). 

since NIOSH believes it would be prudent ,to minimize occupational exposure 

to ethylene thiourea. There is no current Occupational Safety and Health 

Administration (OSHA) exposure standard for ethylene thiourea. 

Background 

Ethylene thiourea is a white crystalline solid which is used extensively as an 

accelerator in the curing of polychloroprene (Neoprene®) and other 

elastomers. NIOSH estimates that approximately 3500 workers in the rubber 

industry have potential occupational exposure to ethylene thiourea. This 

estimate is based on the NIOSH National Occupational Hazard Survey which 

was conducted between 1972 and 1974, and included over 500,000 employees 

at 4775 facilities. In addition, exposure to ethylene thiourea also results 

from the very widely used ethylene bisdithiocarbamate fungicides. Ethylene 

thiourea may be present as a contaminant in the ethylene bisdithiocarbamate fungicides and can also be formed when food containing the 

fungicides is cooked. 

Commercial ethylene thiourea is available as a solid powder, as a dispersion 

in oil (which retards the formation of fine dust dispersions in workplace air), 

and "encapsulated" in a matrix of compatible elastomers. In this latter 

form, ethylene thiourea may be least likely to escape into the workplace air. 

1 

(33) 
(34) 

Laboratory Animal Studies 

Ethylene thiourea has been shown to be carcinogenic and teratogenic 

(causing malformations in offspring) in laboratory animals. In addition, 

ethylene thiourea can cause -myxedema (the drying and thickening of skin, 

together with a slowing down of physical and mental activity), goiter, and 

other effects related to decreased output of thyroid hormone. 

In a recent publication from E. I. du Pont de Nemours and Company's Haskell 

Laboratory, for example, Stula and Krauss report "marked teratogenic 

effects were demonstrated" when ethylene thiourea was applied to the skin 

of laboratory rats. (1) In this study, 50 milligrams ethylene thiourea per 

kilogram body weight was applied as a 2.0% solution in dimethylsulfoxide 

(DMSO) to the skin of pregnant, female Sprague-Dawley rats on the twelfth 

and also on the thirteenth day of gestation. Malformations were observed in 

all of seventy-three fetuses upon sacrifice of the pregnant females on the 

twentieth day of gestation. Appropriate control animals showed no fetal 

abnormality. A number of other reports in the literature further document 

the teratogenic potential of ethylene thiourea (e.g., 2. and references cited 

therein). 

The Stula and Krauss study (1) further demonstrates that dose as well as day 

of gestation on which exposures occur are critical factors. When 50 mg/kg 

ethylene thiourea applications were made as above, but on the tenth and 

eleventh day of gestation, only five of eighty-three fetuses exhibited 

abnormalities; DMSO controls in this case exhibited one abnormality in forty 

fetuses. However, no fetal abnormalities were found among pregnant rats 

similarly exposed to 2.5 mg/kg ethylene thiourea on the tenth and also on the 

eleventh day of gestation. 

Ethylene thiourea has been shown to cause cancer in laboratory animals. In 

one study, for example, Charles River CD rats were fed ethylene thiourea at 

175 or 350 ppm in their diets for eight~en months and then observed while on 

a control diet for an additional six months. (3) Thyroid carcinomas were 

observed in seventeen of twenty-six males (2. with pulmonary metastases) 

and eight of twenty-six females at the high dose level, as well as three of 

twenty-six males and three of twenty-six females at the low dose level. In 

addition, solid-cell adenomas of the'thyroid were observed in one female at 

the high dose level as well as two females at the low dose level. No thyroid 

carcinoma was found among the thirty-two male or thirty-two female 

controls. The International Agency for Research in Cancer (IARC) has 

concurred that oral administration of ethylene thiourea produces thyroid 

carcinoma in rats. (4) Other authors (5, 6) have also reported carcinogenic 

effects of ethylene thiourea in laboratory animals. 

A more complete review of animal experiments on ethylene thiourea will be 

presented in the forthcoming NIOSH Special Occupational Hazard Review. 

2. 
NIOSH Recommendation 

Pending completion of the NIOSH Special Occupational Hazard Review and 

the development of specific recommended control measures for ethylene 

thiourea, the National Institute for Occupational Safety and Health 

recommends, as an interim and prudent measure, that occupational exposure 

to ethylene thiourea be minimized. Exposure should be limited to as few 

employees as possible, while minimizing workplace exposure levels with 

engineering and work practice controls. Although substitution is a possible 

control measure, alternatives to ethylene thiourea or ethylene bisdithiocarbamate fungicides should be fully evaluated with regard to possible 

human health effects. 

IrI . Do aId Millar, M.D. 1- Ass· tant Surgeon General 

Acting Director 

3 

(35) 
(36) 

References 

1. Stula, E. F. and Krauss, W. C., "Embryotoxicity in Rats and Rabbits 

from Cutaneous Application of Amide-Type Solvents and Substituted 

Ureas," Toxicology and Applied Pharmacology, 41, 35-55, 1977. 

2. Khera, K. S. and Tryphonas, L., "Ethylene thiourea-Induced Hydrocephalus: Pre-and Postnatal Pathogenesis in Offspring from Rats 

Given a Single Oral Dose during Pregnancy," Toxicology and Applied 

Pharmacology, 42, 85-97, 1977. 

3. Ulland, B. M. et al., "Thyroid Cancer in Rats from Ethylene Thiourea 

Intake," J. Nat. Cancer Inst., 49, 583-584, 1972. 

4. IARC Monographs on the Evaluation of Carcinogenic Risk of 

Chemicals to Man, 7, 45-52, 1974. 

5. Innes, J. R. M. et al., "Bioassay of Pesticides and Industrial Chemicals 

for Tumorigenicity in Mice: A Preliminary Note," J. Nat. Cancer Inst., 

42, 1101-1114, 1969. 

6. Graham, S. L. et al., "Effects of Prolonged Ethylene Thiourea Ingestion 

on the Thyroid of the Rat, Food and Cosmetic Toxicology, 13, 493-499, 

1975. 

4 
SUGGESTED GUIDELINES FOR MINIMIZING EMPLOYEE EXPOSURE TO 

ETHYLENE THIOUREA (ETU) 

NIOSH recommends that it would be prudent to handle ethylene thiourea in 

the workplace as if it were a human carcinogen and teratogen. Exposure to 

ethylene thiourea should be limited to as few employees as possible, while 

minimizing workplace exposure levels. The area in which it is used should be 

restricted to only those employees essential to the process or operation. 

EXPOSURE MONITORING 

Initial and routine employee exposure surveys should be made by competent 

industrial hygiene and engineering personnel. These surveys are necessary to 

determine the extent of employee exposure and to ensure that controls are 

effective. 

The NIOSH Occupational Exposure Sampling Strategy Manual, NIOSH 

Publication #77-173, may be helpful in developing efficient programs to 

monitor employee exposures to ethylene thiourea. The manual discusses 

determination of the need for exposure measurements, selection of 

appropriate employees for exposure evaluation, and selection of sampling 

times. 

Employee exposure measurements should consist of 8-hour TWA (timeweighted average) exposure estimates calculated from personal or breathing 

zone samples (air that would most nearly represent that inhaled by the 

employees). Area and source measurements may be useful to determine 

problem areas, processes, and operations. 

MINIMIZING EMPLOYEE EXPOSURE 

There are four basic methods of limiting employee exposure to ethylene 

thiourea. None of these is a simple industrial hygiene or management 

decision and careful planning and thought should be used prior to 

implementation of any of these. 

o Product Substitution 

The substitution of an alternative material with a lower potential health and 

5 

(37) 
(38) 

safety risk is one method. However, extreme care must be used when 

selecting possible substitutes. Alternatives to ethylene thiourea should be 

fully evaluated with regard to possible human effects. Unless the toxic 

effects of the alternative have been thoroughly evaluated, a seemingly safe 

replacement, possibly only after years of use, may be found to induce serious 

health effects. 

o Contaminant Controls 

The most effective control of ethylene thiourea, where feasible, is at the 

source of contamination by enclosure of the operation and/or local exhaust 

ventilation. 

If feasible, the process or operation should be enclosed with a slight vacuum 

so that any leakage will result in the flow of air into the enclosure. 

The next most effective means of control would be a well designed local 

exhaust ventilation system that physically encloses the process as much as 

possible, with sufficient capture velocity to keep the contaminant from 

entering the work atmosphere. 

To ensure that ventilation equipment is working properly, effectiveness 

(e.g., air velocity, static pressure, or air volume) should be checked at least 

every three months. System effectiveness should be checked soon after any 

change in production, process, or control which might result in significant 

increases in airborne exposures to ethylene thiourea. 

o Employee Isolation 

A third alternative is the isolation of employees. It frequently involves the 

use of automated equipment operated by personnel observing from a closed 

control booth or room. The control room is maintained at a greater air 

pressure than that surrounding the process equipment so that air flow is out 

of, rather than into, the room. This type of control will not protect those 

employees that must do process checks, adjustments, maintenance, and 

related operations. 

o Personal Protective Equipment 

The least preferred method is the use of personal protective equipment. 

This equipment, which may include respirators, goggles, gloves, and related 

items, should not be used as the only means to prevent or minimize exposure 

during routine operations. 

Exposure to ethylene thiourea should not be controlled with the use of 

respirators except: 

6 
During the time necessary to install or implement engineering or work 

practice controls; or 

In work situations in which engineering and work practice controls are 

technically not feasible; or 

For maintenance; or 

For operations which require entry into tanks or closed vessels; or 

In emergencies. 

Only respirators approved by the National Institute for Occupational Safety 

and Health (NIOSH) should be used. Refer to NIOSH Certified Equipment, 

December 15, 1975, NIOSH publication #76-145 and Cumulative Supplement 

June 1977, NIOSH Certified Equipment, NIOSH publication #77-195. The 

use of faceseal coverlets or socks with any respirator voids NIOSH 

approvals. 

Quantitative faceseal fit test equipment (such as sodiu!D chloride, dioctyl 

phthalate, or equivalent) should be used. Refer to A guide to Industrial 

Respiratory Protection, NIOSH publication #76-189 for guidelines on 

appropriate respira~ory protection programs. 

7 

(39) 

NlaSM 

ETHYLENE DIBROMIDE 

and 

DISULFIRAM 

TOXIC INTERACTION 

U. S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE 

Public Health Service 

Center for Disease Control 

National Institute tor Occupational Safety and Health 

(41) 

April 11,1978 

H H 

I I 

Br- C - C -Sr 

I I 

H H 
(42) 

The Current Intelligence Bulletin is the primary product of the 

Current Intelligence System. The purpose of "the Current Intelligence 

System is to promptly review, evaluate, and supplement new information 

received by NIOSH on occupational hazards that are either unrecognized 

or are greater than generally known. 

As warranted by this evaluation, the information is capsulized and 

disseminated to NIOSH staff, other government agencies, and the 

occupational health community, including labor, industry, academia, 

and public interest groups. With respect to currently known hazard 

information this system also serves to advise appropriate members of 

the above groups of recently acquired specific knowledge which may 

have an impact on their programs or perception of the hazard. Above 

all, the Current Intelligence System is designed to protect the health 

of American workers and to allow them to work in the safest possible 

environment. 

DHEW (NIOSH) Publication No. 78-145 

ii 
(43) 

IDENTI.~'IERS AND SYNONYMS FOR DISULFIRAM 

Chemical AbstraGts Service Registry Number 97-77-8 

NIOSH RTECS Number J01ZZ50 

Chemical Formula CIOHZONZS4 

Abstensil 

Abstinil 

Abstiuyl 

Alcophobin 

Alk-aubs 

Antabus 

Antabuse 

Antadix 

Antaenyl 

Antaethan 

Antaethyl 

Antaetil 

Antalcol 

Antetan 

Antetil 

Anteyl 

Antiaethan 

Antietanol 

Anti-ethyl 

Antietil 

Antikol 

AntivitiulD 

Aversan 

Averzan 

Bis(diethylthiocarbamoyl) disulfide 

Bis(N,N-diethylthiocarbamoyl) disulfide 

Bonibal 

Contralin 

Contrapot 

Cronetal 

Dicupral 

Disetil 

Disulfan 

Disulfiram 

Disulfuram 

1,1 '-Dithiobis(N,N-diethylthioformamide) 

Ekagom TEDS 

Ekagom TETDS 

Ephorran 

Espenal 

Esperal 

Etabus 

Ethyl Thiram 

Ethyl Thiudad 

Ethyl Thiurad 

Ethyl Tuads 

Ethyl Tuex 

Ethyldithiourame 

Ethyldithiurame 

iii 

Exhorran 

Hoca 

Krotenal 

Nocbin 

Noxal 

Refusal 

Ro-Sulfiram 

Stopaethyl 

Stopethyl 

Stopetyl 

TATD 

Tenurid 

Tenutex 

TETD 

Tetidis 

Tetradin 

Tetradine 

Tetraethylthioperoxydicarbonic diamide 

Tetraethylthiram disulfide 

Tetraethylthiuram 

Tetraethylthiuram disulfide 

N ,N ,N'N'-Tetraethylthiuram disulfide 

Tetraetil 

Teturam 

Teturamin 

Thiocid 

Thiosan 

Thioscabin 

Thireranide 

Thiuram E 

Thiuranide 

Tillram 

Tiuram 

TID 

TIS 
(44' 

IDENTIFIERS AND SYNONYMS FOR ETHYLENE DIBROMIDE 

Chemical Abstracts Service Registry Number 106-93-4 

NIOSH RTECS Number KH927S0 

Chemical Formula CZH4 'BrZ 

Aadibroom 

Bromofume 

Celmide 

Dibromoethane 

1,2-0ibromoethane 

ct,8-Dibromoethane 

sym-Dibromoethane 

Oowfume EDB 

Oowfume MC-2 

Oowfume W-8 

Dowfume W-8S 

Dowfume 40 

E-D-BEE 

EOB 

EDB-8S 

ENT 15,349 

Ethylene Bromide 

Ethylene Dibromide 

Fumo-Gas 

Glycol Dibromide 

Iscobrome D 

Kopfume 

Nefis 

Pestmaster 

Pestmaster EOB-8S 

Sanhyuum 

Soilbrom-40 

Soilbrom-85 

Soilfume 

Unifume 

iv 
CURRENT INTELLIGENCE BULLETIN: 

ETHYLENE DIBROMIDE AND DISULFffiAM TOXIC INTERACTION 

April 11, 197B 

The National Institute for Occupational Safety and Health (NIOSH) 

recommends that no worker be exposed to both ethylene dibromide and 

disulfiram (Antabuse® , Ro-Sulfiram®, tetraethylthiuram disulfide; additional 

synonyms are tabulated in the appendix). This interim recommendation is 

based on preliminary results of NIOSH research currently in progress which 

suggests a serious toxic interaction between inhaled ethylene dibromide and 

ingested disulfiram resulting in exceedingly high mortality of laboratory 

rats. 

This Bulletin summarizes the current status of the NIOSH study, other 

pertinent data, occupational health implications, and NIOSH 

recommendations for reducing the risk from the toxic interaction. 

Background --- Ethylene Dibromide 

Approximately 300 million pounds of ethylene dibromide are produced 

annually in the United States. Ethylene dibromide, a volatile liquid, is used 

primarily as a lead scavenger in leaded fuels (to retard lead deposition in the 

engine), but this use is decreasing as the consumption of leaded gasoline 

decreases. Ethylene dibromide is also used as a soil, grain, and fruit 

fumigant, as an intermediate in the synthesis of dyes and pharmaceuticals, 

and as a solvent for resins, gums, and waxes. NIOSH estimates that 

approximately 9,000 employees are potentially exposed to ethylene 

dibromide during the course of these uses. (1) In addition, an estimated 

650,000 gasoline station attendants are potentially exposed to very low 

levels of ethylene dibromide. (1) McDermott and Killiany have estimated 

maximum expected airborne concentrations of ethylene dibromide to be 

O.OB parts per million parts of air (ppm) at 500 ppm leaded gasoline vapor in 

air. (2) 

An employee exposure ceiling of 0.13 ppm (1.0 mg/m3

), as determined over 

any fifteen-minute sampling period, was recommended by NIOSH in 

August 1977 for ethylene dibromide. (1) However, toxic interaction effects 

with other chemicals were not considered in the development of this 

recommended standard. The current Occupational Safety and Health 

Administration, Department of Labor, standard for occupational exposure to 

ethylene dibromide is 20 ppm (B-hour time-weighted average). 

Ethylene dibromide itself is a very toxic compound. Reported adverse 

health effects of employees chronically exposed to ethylene dibromide may 

1 

(AS) 
(46) 

include the induction of cancer and sterility as well as malformations and 

heritable changes in offspring. Ethylene dibromide may also cause adverse 

effects to the liver, kidneys, heart, and other internal organs and systems. 

Skin contact with ethylene dibromide may cause chemical burns as well as 

systemic effects due to absorption of ethylene dibromide through the skin. 

A summary of the health effects of ethylene dibromide may be found in the 

NIOSH Criteria Document. (1) 

Background -- Disulfiram 

Disulfiram is a prescription drug used as an alcohol deterrent and also is an 

accelerator used in the manufacture of rubber. Disulfiram may also be used 

as a fungicide and insecticide. 

Disulfiram is widely used in alcoholism control programs under the 

tradenames Antabuse ®and Ro-Sulfiram®. The intake of even small quantities 

of ethanol (ethyl alcohol) while on disulfiram results in flushing, breathing 

difficulty, nausea, vomiting, and low blood pressure. This violent and 

unpleasant reaction reinforces an individual's resolve to abstain from 

alcohol. The human therapeutic dose of disulfiram ranges from 125 to 500 

mg/day; disulfiram therapy may continue for many months, even years. 

Although the literature does contain reports of carcinogenic effects of 

disulfiram in laboratory animals, the International Agency for Research in 

Cancer (IARC) has concluded that, "the limited data available do not allow 

an evaluation of the carcinogenicity of disulfiram to be made." (3) 

Disulfiram is currently being tested for carcinogenicity by the National 

Cancer Institute. 

NIOSH estimates that approximately 70,000 workers have occupational 

exposure to disulfiram. This _ estimate is based on the NIOSH National 

Occupational Hazard Survey which was conducted between 1972 and 1974, 

and included over 500,000 employees at 4,775 facilities. In addition, there 

may be as many as 100,000 people on disulfiram therapy for alcoholism. 

Laboratory Animal Study of Toxic Interaction 

In the NIOSH-sponsored research currently in progress, laboratory rats 

exposed to 20 ppm ethylene dibromide by inhalation (the current 8-hour TWA 

OSHA exposure standard) and also receiving a diet containing 0.05% 

disulfiram are experiencing exceedingly high mortality levels as well as a 

high incidence of tumors (including hemangiosarcomas of the liver, spleen, 

and kidney). Even in those sites where tumors often occur spontaneously in 

rats, such as the mammary gland in females, the incidence of tumors 

appears to be increased and the tumors are occurring at an earlier than 

expected age. These results are preliminary and control animals have not 

yet been completely studied. Although the clinical significance of the data 

has not yet been evaluated, great caution is indicated. 

2 
The NIOSH-sponsored research is being conducted by Midwest Research 

Institute, Kansas City, Missouri, under NIOSH contract #210-76-0131 

(September 29, 1976 to January 31, 1979). Four groups of animals are in the 

study, each group comprised of 48 male and 48 female Sprague-Dawley rats. 

After approximately thirteen months of exposure, 45 of the 48 male and 47 

of the 48 female rats exposed simultaneously to ethylene dibromide and 

disulfiram have died or have been terminated because they were dying (due 

to the formation of tumors.) A description of the four groups as well as a 

summary of their mortality experience at the end of approximately thirteen 

months of treatment is presented in Table 1. 

TABLE 1 - Number of Deaths or Terminations/Total Number of Rats 

Group Treatment Male Female 

Untreated Filtered air; control diet 0/48 3/48 

Disulfiram only Filtered air; diet containing 3/48 2/48 

0.05% disulfiram by weight 

Ethylene dibromide Inhalation of 20 ppm ethylene 15/48 9/48 

only dibromide 6 hours per day, 

5 days per week; control diet 

Ethylene dibromide/ Inhalation of 20 ppm ethylene 45/48 47/48 

disulfiram dibromide 6 hours per day, 5 

days per week; diet containing 

0.05% disulfi.ram by weight 

The extent to which this toxic interaction is specific for ethylene dibromide 

and disulfiram is not known. ·Similar toxic interactions may occu,r between 

disulfiram, as well as chemicals structurally related to disulfiram, and other 

halogenated hydrocarbons. 

NIOSH Recommendations 

While current NIOSH research continues and its significance is further 

evaluated, it is recommended, as an interim and prudent measure, that no 

worker be exposed to both e thylene dibromide and disulfiram. 

3 

(47) 
(48) 

Workers should not be exposed to ethylene dibromide during the course of 

disulfiram therapy. Disulfiram (Antabuse (I), Ro-Sulfiram(l)) should not be 

administered to workers having potential occupational exposure to ethylene 

dibromide except in those cases where, in the best judgment of the 

responsible physician, the benefit of disulfiram therapy strongly outweighs 

the risk to the particular patient. 

Whenever disulfiram [bis(diethylthiocarbamoyI) disulfide, tetraethylthiuram 

disulfide] is used in the workplace (e.g., as an accelerator in rubber 

production, as a fungicide or insecticide), precautions should be taken so 

that no worker is exposed to both ethylene dibromide and disulfiram. 

Although NIOSH recognizes the complexity and many combinations possible 

in evaluating toxic interactions between various agents, NIOSH believes this 

is an area in need of further attention and study. 

h/ J. D aId Millar, M.D. 

(. Assistant Surgeon General 

Acting Director 

4 
References 

1. Criteria for a Recommended Standard •••• Occupational Exposure to 

Ethylene Dibromide, U.S. Department of Health, Education, and 

Welfare, Public Health Service, Center for Disease Control, National 

Institute for Occupational Safety and Health, Cincinnati, Ohio, 

August 1977. 

2. McDermott, H. J., and Killiany, S. E., Jr., "Quest for a Gasoline TLV," 

Am. Ind. Hyg. Assoc. J., 39, 110-117, 1978. 

3. rARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals 

in Man, 12, 85-95, 1976. 

5 

(49) 

( 51) 

JOINT 

MiaSM /NI:I. . 

April 17 I 1978 

DIRECT BLUE 6 

DIRECT BLACK 38 

DIRECT BROWN 95 COPPER COMPLEX 

DERIVED FROM 

COONa OH OH 

HO-@-N=N-@-©-N=N~N=N-@. HO~ S03Na 

Benzidine Derived Dyes 

U. S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE 

Public Health Service 

Center for Disease Control 

National Institute for 

Occupational Safety and Health 

National Institutes of Health 

National Cancer Institute 
( 52) 

The Current Intelligence Bulletin is the primary product of the 

Current Intelligence System. The purpose of the Current Intelligence 

System is to promptly review, evaluate, and supplement new information 

received by NIOSH on occupational hazards that are either unrecognized 

or are greater than generally known. 

As warranted by this evaluation, the information is capsulized and 

disseminated to NIOSH staff,. other government agencies, and the 

occupational health community, including labor, industry, academia, 

and public interest groups. With respect to currently known hazard 

information this system also serves to advise appropriate members of 

the above groups of recently acquired specific knowledge which may 

have an impact on their programs or perception of the hazard. Above 

all, the Current Intelligence System is designed to protect the health 

of American workers and to allow them to work in the safest possible 

environment. 

FURTHER INFORMATION: 

National Institutes of Health 

National Cancer Institute 

Bethesda, Maryland 20,014 

Melva Weber 

(301) 496-6641 

SYNONYMS 

Identifiers and Synonyms on Attached Sheets 

Center for Disease Control 

National Institute for 

Occupational Safety and Health 

Rockville, Maryland 20857 

Jack Hardesty 

(301) 443-2140 

DHEW (NIOSH) Publication No. 78-148 

ii 
IDENTIFIERS AND SYNONYMS FOR DIRECT BLACK 38 

Chemical Abstracts Service Registry Number 1937-37-7 

NIOSH/RTECS Number JM71700 

Chemical Formula C34HZSN907SZNaZ 

Abco Direct Black GX 

Airedale Black ED 

Aizen Direct Deep Black EH 

Aizen Direct Deep Black GH 

Aizen Direct Deep Black RH 

Amanil Black GL 

Amanil Black WD 

Apomine Black GX 

Atlantic Black BD 

Atlantic Black C 

Atlantic Black E 

Atlantic Black EA 

Atlantic Black GAC 

Atlantic Black GG 

Atlantic Black GXCW 

Atlantic Black GXOO 

Atlantic Black SD 

Atul Direct Black E 

Azine Deep Black EW 

Azocard Black EW 

Azomine Black' EWO 

Belamine Black GX 

Bencidal Black E 

Benzanil Black E 

Benzo Deep Black E 

Benzo Leather Black E 

Benzoform Black BCN-CF 

Black ZEMBL 

Black 4EMBL 

Brasilamina Black GN 

Brilliant Chrome Leather Black H 

C.I. 30Z35 

C.I. Direct Black 38 

Calcomine Black 

Calcomine Black EXL 

Carbide Black E 

Chloramine Black C 

Chloramine Black EC 

Chloramine Black ERT 

Chloramine Black EX 

Chloramine Black EXR 

iii 

Chloramine Black XO 

Chloramine Carbon Black S 

Chloramine Carbon Black SJ 

Chloramine Carbon Black SN 

Chlorazol Black E 

Chlorazol Black E (Biological Stain) 

Chlorazol Black EA 

Chlorazol Black EN 

Chlorazol Burl Black E 

Chlorazol Leather Black ENP 

Chlorazol Silk Black G 

Chrome Leather Black E 

Chrome Leather Black EC 

Chrome Leather Black EM 

Chrome Leather Black G 

Chrome Leather Brilliant Black ER 

Coir Deep Black C 

Columbia Black EP 

Diacotton Deep Black 

Diacotton Deep Black RX 

Diamine Deep Black EC 

Diamine Direct Black E 

Diaphtamine Black V 

Diazine Black E 

Diazine Direct Black E 

Diazine Direct Black G 

Diazol Black ZV 

Diphenyl Deep Black G 

Direct Black Methyl 

Direct Black A 

Direct Black BRN 

Direct Black CX 

Direct Black CXR 

Direct Black E 

Direct Black EW 

Direct Black EX 

Direct Black FR 

Direct Black GAC 

Direct Black GW 

Direct Black GX 

Direct Black GXR 

(53) 
(54 ) 

Page 2 - Direct Black 38 

Direct Black JET 

Direct Black Meta 

Direct Black Methyl 

Direct Black N 

Direct Black RX 

Direct Black SD 

Direct Black WS 

Direct Black Z 

Direct Black 3 

Direct Black 38 

Direct Deep Black E 

Direct Deep Black E Extra 

Direct Deep Black EA-CF 

Direct Deep Black EAC 

Direct Deep Black EW 

Direct Deep Black EX 

Enianil Black CN 

Erie Black B 

Erie Black BF 

Erie Black GAC 

Erie Black GXOO 

Erie Black JET 

Erie Black NUG 

Erie Black RXOO 

Erie Brilliant Black S 

Erie Fibre Black VP 

Fenamin Black E 

Fibre Black VF 

Fixanol Black E 

Formaline Black C 

Formic Black C 

Formic Black CW 

Formic Black EA 

Formic Black MTG 

Formic Black TG 

Hispamin Black EF 

Interchem Direct Black Z 

Kayaku Direct Deep Black EX 

Kayaku Direct Deep Black GX 

Kayaku Direct Deep Black S 

Kayaku Direct Leather Black EX 

Kayaku Direct Special Black AAX 

Lurazol Black BA 

Meta Black 

Mitsui Direct Black EX 

Mitsui Direct Black GX 

iv 

Nippon Deep Black 

Nippon Deep Black GX 

Paper Black BA 

Paper Black T 

Paper Deep Black C 

Paramine Black B 

Paramine Black E 

Peeramine Black E 

Peeramine Black GXOO 

Phenamine Black BCN-CF 

Phenamine Black CL 

Phenamine Black E 

Phenamine Black E 200 

Pheno Black EP 

Pheno Black SGN 

Pon tamine Black E 

Pontamine Black EBN 

Sandopel Black EX 

Seristan Black B 

Telon Fast Black E 

Tetrazo Deep Black G 

Tertrodirect Black E 

Tetrodirect Black EFD 

Union Black EM 

Vondacel Black N 
(55) 

IDENTIFIERS AND SYNONYMS FOR DIRECT BLUE 6 

Chemical Abstracts Service Registry Number Z60Z-46-2 

NIOSH/RTECS Number QJ64000 

Chemical Formula C3ZHZ0014N6S4Na4 

Airedale Blue 2BD 

Aizen Direct Blue 2BH 

Amanil Blue ZBX 

Atlantic Blue ZB 

Atul Direct Blue 2B 

Azocard Blue 2B 

Azomine Blue ZB 

Belamine Blue ZB 

Bencidal Blue 2B 

Benzanil Blue ZB 

Benzo Blue BBA-CF 

Benzo Blue BBN-CF 

Benzo Blue GS 

Blue 2B 

Blue 2B Salt 

Brasilamina Blue ZB 

Calcomine Blue 2B 

Chloramine Blue 2B 

Chlorazol Blue B 

Chlorazol Blue BP 

Chrome Leather Blue 2B 

CI22610 

C.I. 22610 

C.I. Direct Blue 6 

C.I. Direct Blue 6, Tetrasodium Salt 

Cresotine Blue 2B 

Diacotton Blue BB 

Diamine Blue 2B 

Diamine Blue BB 

Diaphtamine Blue BB 

Diazine Blue ZB 

Diazol Blue ZB 

Diphenyl Blue 2B 

Diphenyl Blue KF 

Diphenyl Blue MZB 

Direct Blue A 

Direct Blue ZB 

Direct Blue 6 

Direct Blue BB 

Direct Blue GS 

Direct Blue K 

Direct Blue MZB 

v 

Enianil Blue ZBN 

Fenamin Blue 2B 

Fixanol Blue ZB 

Hispamin Blue 2B 

Indigo Blue ZB 

Kayaku Direct 

Kayaku Direct Blue BB 

Mitsui Direct Blue ZBN 

Naphtamine Blue 2B 

Niagara Blue 2B 

Nippon Blue BB 

Paramine Blue ZB 

Phenamine Blue BB 

Pheno Blue ZB 

Pontamine Blue BB 

Sodium Diphenyl-4,4'-Bis-Azo-2."-S"-Amino 

-1 "-Naphthol-3" ,6"-Disulphonate 

Tertrodirect Blue 2.B 

Vondacel Blue 2B 
( 56) 

IDENTIFIERS AND SYNONYMS FOR DIRECT BROWN 95 

Chemical Abstracts Service Registry Number 16071-86-6 

NIOSH/RTECS Number JM78780 

Chemical Formula C31 HZON609SNaZCu 

Aizen Primula Brown BRLH 

Aizen Primula Brown PLH 

Amanil Fast Brown BRL 

Amanil Supra Brown LBL 

Atlantic Fast Brown BRL 

A tlan tic Resin Fast Brown BRL 

Belamine Fast Brown BRLL 

Benzanil Supra Brown BRLL 

Benzanil Supra Brown BRLN 

Brown 4EMBL 

C.I. 30145 

C.I. Direct Brown 

Calcodur Brown BRL 

Chloramine Fast Brown BRL 

Chloramine Fast Cutch Brown PL 

Chlorantine Fast Brown BRLL 

Chrome Leather Bl"own BRLL 

Chrome Leather Brown BRSL 

Cuprofix Brown GL 

Derma Fast Brown W-GL 

Dermafix Brown PL 

Dialuminous Brown BRS 

Diaphtamine Light Brown BRLL 

Diazine Fast Brown RSL 

Diazol Light Brown BRN 

Dicorel Brown LMR 

Diphenyl Fast Brown BRL 

Direct Brown 95 

Direct Brown BRL 

Direct Fast Brown BRL 

Direct Fast Brown LMR 

Direct Light Brown BRS 

Direct Supra Light Brown ML 

Durazol Brown BR 

Durofast Brown BRL 

Eliamina Light Brown BRL 

Enianil Light Brown BRL 

Fastolite Brown BRL 

F'astusol Brown LBRSA 

Fastusol Brown LBRSN 

Fenaluz Brown BRL 

Helion Brown BRSL 

vi 

Hispaluz Brown BRL 

KCA Light Fast Brown BR 

Kayarus Supra Brown BRS 

Paranol Fast Brown BRL 

Peeramine Fast Brown BRL 

Pontamine Fast Brown BRL 

Pontamine Fast Brown NP 

Pyrazol Fast Brown BRL 

Pyrazoline Brown, BRL 

Saturn Brown LBR 

Sirius Supra Brown BRL 

Sirius Supra Brown BRS 

Solantine Brown BRL 

Solar Brown PL 

Solex Brown R 

Solius Light Brown BRLL 

Solius Light Brown BRS 

Sumilight Supra Brown BRS 

Suprazo Brown BRL 

Suprexcel Brown BRL 

Tertrodirect Fast Brown BR 

Tetramine Fast Brown BRDN Extra 

Tetramine Fast Brown BRP 

Tetramine Fast Brown BRS 

Triantine Brown BRS 

Triantine Fast Brown OG 

Triantine Fast Brown OR 

Triantine Light Brown BRS 

Triantine Light Brown OG 
NIOSH/NCI JOINT CURRENT INTELLIGENCE BULLETIN 

DIRECT BLACK 38, DIRECT BLUE 6, AND DIRECT BROWN 95 

BENZIDINE-DERIVED DYES 

April 18, 1978 

The National Institute for Occupational Safety and Health (NIOSH) recommends 

that three widely used benzidine-derived dyes, Direct Black 38, Direct Blue 6, and 

Direct Brown 95, be handled in the workplace as if they were human carcinogens. 

This recommendation is based primarily upon a preliminary analysis of National 

Cancer Institute (NCI) data from short-term feeding studies, and on early results 

from NIOSH field studies. Cancerous and precancerous liver conditions were found 

in rats, similar to the damage produced by known liver carcinogens. Degeneration 

of liver cells was found in mice. Although the dyes tested by NCI contained less 

than 4 ppm residual benzidine when fed to the test animals, greater quantities of 

benzidine were found in the urine of dosed rats and mice. Caution is also indicated 

by preliminary results from NIOSH field studies showing that humans working with 

these same dyes also excrete higher than expected levels of benzidine in their 

urine. Both laboratory and field studies indicate that these benzidine-derived dyes 

can be metabolized to benzidine which is present in the urine of animals and 

humans. 

Based on the data from the short-term study, NCI scientists believe a cancercausing potential exists upon exposure to the benzidine-derived dyes, most likely 

through the mechanism of metabolic conversion of the dyes to benzidine in the 

animal system. This NIOSH/NCI Joint Bulletin summarizes the results of the NCr 

animal study, the NIOSH field studies, other pertinent data, their implication for 

occupational health, and suggested guidelines for minimizing employee exposure to 

the three dyes. 

Potential Occupational Exposures 

The National Occupational Hazard Survey (NOHS), conducted between 197Z 

and 1974 by the National Institute for Occupational Safety and Health, indicates 

that workers are occupationally exposed to Direct Black 38, Direct Blue 6, and 

Direct Brown 95 in a variety of industries including: paper and allied products, 

petroleum and related industries, rubber and plastic products, leather and leather 

products, instrumentation and measuring devices, and banking. In addition, the 

1 

(57) 
(58) 

textile industry accounts for a substantial occupational exposure. It is estimated 

that 25 percent of the benzidine-derived azo dyes are applied to textiles, 40 

percent to paper, 15 percent to leather, and the remainder to other diverse 

applications. (1) 

TJ.:1e Colour Index, (2) a reference by Great Britain's Society of Dyers and 

Colourists, reports the following uses for the three dyes: 

o Direct Black 38: Dyeing or staining of wool, silk, fibers 

for rope and matting, hogs hair, cellulose, acetate, nylon, 

and biological stains. 

o Direct Brown 95: Dyeing or staining silk, cotton, acetate, 

cellulose, wool, nylon, leather, paper, and certain plastics. 

o Direct Blue 6: Dyeing or staining silk, wool, cotton, nylon, 

leather, paper, biological stains and writing inks. 

Historically, benzidine has been an important intermediate in dye production since 

its introduction to the dyestuff industry around 1890. (3,4) In 1948, production of 

benzidine-derived dyes was 35 million pounds which accounted for 25% of all 

domestic dyes manufactured and almost all of the direct class dyes. (5) Domestic 

production of direct benzidine-derived dyes has dropped to 11.4 million pounds in 

1971. (6) Domestic production in 1978 should be limited to 12 benzidine dyes. The 

latest domestic production figures for Direct Black 38 show 7.3 million pounds in 

1971, (6) down to 2.2 million pounds in 1975,(7) which rose to 3.76 million pounds in 

1976. (8) Direct Brown 95 has shown an .increased production to 600,000 pounds in 

1976 which is up from 406,000 pounds in 1975 and 343,000 pounds in 1974. (8) 

Domestic production for Direct Blue 6 indicates that 327,000 pounds were produced 

in 1973, which is the last available figure for that dye. (9) 

In the general population, unspecified exposure levels to the three dyes are thought 

to occur through the use of retail packaged dyes for home dyeing and for home and 

school use in art and craft projects such as tie-dyeing or batik. The Art Hazards 

Project of the Center for Occupational Hazards, New York City, has reported that 

package dyes sold in supermarkets, variety stores and hardware stores are 

combinations of direct, acid and basic dyes, and thus may contain benzidine-derived 

dye components. (10) Two of these dyes, Direct Black 38 and Direct Blue 6, have 

been used in hair dyes. (11) 

NCI Dose-Ranging Feeding Study (11) 

Ninety-day animal feeding tests have been completed by the National Cancer 

Institute for three widely-used dyes, Direct Black 38, Direct Blue 6, and Direct 

Bro~n 95. The first-phase tests are conducted routinely to establish dosage levels 

2 
in mice and rats for chemicals being screened for cancer-causing activity. The 

dose-ranging studies commonly precede standard bioassays--animal lifetime tests 

at dosages that do not shorten lifespans or impair growth. 

All three of the dyes are benzidine-derived, having a unit of benzidine in their 

chemical structure. Benzidine is a known animal and human c~cer-causing agent. 

(12) Residual free benzidine in the feed was below 4 parts per million (ppm). 

A total of 120 rats and 120 mice were divided into groups of 10. One group of each 

sex and each species was reserved as undo sed controls, while five groups of each 

sex and species received differing dosages of the dyes in feed. At the 4th and 12th 

week of the study, urine was collected from dosed rats and mice for benzidine 

analysis. After 91 days of feeding and one day of observation, the surviving 

animals were killed and their tissues examined. 

After the 90-day trial, significant incidences of cancerous and precancerous 

changes in the liver were found in both male and female rats dosed with any of the 

three dyes, whereas, untreated control rats had no liver damage. The liver changes 

in dosed animals were similar to changes caused by benzidine. 

In mice, all three dyes were found harmful to the liver, but no cancerous changes 

were found. This finding is compatible with the interpretation that the toxic 

effects may be related to benzidine, because benzidine is more likely to produce 

cancer in rats than in. mice. No liver abnormalities or damage to any internal 

organs were found in the control animals of either species. 

In addition, although the dyes were essentially benzidine-free when fed to the 

animals, substantial benzidine was found in the urine of dosed rats and mice, an 

indication that animal systems metabolize the dyes to benzidine. 

The technical report "13-Week Sub chronic Toxicity Studies -- Direct Blue 6, Direct 

Black 38, and Direct Brown 95 Dyes" is available from the Office of Cancer 

Communications, National Cancel" Institute, Bethesda, Maryland 20014. 

Other Laboratory Animal Studies 

As an historical point, an early realization of the metabolism of azo compounds in 

mammals came as a result of feeding Orange I, an azo dye, to dogs in 1911. (13) An 

intermediate of the dye, sulfanilic acid, was identified in the urine demonstrating 

for the first time that azo compounds may be metabolized by reductive cleavage of 

the azo group. Since then it has been repeatedly demonstrated that the intestinal 

flora within animals and many animal hepatic enzyme systems are capable of 

splitting the azo bond. (14,15) The majority of this work was performed with azo 

dyes intended for food coloring. 

Yoshida and Miyakawa found that when sulfonated benzidine azo dyes were injected 

into surgically removed mice intestines and then incubated, free benzidine was 

3 

(59) 
(nO) 

later found. They also showed that Escherichia coli as well as soil bacteria were 

quite capable of reducing benzidine dyes when incubated at 37 C. (16) 

Another study showed that rhesus monkeys, fed benzidine-derived dyes with no 

residual benzidine, excreted benzidine in their urine. The levels excreted were 

estimated as being almost as high as if an equal amount of pure benzidine, as found 

in the dye moiety, were fed instead to the monkeys. (I7) These studies lead NIOSH 

to believe that when dyes of these types are ingested by man, they result in 

benzidine in the urine thus posing a potential carcinogenic hazard. 

NIOSH Field Studies 

Preliminary results from NIOSH studies indicate the presence of benzidine, or 

monacetylbenzidine (MAB), a metabolite of benzidine, in the urine of workers in 

four out of five industrial facilities in which urine samples were collected. The 

facilities surveyed to date include two benzidine dye manufacturers, two textile 

finishing companies and a leather tannery. 

In one dye manufacturing plant, benzidine and MAB were found in all dye workers 

who worked solely with the finished dyes. Bulk benzidine-based dyes were 

quantitatively analyzed for residual free benzidine content which ranged from less 

than 1 to 19 ppm. It was conservatively estimated that about 20 times more 

benzidine and up to 200 times more MAB were present in the urine of these dye 

workers, than if they had been exposed only to the residual benzidine content in the 

dyes. The concentrations of benzidine found in the urine of these workers were 

significant fractions of those concentrations associated with a high incidence of 

bladder cancer as reported in the scientific literature. Among textile dyers 

included in the NIOSH study, four of ten had benzidine or MAB present in their 

urine and all had elevated aromatic amine levels. No benzidine or MAB was 

detected in urine samples collected at a leather tannery where good work practices 

were observed. While there was bioiogical variability in body burden tolerance and 

differences in metabolism among those studied, it appears likely that work 

practices and personal hygiene played a major role in minimizing exposure. 

Analyses of data from. these NIOSH studies are ongoing. 

The relatively large particle size of the dry dye powders causes inhaled dyes to be 

deposited largely in the upper respiratory tract and then ingested. Prevention of 

worker inhalation or ingestion of these dyes would greatly reduce absorption into 

the body and subsequent benzidine exposure. 

Epidemiological and Medical Studies -- Benzidine-Based Dyes 

A strong association relating human exposure to benzidine-based dyes with the 

subsequent development of bladder tumors was presented after a c~se-control 

mortality study of 200 bladder cancer patients in Japan. (16) The patients were 

found to have been predominantly kimono painters and .dyers. The kimono painters 

4 
had the habit of forming a point on their brushes by drawing the brush between 

their lips, which allowed for ingestion of the dyes. 

Several other case-control mortality studies indicate an increased risk of 

developing bladder cancer in the textile and leather industries. both large users of 

direct dyes. However, only a few references have been made concerning benzidinederived dyestuffs. 

In Russia, a medical study concerning the early detection of bladder tumors among 

textile dyers using benzidine-derived dyes found an unusual incidence of bladder 

lesions, some of which were suggested as being of a precancerous nature. The 

greatest number of such lesions were found in those workers with the highest 

potential exposure to these dyes.(18) 

The National Institute for Occupational Safety and Health and the National Cancer 

Institute have jointly prepared this Bulletin to facilitate the rapid, dissemination of 

our preliminary findings on three benzidine-derived dyes: Direct Black 38, Direct 

Blue 6, and Direct Brown 95. NIOSH recommends that these dyes be handled in the 

workplace as if they were human carcinogens and requests that producers, 

distributors, professional associations, and unions transmit the information in this 

Bulletin to their customers, employees, associates, and members. 

Arthur C. Upton, M.D. 

Director 

National Cancer Institute 

~. nald Millar, M.D. 

Assistant Surgeon General 

Acting Director, 

5 

National Institute for Occupational 

Safety and Health 

(61) 
( 62) 

NIOSH Action on Benzidine-Derived Dyes 

1. The NIOSH Industrial Hygiene Section will shortly conduct a study in which 

workers who have had a one-day exposure to benzidine-based dyes are monitored over several days. This will hopefully confirm some assumptions on the 

excretion kinetics of such exposure and better establish the best time to 

monitor a worker's urine for benzidine. 

2. The NIOSH Clinical and Biochemical Support Section has an interagency 

agreement with the National Center for Toxicological Research to conduct 

animal metabolism studies. Test animals will be fed Direct Black 38, Direct 

Blue 6 and Direct Brown 95. Metabolites will be identified in the urine and 

evaluated for mutagenic activity. Additional dyes made from 3,3-dimethylbenzidine, 3,3-dimethoxybenzidine, and 3,3-dichlorobenzidine will also be 

tested. 

6 
SUGGESTED GUIDELINES FOR MINIMIZING EMPLOYEE EXPOSURE TO 

DIRECT BLACK 38, DIRECT BLUE 6, DIRECT BROWN 95 

-- BENZIDINE-DERIVED DYES 

NIOSH recommends that it would be prudent to handle Direct Black 38, Direct Blue 

6, and Direct Brown 95 in the wGrkplace as if they were human carcinogens. 

Exposure to Direct Black 38, Direct Blue 6, and Direct Brown 95 should be limited 

to as few employees as possible, while minimizing workplace exposure levels. The 

area in which they are used should be restricted to only those employees essential 

to the process or operation. 

EXPOSURE MONITORING 

Initial and routine employee exposure surveys should be made by competent 

industrial hygiene and engineering personnel. These surveys are necessary to 

determine the extent of employee exposure and to ensure that controls are 

effective. 

The NIOSH Occupational Exposure Sampling Strategy Manual, NIOSH Publication 

#77-173, may be helpful in developing efficient programs to monitor employee 

exposures to Direct Black 38, Direct Blue 6, and Direct Brown 95. The manual 

discusses determination of the need for exposure measurements, selection of 

appropriate employees for exposure evaluation, and selection of sampling times. 

Employee exposure measurements should consist of 8-hour TWA (time-weighted 

average) exposure estimates calculated from personal or breathing zone samples 

(air that would most nearly represent that inhaled by the employees). Area and 

source measurements may be useful to determine problem areas, processes, and 

operations. 

MINIMIZING EMPLOYEE EXPOSURE 

There are four basic methods of limiting employee exposure to Direct Black 38, 

Direct Blue 6, and Direct Brown 95. None of these is a simple industrial hygiene 

or management decision and careful planning and thought should be used prior to 

implementation of any of these. 

o Product Substitution 

The substitution of an alternative material with a lower potential health and safety 

7 

(63) 
risk is one method. However, extreme care must be used when selecting possible 

substitutes. Alternatives to Direct Black 38, Direct Blue 6, and Direct Brown 95 

should be fully evaluated with regard to possible human effects. Unless the toxic 

effects of the alternative have been thoroughly evaluated, a seemingly safe 

replacement, possibly only after years of use, may be found to induce serious health 

effects. 

o Contaminant Controls 

The most effective control of Direct Black 38, Direct Blue 6, and Direct Brown 95, 

where feasible, is at the source of contamination by enclosure of the operation 

and/or local exhaust ventilation. 

If feasible, the process or operation should be enclosed with a slight vacuum so that 

any leakage will result in the flow of air into the enclosure. 

The next most effective means of control would be a well designed local exhaust 

ventilation system that physically encloses the process as much as possible, with 

sufficient capture velocity to keep the contaminant from entering the work atmosphere. 

To ensure that ventilation equipment is working properly, effectiveness (e.g., air 

velocity, static pressure, or air volume) should be checked at least every three 

months. System effectiveness should be checked soon after any change in production, process, or control which might result in significant increases in airborne 

exposures to Direct Black 38, Direct Blue 6, and Direct Brown 95. 

o Employee Isolation 

A third alternative is the isolation of employees. It frequently involves the use of 

automated equipment op~rated by personnel observing from a closed control booth 

or room. The control room is maintained at a greater air pressure than that 

surrounding the process .equipment so that air flow is out of, rather than into, the 

room. This type of control will not protect those employees that must do process 

checks, adjustments, maintenance, and related operations. 

o Personal Protective Equipment 

The least preferred method is the use of personal protective equipment. This 

equipment, which may include respirators, goggles, gloves, and other devices should 

not be used as' the only means to prevent or minimize exposure during routine 

operations. 

Exposure to Direct Black 38, Direct Blue 6, and Direct Brown 95 should not be 

controlled with the use of respirators except: 

8 
During the time period necessary to install or implement engineering or work 

practice controls; or 

In work situations in which engineering and work practice controls are technically not feasible; or 

For maintenance; or 

For operations which require entry into tanks or closed vessels; or 

In emergencies. 

Only respirators approved by the National Institute for Occupational Safety and 

Health (NIOSH) should be used. Refer to NIOSH Certified Equipment, December 

15, 1975, NIOSH publication #76-145 and Cumulative Supplement June 1977, NIOSH 

Certified Equipment, NIOSH publication #77-195. The use of faceseal coverlets or 

socks with any respirator voids NIOSH approvals. 

Quantitative faceseal fit test equipment (such as sodium chloride, dioctyl 

phthalate, or equivalent) should be used. Refer to A guide to Industrial Respir~tory 

Protection, NIOSH publication #76-189 for guidelines on appropriate respirato,y 

protection programs. 

In addition, proper maintenance procedures, good housekeeping in the work area 

and education of employees concerning the nature of the hazard, its control and 

personal hygiene are all aspects of a good control program. 

9 

(65) 
(66) 

REFERENCES 

1. Environmental Protection Agency, 40 CFR Part 129 "Benzidine: Proposed 

Toxic Pollutant Effluent Standards" Federal Register Vol. 41, No. 127, June 

30, 1973. 

2. Color Index, 1971, 3rd Ed. The Society of Dyers and Colourists -American 

Association of Textile Chemists and Colorists, Lund, Humphries, Bradford and 

London, (eds.), London, England. 

3. Venkataraman, K., 1952. The Chemistry of Synthetic Dyes. Academic Press, 

New York p. 506-514. 

4. Lubs, H.A., 1952. The Chemistry of Synthetic Dyes and Pigments. American 

Chemical Society Monograph No. 127,Washington, D.C. 

5. Synthetic Organic ' Chemicals, 1948. U.S. Tariff Commission, Report on 

Synthetic Organic Dyes. Series 6-2. 

6. u.S. International Trade Commission, United States Production & Sales, 1971. 

Synthetic Organic Chemicals (1973), Washington, D.C. 

7. Synthetic Organic Chemicals: United States Production and Sales, 1975. U.S. 

International Trade Commission Report 806 (1977), Washington, D.C. 

8 Synthetic Organic Chemicals: United States Production and Sales, 1974. U.S. 

International Trade Commission Repm·t 762 (1976), Washington, D.C. 

9. Synthetic Organic Chemicals: United States Production and Sales, 1973. U.S. 

International Trade Commission Report, Washington, D.C. 

10. Jenkins, C. Dye Hazards Report, February, 1978. 

11. 13-Week Sub chronic Toxicity Studies of Direct Blue 6, Direct Black 38, and 

Direct Brown 95 Dyes. National Cancer Institute. Carcinogenesis Technical 

Report. DHEW Publication #"NIH" 78-1358, 1978. 

12. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to 

Man. Vol. 1, 80. 

13. Sisley, P., Porcher, C. DuSort des Matieres Colorantes dans L'organesma 

animal. In Walker, R., 1970. The Metabolism of Azo Compounds - A Review 

of the Literature. Food and Cosmetic Toxicology, 8, 659-676. 

14. Radomski, J., Hellinger, T., 1961. The Absorption, Rate, and Excretion in 

Rats of the Water Soluble Azo Dyes, FD&C Red No.2, FD&C Red No.4, and 

FD&C Yellow No.6. J. Pharmaceutical and Experimental Therapy, 136, 259-

266. 

10 
15. Roxan, J.J., Ryan, A.J., Wright, 1967. Reduction of Water Soluble Azo Dyes 

by Intestinal Bacteria. Food and Cosmetic Toxicology. S, 367-369. 

16. Yoshida, 0., Miyakaqa, M., 1973. Etiology of Bladder Cancer: "Metabolic" 

Aspects. In Analytical and Experimental Epidemiology of Cancer. Nakahara, 

Hirayoma, Wishioka, et al., (eds.), University Park Press, Baltimore, P. 31-39. 

17. Rinde, E., Troll, W., 1975. Metabolic Reduction of Benzidine Azo Dyes 

to Benzidine in the Rhesus Monkey. J. National Cancer Institute, 55, 181-

182.. 

18. Korosteleva, T.A., Kljuckareu, B.V., Belokhuostave, A.T., Ayzomyatnikov, 

A.A., 1973. Immunological Diagnosis in Early Stages of Occupational Cancer 

of the Urinary Bladder. Problems of Oncology 19.2., p. 2.832.. 

11 

(67) 

(69) 

NlaSM 

April 19, 1978 

ETHYLENE DICHLORIDE 

H H 

I I 

CI-C-C-CI 

I I ( 1,2 - O;chID'D~'hDne ) 

H H 

U. S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE 

Public Health Se,,,/ce 

Center tor Disease Control 

National Institute 10' Occupational Salety and Health 
(70) 

The Current Intelligence Bulletin is the primary product of the 

Current Intelligence System. The purpose of the Current Intelligence 

System is to promptly review, evaluate, and supplement new info:rmation 

received by NIOSH on occupational hazards that are either unrecognized 

or are greater than generally known. 

As warranted by this evaluation, the information is capsulized arid 

disseminated to NIOSH staff, other government agencies, and the 

occupational health community, including labor, industry, academia, 

and public interest groups. With respect to currently known hazard 

information this system also serves to advise appropriate! .members of 

the above groups of recently acquired specific knowledge which may 

have an impact on their programs or perception of the hazard. above 

all, the Current Intelligence System is designed to protect the health 

of American workers and to allow them to work in the safest possible 

environment. 

Synonyms & Identifiers 

NIOSH-RTECS: KI05Z50 

CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER: 107-06-Z 

CHEMICAL FORMULA: CZH4CIZ 

Ct, 8-DICHLOROETHANE 

1,Z-BICHLOROETHANE 

BROCIDE 

DESTRUXOL BORER-SOL 

DI-CHLOR-MULSION 

1,Z-DICHLORETHANE 

1,Z-DICHLOROETHANE 

DICHLOROETHYLENE 

DUTCH UQUID 

EDC 

ENT 1,656 

ETHYLENE CHLORIDE 

ETHYLENE DICHLORIDE 

GLYCOL DICHLORIDE 

sym-DICHLOROETHANE 

DHEW (NIOSH) Publication No. 78-149 

ii 
CURRENT INTELLIGENCE BULLETIN: 

ETHYLENE DICHLORIDE (I,Z-DICHLOROETHANE) 

April 19, 1978 

The National Institute for Occupational Safety and Health (NIOSH) recommends that as 

a prudent measure, ethylene dichloride (l,Z-dichloroethane) be handled in the workplace 

as if it were a human carcinogen. This recommendation is based primarily upon an 

analysis of National Cancer Insitute (NCr) data indicating that laboratory rats and mice 

fed ethylene dichloride experienced a statistically significant excess of malignant and 

benign tumors, as compared to controls (1). 

NIOSH has prepared this Bulletin to advise you of the findings of the NCI study, other 

pertinent data, including findings on the mutagenic and teratogenic qualities of ethylene 

dichloride, and their implications for occupational health. Also included are "Suggested 

Guidelines for Minimizing Employee Exposure to Ethylene Dichloride." We are 

requesting that producers, -distributors, professional associations, and unions transmit 

the information in this Bulletin to their customers, employees, associates, and members. 

Background 

The current Department of Labor, Occupational Safety and Health Administration 

(OSHA) standard for occupational exposure to ethylene dichloride is 50 ppm (8-hour 

time-weighted average). In March 1976, NIOSH recommended an exposure limit of 

5 ppm (time-weighted average for up to a lO-hour workday, 40-hour workweek) (Z). 

Neither of these levels may provide adequate protection from potential carcinogenic 

effects because they were selected to prevent toxic effects other than cancer. The 

NIOSH recommendation was based on reports of adverse effects on the nervous system 

and liver of workers exposed to 10-15 ppm ethylene dichloride. Exposure to higher levels 

was also reported to affect the cardiac and respiratory systems. We further advised 

nursing mothers not to work with ethylene dichloride since the chemical has been found 

in the milk of exposed human mothers. At the time of the recommendation, there were 

no reports that ethylene dichloride caused cancer in animals or man. However, we did 

note that information on this subject was inadequate and that the National Cancer 

Institute (NCI) was conducting bioassay tests on ethylene dichloride. 

Production and Use 

Ethylene dichloride is one of the highest volume chemicals used in the United States. It 

is a colorless oily liquid with a chloroform-like odor, detectable over the range of 6 to 

40 ppm, with a sweet taste (3). Patty (4) concluded that a person can become adapted 

to the odor of ethylene dichloride at low concentrations and that its odor is probably not 

sufficiently striking to be considered a significant warning of hazardous chronic 

exposure. Ethylene dichloride (I,Z-di chloroe thane) , which has a carbon-carbon single 

bond, should be distinguished from I,Z-dichloroethene which has a carbon-carbon double 

bond. -

Between 1973 and 1976, the United States annual average production of ethylene 

1 

(71) 
(72) 

dichloride was approximately 10 billion pounds. During these years, most of it was used 

as an intermediate in the production of vinyl chloride, but it was also used in the 

production of other chemicals, such as l,l,l-trichloroethane, trichloroethylene, perchloroethylene, vinylidene chloride, and ethyleneamines (5). Ethylene dichloride is a lead 

scavenger, and therefore appears as a component of most leaded fuels. Ethylene 

dichloride was also used as an extraction solvent, as a solvent for textile cleaning and 

metal degreasing, in certain adhesives, and as a component in fumigants for upholstery, 

carpets, and grain. Other miscellaneous applications include paint, varnish, and finish 

removers, soaps and scouring compounds, wetting and penetrating agents, organic 

synthesis, ore flotation, and as a dispersant for nylon, rayon, styrene-butadiene rubber 

and other plastics. 

Potential Occupational Exposures 

The National Institute for Occupational Safety and Health estimates that as many as Z 

million workers may have occupational exposure to ethylene dichloride. Of these 

workers, an estimated 34,000 are exposed to ethylene dichloride 4 hours or more per 

day. These projections are based on the NIOSH National Occupational Hazards Survey 

(NOHS) conducted between 197Z and 1974, which encompassed some 500,000 employees 

at approximately 4,775 facilities. According to the survey, numerous exposures 

occurred in the following industries: cheomical and allied products, printing and 

publishing, electrical equipment and supplies, wholesale and retail trade, food and 

kindred products, leather and leather products, and machinery. 

Laboratory Animal Studies for Carcinogenicity 

On March 6, 1978, the Clearinghouse on Environmental Carcinogens (NCI) reviewed and 

accepted the results of the bioassay of ethylene dichloride, which was performed under 

contract for the National Cancer Institute. 

In the bioassay, technical grade I,Z-dichloroethane was tested for possible 

carcinogenicity in Osborne-Mendel rats and B6C3Fl mice. I,Z-Dichloroethane in corn 

oil was force-fed at either of two dosages, to groups of 50 male and 50 female animals 

of each species. Untreated and vehicle control animals were also used. The timeweighted average high and low doses of I,Z-dichloroethane in the chronic study were 95 

and 47 mg/kg/day, respectively for rats of both sexes. The high and low time-weighted 

average doses for the male mice were 195 and 97 mg/kg/day, respectively, and Z99 and 

149 .mg/kg/day, respectively for the female mice. 

To relate some of the above information to the work environment, a 70 kg man 

breathing a typical 10 cu m/day (over an 8-hour work shift) of air contaminated with 50 

ppm of ethylene dichloride (the current OSHA standard for exposure to ethylene 

dichloride) would have an inhalation exposure of about 30 mg/kg/day. Because 

respiration rate increases with exertion, jobs with higher exertion are likely to be 

associated with increased respiratory intake. 

2 
The National Cancer Institute has concluded that under the conditions of the study, 1,Zdichloroethane was carcinogenic to Osborne-Mendel rats and B6C3F1 mice. Table 1 

summarizes the statistically significant tumors found in the NCr Bioassay of 1,Zdichloroethane. 

TABLE 1 

Statistically Significant Tumors Found in NCr Bioassay of 1,Z-Dichloroethane 

Species/Sex 

Rats/Male 

Rats/Female 

Mice/Female 

Mice/Female 

Mice/Male 

&: Female 

Adverse Effect 

Squamous-Cell Carcinomas 

Hemangiosarcomas 

Fibromas 

Adenocarcinomas 

Adenocarcinomas 

Stromal Polyps 

Stromal Sarcomas 

Adenomas 

Site 

Forestomach 

Circulatory System 

Subcutaneous Tissue 

Mammary Gland 

Mammary Gland 

Endometrium 

Endometrium 

Alveoli and 

Bronchioli 

Two additional studies to assess the carcinogenic potential of ethylene dichloride are 

currently underway. In an ethylene dichloride inhalation study being conducted in Italy 

by Dr. C. Maltoni, animals will be exposed to ethylene dichloride for Z years and 

observed until the end of their natural lives. No evidence of any exceptional tumor in 

rats or mice has been found following 100 weeks of exposure (6). Also, Dr. B. M. 

Goldschmidt has informed NIOSH of bioassays of 1,Z-dichloroethane being conducted at 

the New York University Institute of Environmental Medicine. Groups of 30 female 

mice received skin applications of 1,Z-dichloroethane for more than one year. None of 

the animals developed skin tumors, and autopsies did ;not reveal any unexpected 

internal lesions or tumors (7). 

Other Laboratory Animal Studies 

The toxic effects of ethylene dichloride exposure have been studied in a large number of 

animal species (Z). Acute exposure to ethylene dichloride seemed to most frequently 

affect the cardiovascular system as evidenced by extreme lowering of blood pressure, 

and cardiac impairment. Other toxic effects include pulmonary edema, fatty 

degeneration of the liver and kidney (renal tubules) and degeneration of the adrenal 

cortex. Also, ethylene dichloride is reported to be a weak mutagen in bacteria and 

3 

(73) 
(74) 

mutagenic in fruit flies (8). In the rat, ethylene dichloride has been report~d to cross 

the placental barrier, accumulate in the placenta and fetal tissues, and cause abnormal 

development of the fetus (9,10,11). 

Human Toxicity 

The acute effects of ethylene dichloride are similar for all routes of entry: ingestion, 

inhalation, and skin absorption. Acute exposures result in nausea, vomiting, dizziness, 

internal bleeding, bluish-purple discoloration of the mucous membranes and skin 

(cyanosis), rapid but weak pulse, and unconsciousness. Acute exposures can lead to 

death from respiratory and circulatory failure. Autopsies in such situations have 

revealed \videspread bleeding and damage in most internal organs. Repeated long-term 

exposures to ethylene dichloride have resulted in neurologic changes, loss of appetite 

and other gastrointestinal problems, irritation of the mucous membranes, liver and 

kidney impairment, and death (Z). 

NIOSH Recommendation 

The National Institute for Occupational Safety and Health is currently preparing an 

update to the March 1976 recommendations regarding exposure to ethylene dichloride, 

which will address the carcinogenic potential of this substance in the workplace. The 

NeI laboratory study showing ethylene dichloride to be a carcinogen in two animal 

species uti1i~ed forced-feeding (directly into the stomach) for the route of exposure. 

However, it is important to keep in mind that ethylene dichloride can and does enter the 

body via inhalation and through the skin, ·as well as orally. When evaluating the test 

results or potential exposure to the substance in the workplace, in addition to the route 

of entry into the body, the amount of ethylene dichloride which is absorbed and actually 

reaches the target tissue or organ is a significant issue in determining the extent or 

possibility of the health hazard. 

Animal studies are valuable in helping identify human carcinogens. Although humans 

may be more sensitive or less sensitive than experimental animals to specific chemical 

compounds, substances that cause cancer in experimental animals must be considered to 

pose a potential cancer ri.sk in man. Safe levels of exposure to carcinogens have not 

been demonstrated, but the probability of cancer development is lowered with 

decreasing exposure to carcinogens. 

As an interim and prudent measure while the carcinogenicity of ethylene dichloride is 

being further evaluated, NIOSH recommends that occupational exposure be minimized. 

Exposures should be limited to as few employees as possible, while minimizing 

workplace exposure levels with ~ering and work practice controls. 

a illar, M.D. 

tant Surgeon General 

Acting Director 

4 
REFERENCES 

I. Bioassay of 1,2-Dichloroethane for Possible Carcinogenicity. DHEW Publication No. (NIH) 78-1305. U.S. Department of Health, Education, and Welfare, 

Public Health Service, National Institutes of Health, National Cancer Institute, 

(Camera-Ready Copy dated 1/10/78). 

2. Criteria for a Recommended Standard •••• Occupational Exposure to Ethylene 

Dichloride (I,2-dichloroethane). DHEW Publication No. (NIOSH) 76-139, U.S. 

Department of Health, Education, and Welfare, Public Health Service, Center 

for Disease Control, National Institute for Occupational Safety and Health, 

March 1976. 

3. Hellman, T.M. and Small, F.H. "Characterization of the Odor Propertjes of 101 

Petrochemicals Using Sensory Methods," Journal of the Air Pollution Control 

Association, 24(10):979-982, 1974. 

4. Patty, F.A. Industrial Hygiene and Toxicology, Second Revised Edition, 

Volume n, Fawcett, D.W., Irish, D.D., eds. John Wiley & Sons, Inc., New York. 

5. Stanford Research Institute. Chemical Economics Handbook. Menlo Park, 

California, October, 1977. 

6. Letter to Director, National Institute for Occupational Safety and Health 

(NIOSH) from Mr. Albert C. Clark, Manufacturing Chemists Association 

(MCA), December 22, 1977. Letter to Dr. Arthur Gregory (NIOSH) from Ms. 

Lucille C. Henschel (MCA), February 28, 1978. 

7. Letter to Dr. Arthur Gregory, National Institute for Occupational Safety and 

Health (NIOSH) from B.M. Goldschmidt, Ph.D., New York University Medical 

Center, Institute of Environmental Medicine, February 28, 1978. 

8. Fishbein, L. "Industrial Mutagens and Potential Mutagens I. Halogenated 

Aliphatic Derivatives," Mutation Research, 32:267-308, 1976. 

9. Vozovaya, M.A. "The Effect of Dichloroethane on the Sexual Cycle and 

Embryogenesis of Experimental Animals," Akusk. Ginekol. (Moskow), 2:57-59, 

1977. 

10. Vozovaya, M.A. "The Effect of Small Concentrations of Benzene and 

Dichloroethane Separately and Combined on the Reproductive Function of 

Animals," Gig. Sanit. (Moskow), 6:100-102, 1976. 

11. Vozovaya, M.A. "The Effect of Small Concentrations of Benzene, Dichloroethane Alone and Combined, on the Reproductive Function of Animals and the 

Development of the Progeny," Gig. Tr. Prof. Zabol. (Moskow), 7:20-23, 1975. 

5 

(75) 
(76) 

SUGGESTED GUIDELINES FOR MINIMIZING EMPLOYEE EXPOSURE TO 

ETHYLENE DICHLORIDE (l,Z-DICHLOROETHANE) 

NIOSH recommends that it would be prudent to handle ethylene dichloride in the 

workplace as if it were a human carcinogen. Exposure to ethylene dichloride 

should be limited to as few employees as possible, while minimizing workplace 

exposure levels. The area in which it is used should be restricted to only those 

employees essential to the process or operation. 

EXPOSURE MONITORING 

Initial and routine employee exposure surveys should be made by competent 

industrial hygiene and engineering personnel. These surveys are necessary to 

determine the extent of employee exposure and to ensure that controls are 

effective. 

The NIOSH Occupational Exposure Sampling Strategy Manual, NIOSH Publication 

#77-173, may be helpful in developing efficient programs to monitor employee 

exposures to ethylene dichloride. The. manual discusses determination of the need 

for exposure measurements, selection of appropriate employees for exposure 

evaluation and selection of sampling times. 

Employee exposure measurements should consist of 8-hour TWA (time-weighted 

average) exposure estimates calculated from personal or breathing zone samples 

(air that would most nearly represent that inhaled by the employees). Area and 

source measurements may be useful to determine problem areas, processes, and 

operations. 

MINIMIZING EMPLOYEE EXPOSURE 

There are four basic methods of limiting employee exposure to ethylene 

dichloride. None of these is a simple industrial hygiene or management decision 

and careful planning and thought should be used prior to implementation of any of 

these. 

o Product Substitution 

The substitution of an alternative material with a lower potential health risk is 

one method. However, extreme care must be used when selecting possible 

substitutes. Alternatives to ethylene dichloride should be fully evaluated with 

regard to possible human effects. Unless the toxic effects of the alternative have 

been thoroughly evaluated a seemingly safe replacement, possibly only after years 

of use, may be found to induce serious health effects. 

6 
o Contaminant Controls 

The most effective control of ethylene dichloride, where feasible, is at the source 

of contamination by enclosure of the operation and/or local exhaust ventilation. 

If feasible, the process or operation should be enclosed with a slight vacuum so 

that any leakage will result in the flow of external air into the enclosure. 

The next most effective means of control would be a well designed local exhaust 

ventilation system that physically encloses the process as much as possible, with 

sufficient capture velocity to keep the contaminant from entering the work 

atmosphere. 

To ensure that ventilation equipment is working properly, effectiveness (e.g., air 

velocity, static pressure, or air volume) should be checked at least every three 

months. System effectiveness should be checked soon after any change in 

production, process, or control which might result in significant increases in 

airborne exposures to ethylene dichloride. 

o Employee Isolation 

A third alternative is the isolation of employees. It frequently involves the use of 

automated equipment operated by personnel observing from a closed control booth 

or room. The control room is maintained at a greater air pressure than that 

surrounding the process equipment so that air flow is out of, rather than into, the 

room. This type of control will not protect those employees that must do process 

checks, adjustments, maintenance, & related operations. 

o Personal Protective Equipment 

The least preferred method is the use of personal protective equipment. This 

equipment, which may include respirators, goggles, gloves, etc., should not be used 

as the only means to prevent or minimize exposure during routine operations. 

Exposure to ethylene dichloride should not be controlled with the use of 

respirators except: 

-- During the time period necessary to install or implement engineering or work 

practice controls; or 

--In work situations in which engineering and work practice controls are 

technically not feasible; or 

-- For nlaintenance; or 

-- For operations which require entry into tanks or closed vessels; or 

--In emergencies. 

Only respirators approved by the National Institute for Occupational Safety and 

7 

(77) 
(78) 

Health (NIOSH) should be used. Refer to NIOSH Certified Equipment, December 15, 

1975, NIOSH publication #76-145 and Cumulative Supplement June 1977, 

NIOSH Certified Equipment, NIOSH publication #77-195. The use of faceseal coverlets 

or socks with any respirator voids NIOSH approvals. 

Quantitative faceseal fit test equipment (such as sodium chloride, dioctyl phthalate, or 

equivalent) should be used. Refer to A Guide to Industrial Respiratory Protection, 

NIOSH publication #76-189 for Guidelines on appropriate respiratory protection 

programs •• 

In addition, proper maintenance procedures, good housekeeping in the work area and 

education of employees concerning the nature of the hazard, its control and personal 

hygiene are all aspects of a good control program. 

8 
JOINT 

NlaSM / D5NR 

® 

NIAX Catalyst ESN .... 

a mixture of 

CH3 , 

/NCH2CH2CN 

C H3 Dim elhylomin opropionilrile 

CH3 CH3 

, / 

CH 

/NCH2 CH20CH2CH2N, 

3 CH3 

Bisj2-fdimelhYIOminoJelhyj ether 

U. S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE 

Public Health Se,,,ice 

Cente, to, Disease Cont,ol 

Natlonallnstitufe '0' Occupational Sa'ety and Health 

u. S. DEPARTMENT OF LABOR 

Occupational Safety and Health Administration 

(79) 

May 22,1978 
(80) 

This CUrrent Intelliqence Bulletin is a joint effort of the National 

Institute for Occupational Safety and Health (NIOSH) and the 

Occupational Safety and Health Administration (OSHA) and is part of 

the NIOSH CUrrent Intelliqence System. The purpose of the Current 

Intelliqence Systeri; is to promptly review, evaluate, and supplement 

new information received by NIOSH on occupational hazards that are 

either unrecognized or are greater than generally known. 

As warranted by this evaluation, the information is capsulized and 

disseminated to NIOSH staff, other qovernment agencies, and the 

occupational health community, includinq labor, industry, academia, 

and public interest qroups. With. respect to currently known hazard 

information this system also serves to advise appropriate members of 

the above. groups of recently acquired spe.cific knowledge which may 

have an impact on their proqrams or perception of the hazard. Above 

all, the Current Intelligence System is desiqned to protect the health 

of American workers and to allow them to work in the safest possible 

environment. 

IDENTIFIERS AND SYNONYMS FOR DIMETHYLAMINOPROPIONITRILE 

Chemical Abstracts Service Registry Number 1738-ZS-6 

NIOSH RTECS Number UGIS7S0 

Chemical Formula C SH10Ni 

3-(Dimethylamino)propanenitrile 

3-(Dimethylamino)propionitrile 

a -(Dimethylamino)propionitrile 

N,N-Dimethylamino-3-propionitrile 

3-(N ,N -Dime thylamino)propioni trile 

a -N-Dimethylaminopropionitrile 

IDENTIFmRS AND SYNONYMS FOR BIS(Z-(DIMETHYLAMINO)ETHYL) ETHE:1 

Chemical Abstracts Service Registry Number 3033-6Z-3 

NIOSH RTECS Number KR94600 

Chemical Formula CgHZONZO 

A99 

A99 amine 

Bis Z-(dimethylamino)ethyl ) ether 

Kalpur PC 

NIAX A99 

Z,Z'-Oxybis(N ,N-dimethylethanamine) 

Z,Z'Oxybis(N,N-dimethylethylamine) 

DHEW (NIOSH) Publication No. 78-157 

ii 
JOINT NIOSH/OSHA 

CURRENT INTELLIGENCE BULLETIN: NIAXIliCATALYST ESN 

A Mixture of Dimethylaminopropionitrile and Bis(Z-(dimethylamino) ethyl ) ether 

May 18, 1978 

The National Institute for Occupational Safety and Health (NIOSH) and the 

Occupational Safety and Health Administration (OSHA) jointly recommend 

that NIAXIII Catalyst ESN and its components, dimethylaminopropionitrile 

and bis (Z-(dimethylamino)ethyl) ether, as well as formulations containing 

either component, be handled in the workplace as exceedingly hazardous 

materials. Investigations of outbreaks of urinary dysfunction among 

workers at a number of facilities that manufacture flexible polyurethane 

foam strongly suggest an association between NIAXIII Catalyst ESN and the 

urological disorders. There is no current Federal standard for occupational 

exposure to NIA~ Catalyst ESN or either of its components. However, on 

April 7, 1978, OSHA issued a Health Hazard Alert and indicated "it is 

imperative that worker exposure to ESN and its components be completely 

avoided." 

Background 

NIAXIII Catalyst ESN, a proprietary product of Union Carbide Corporation, 

is composed of dimethylaminopropionitrile (95%) and bis( Z-(dimethylamino) ethyl) ether (5%). Similar mixtures were also marketed as NIAXIII 

Catalysts 125 and 1 Z6. These catalysts were used in the manufacture of 

flexible polyurethane foams and may comprise from 0.5% to Z% of the wet 

urethane liquid prior to foaming. Union Carbide has voluntarily 

discontinued the sale of these three catalysts as well as dimethylaminopropioni trile. 

Dimethylaminopropionitrile is also used as a component of acrylamide 

based gels (for soil grouting and other purposes), and as an intermediate in 

the synthesis of dimethylaminopropylamine and some pharmaceuticals. 

Manufacturers of dimethylaminopropionitrile include Abbott Laboratories, 

American Cyanamid Company, Jefferson Chemical Company, and Union 

Carbide Corporation. 

Bis( 2-(dimethylamino) ethyl ) ether is manufactured in the United States 

exclusively by.Union Carbide and used extensively in their line of catalysts 

for flexible polyurethane foams. Bis (2-(dimethylamino)ethyl ) ether may 

1 

(81) 
(82) 

comprise from 0.02% to 0.1% of the wet urethane liquid prior to foaming. 

NIOSH and OSHA are unaware of any other application of bis(2-(dimethylamino)ethyl )ether. 

Human Toxicity 

Preliminary results of NIOSH Health Hazard Evaluations suggest NIAX® 

Catalyst ESN is neurotoxic, producing urinary bladder dysfunction as the 

prevailing clinical feature. 

Of the ten industrial facilities reported to have used commercial quantities 

of NIAX® Catalyst ESN, five are known to have had excessive numbers of 

their workers seek medical attention for urological and/or neurological 

problems. Common urinary tract symptoms after exposure include difficulty beginning urination, inadequate bladder emptying, strain on 

urination, increase d duration of voiding time, and post void fullness. Other 

symptoms include frequent urination, pain and burning on urination, as well 

as impotence. Neurological manifestations include dysesthesias in the form 

of pins and needles sensation in the hands and feet. Muscular weakness, 

lassitude, nausea, and vomiting were also reported. Exposure may occur' by 

inhalation, skin absorption, and ingestion. 

NIOSH epidemiological and medical studies are presently underway in two 

of the industrial facilities involved. Clinical manifestations in exposed 

workers coincide with the introduction or increased use of the catalyst in 

manufacturing processes. After exposure is discontinued, improvement 

occurs in some indiv.iduals over a variable period of time. NIOSH is investigating whether symptoms persist after exposure to the catalyst is 

eliminated. 

Approximately a third of the hundred workers exposed at one plant and half 

of the two hundred exposed workers at the other plant studied reported 

urinary problems. Detailed clinical and laboratory studies of eight workers 

severely affected with urinary problems revealed that five of the eight did 

not have a bladder reflex and were therefore unaware of the need to void 

as their bladders became full. Though not conclusive, the evidence 

suggests that the absent bladder reflex may be the cause of urinary 

r etention and abnormal change in bladder habits. Long term urinary 

retention can lead to urinary tract infection and kidney damage, and thus 

can pose a threat to life. In addition to bladder dysfunction, some of the 

workers were found to have decreased nerve conduction times of the lower 

legs. 

Sufficient evidence does exist to suggest that occupational exposure to 

NIAX· Catalyst ESN is associated with the urinary and neurologic abnormalities. The extent of toxicity of the catalyst to other systems and 

organs including kidney, liver, eye and skin are unknown. Definitive 

information regarding safe levels of exposure to NIAX® Catalyst ESN or its 

components is not available at this time. 

z 
Animal Studies 

Dr. Alan Pestronk (The Johns Hopkins University) is currently investigating 

the effect of NIAX· Catalyst ESN, as well as its components, on the 

nervous system of laboratory rats. Results of this study are not yet 

available. Several propionitriles have been previously reported to be 

neurotoxins, however, specific data regarding the neurotoxicity of 

dimethylaminopropionitrile could not be located. Union Carbide is also 

sponsoring toxicity studies of NIAX. Catalyst ESN, dimethylaminopropionitrile and bis(Z-(dimethylamino)ethyl)ether; these studies have been 

in progress for approximately two weeks but have not proceeded far enough 

to be adequately evaluated. 

Conclusions 

Although there does appear to be an association between NIAX· Catalyst 

ESN and the outbreaks of urinary dysfunction, it is not now known whether 

either component of the mixture could cause the disorder itself. Additional 

research in this area is clearly appropriate. Union Carbide has suggested 

that the nitrile component (dimethylaminopropionitrile) may be the 

caus'ative agent. They stated that bis( Z-(dimethylamino)ethyl) ether has 

been used in urethane catalyst systems for fifteen years and proper use of 

the material has 'not been known to cause any adverse health effects. 

(Acute overexposure may result in symptoms characteristic of amine 

toxicity) . 

Recommendation 

The National Institute for Occupational Safety and Health (NIOSH) and the 

Occupational Safety and Health Administration (OSHA) jointly recommend 

that occupational exposure to NIAX· Catalyst ESN its components, 

dimethylaminopropionitrile and bis (Z-(dimethylamino)ethyl) ether, as well 

as formulations containing either component, be minimized. Exposures 

should be limited to as few employees as possible, while minimizing 

workplace exposure levels with engineering and work practice controls. 

Exposed employees should be carefully monitored for potential disorders of 

the nervous and genitourinary system. Although substitution is a possible 

control measure, alternatives to NIAX·Catalyst ES .. ~ or its components 

should be fully evaluated with regard to possible adve se health effects. 

2~~~-'~ rula Bingham, plio • 

Assistant Secr y of Labor 

Occupational Safety and Health 

Administration 

-\,~~ J. 'tJonald Millar, M.D. 

AsJistant Surgeon General 

Acting Director 

3 

National Institute for 

Occupational Safety and 

Health 

(83) 
(84 ) 

SUGGESTED GUIDELINES FOR MINIMIZING EMPLOYEE EXPOSURE TO 

NIAX®CATALYST ESN and its Components, 

Dimethylaminopropionitrile and Bis(Z-(dimethylamino)ethyI) ether 

NIOSH and OSHA recommend that it would be prudent to handle NIAX® 

Catalyst ESN and its components in the workplace as exceedingly hazardous 

materials. Workplace exposure levels and employee exposure should be 

minimized. The area in which NIAX® Catalyst ESN, or either of its components, is used should be restricted to only those employees essential to the 

process or operation. 

EXPOSURE MONITORING 

Initial and routine employee eKposure surveys should be made by competent 

industrial hygiene and engineering personnel. These surveys are necessary to 

determine the extent of employee exposure and to ensure that controls are 

effective. The sampling and analytical method recommended by the Union 

Carbide Corporation for the bis-ether component of NIAX- Catalyst ESN is 

currently being used and evaluated by NIOSH as a procedure for the analysis 

of dimethylaminopropionitrile as well as bis(Z-(dimethylamino)ethylkther. 

The NIOSH Occupational Exposure Sampling Strategy Manual, NIOSH 

Publication #77-173, may be helpful in developing efficient programs to 

monitor employee exposures to NIAX ® Catalyst ESN and its components. 

The manual discusses determination of the need for exposure measurements, 

selection of appropriate employees for exposure evaluation, and selection of 

sampling times. 

Employee exposure measurements should consist of 8-hour TWA (timeweighted average) exposure estimates calculated from personal or breathing 

zone samples (air that would most nearly represent that inhaled by the 

employees). Area and source me~sur~ments may be useful to determine 

problem areas, processes, and operations. 

MINIMIZING EMPLOYEE EXPOSURE 

There are four basic methods of limiting employee exposure to NIAXCatalyst ESN and its components. None of these is a simple industrial 

hygiene or management decision and careful planning and thought should be 

used prior to implementation of any of these. 

4 
o Product Substitution 

One method is the substitution of an alternative material with a lower 

potential health risk. However, extreme care must be used when selecting 

possible substitutes. Alternatives to NIAX ® Catalyst ESN and its 

components should be fully evaluated with regard to possible human effects. 

Unless the toxic effects of the alternative have been thoroughly evaluated, a 

seemingly safe replacement may be found to induce serious health effects, 

possibly only after years of use. 

o Contaminant Controls 

The most effective control of NIAX® Catalyst ESN and its components is by 

local exhaust ventilation and/or enclosure of the operation at the source of 

con tam ina tion. 

If feasible, the process or operation should be enclosed with a slight vacuum 

so that any leakage will result in the flow of air into the enclosure. 

The next most effective means of control is a well designed local exhaust 

ventilation system that physically encloses the process as much as possible, 

with sufficient capture velocity to keep the contaminant from entering the 

work atmosphere. 

To ensure that ventilation equipment is working effectively, air velocity, 

static pressure, or air volume should be checked every three months. 

System effectiveness should be checked soon after any change in production, 

process, or control which might result in significant increases in airborne 

exposures to NIAX® Catalyst ESN or its components. 

In cases where the contaminant release is not excessive and is not in the 

workers' breathing area, good general dilution ventilation may assist in 

keeping the contaminant levels from reaching hazardous levels. 

Care should be exercised in controlling exposure resulting from residual 

material in off-gassing from the uncured or curing products. 

o Employee Isolation 

A third alternative is the isolation of employees. It frequently involves the 

use of automated equipment operated by personnel observing from a closed 

control booth or room. The control room is maintained at a greater air 

pressure than that surrounding the process equipment so that air flow is out 

of, rather than into, the room. This type of control will not protect those 

employees who must do process checks, adjustments, maintenance, and 

related operations. 

5 

(85) 
(86) 

o Personal Protective Equipment 

The least desirable way to control employee exposures is with the use of 

personal protective equipment, which may include respirators, gloves, 

goggles, etc. This equipment should not be used as the only means to 

prevent or minimize exposure during routine operations. 

Exposure to NIAX· Catalyst ESN or its components should not be controlled 

with the use of respirators except: 

During the time period necessary to install or implement engineering 

or work practice controls; or 

In work situations in which engineering and work practice controls 

are technically not feasible; or 

For maintenance; or 

For operations which require entry into tanks or closed vessels; or 

In emergencies. 

Neither NIOSH or OSHA has definitive information concerning the warning 

properties of NIAX· Catalyst ESN or its components or the service lives of 

typical industrial respirator for these substances. Therefore, as an interim 

recommendation, NIOSH and OSHA feel that only the following type respirators may be used for personal respiratory protection against NIAxt' 

Catalyst ESN or its components as allowed under the previous guidelines. 

A type C supplied-air respirator with a full 

facepiece operated in pressure-demand or 

other positive pressure mode or with a full 

facepiece, hood, or helmet operated in 

continuous-flow mode. 

Self-contained breathing apparatus with a 

full facepiece operated in pressure-demand 

or other positive pressure mode. 

A combination respirator which includes a 

type C supplied-air respirator with a full 

facepiece operated in pressure-demand 

mode or other positive pressure or 

continuous-flow mode and an auxiliary selfcontained breathing apparatus operated in 

pressure-demand or positive pressure mode. 

Only respirators approved by the National Institute for Occupational Safety 

and Health (NIOSH) should be used. Refer to NIOSH Certified Equipment, 
December 15, 1975, NIOSH pUblication #76-145 and Cumulative Supplement 

June 1977, NIOSH Certified Equipment, NIOSH publication #77-195. The 

use of faceseal coverlets or socks with any respirator voids NIOSH 

approvals. 

Refer to A Guide to Industrial Respiratory Protection, NIOSH publication 

#76-189 for guidelines on appropriate respiratory protection programs. 

Proper maintenance procedures and good housekeeping in the work area are 

very important aspects of a good control program. In addition, it is vital 

that employees be educated as to the nature and control of the hazard, and 

y>roper personal hygiene. 

7 

(87) 

NlaSM 

August 21, 1978 

CHLOROETHANES: 

REVIEW 

, 

OF TOXICITY 

H H 

I I 

H-C-C-CI 

I I 

H H 

Chloroethane 

( £,"),, t:II'tlTI'tH J 

H CI 

I I 

H- C-C-CI 

I I 

H CI 

" " 1-Trichloroethane 

( M"II)'I CII'tlTtlftl"" J 

CI CI 

I I 

H-C-C-H 

I I 

CI CI 

1,1,2,2-Tetrachloroethane 

H CI 

I I 

H-C - C-H 

I I 

H CI 

1,1,-Dichloroethane 

H CI 

I I 

CI - C- C-H 

I I 

H CI 

1,1,2-Trichloroethane 

CI CI 

I I 

H-C- C-CI 

I I 

CI CI 

Pentachloroetitane 

H H 

I I 

CI - c- C-CI 

I I 

H H 

1,2-Dichloroethane 

( £111,1.". Dicll'tI,id.J 

H CI 

I I 

CI - c- C-CI 

I I 

H CI 

1,1,1.2-Tetrachloroeth_ 

CI CI 

I I 

CI - C- C-CI 

I I 

CI CI 

Hexachloroethane 

U. S. DEPARTMENT OF HEALTH. EDUCATION. AND WELFARE 

PulJllc He.lth SerYice 

Cente,lo, Di ..... Cont,ol 

N.tion.,lnatltute fo, Occup.tion.' S.fe', and Health 

(89) 
.( 90) 

The NIOSH Current Intelligence Bulletin is the primary product of the Current 

Intelligence System. The purpose of the Current Intelligence System is to promptly 

review, evaluate, and supplement new information received by NIOSH on 

occupational hazards that are either unrecognized or are greater than generally 

known. 

As warranted by this evaluation, the information is capsulized and disseminated to 

NIOSH staff, other government agencies, and the occupational health community, 

including labor, industry, academia, and public interest groups. With respect to 

currently known hazard information this system also serves to advise appropraate 

members of the above groups of recently acquired specific knowledge which may 

have an impact on their programs or perception of the hazard. Above all, the 

Current Intelligence System is designed to protect the health of American workers 

and to allow them to work in the safest possible environment. 

IDENTIFIERS AND SYNONYMS FOR THE NINE CHLOROETHANES ARE USTED 

IN THE REAR POR nON OF THIS BULLETIN 

ERRATA 

In Bulletins #22 through #25 it was stated that the NIOSH National Occupational 

Hazard Survey (NOHS) had included "over 500,000 employees at 4,775 facilities." 

Actually the Survey included nearly 900,000 employees at 4,636 facilities. 

In Bulletin #23 NIOSH erroneously listed Dowfume ® MC-2 as a synonym for 

ethylene dibromide. Dow Chemical USA has advised NIOSH that Dowfume®MC-2 

actually is 98% methyl bromide and 2% chloropicrin. 

DHEW (NIOSH) Publication No. 78-181 
NIOSH CURRENT INTELLIGENCE BULLETIN 

CHLOROETHANES: REVIEW OF TOXICITY 

The National Institute for Occupational Safety and Health (NIOSH) recommends 

that it would be prudent to handle I,Z-dichloroethane (ethylene dichloride); 1,I,Ztrichloroethane; 1,I,Z,Z-tetrachloroethane; and h~xachloroethane in the workplace 

as if they were human carcinogens. This recommendation is based primarily on 

consideration of National Cancer Institute (NCI) data indicating that laboratory 

animals administered these compounds experienced a statistically significant 

excess of cancer as compared to control animals (1-4). Additionally, NIOSH 

recommends that five other chloroethane compounds: chloroethane* (ethyl 

chloride); 1,I-dichloroethane; 1,1,I-trichloroethane (methyl chloroform); 1,1,I,Ztetrachloroethane; and pentachloroethane be closely monitored for carcinogenic 

effects in humans and/or laboratory animals. These five should also be treated in 

the workplace with caution because of their relation to the four chloroethanes 

shown to be carcinogenic in laboratory animals. 

This Current Intelligence Bulletin summarizes information on some of the 

similarities and dissimilarities within the chloroethane group. NIOSH is concerned 

about the carcinogenic potential of chloroethanes based on emerging data from the 

NCI bioassay program. Concern for the carcinogenic potential of all members of 

the chloroethane series is based upon structural similarities within the group as 

well as the structural similarities to other carcinogenic organochlorine compounds. 

Extreme care must be used when selecting possible substitutes, and the alternatives 

should be fully evaluated with regard to human effects. 

At present, NIOSH is not aware of any evidence associating chloroethane 

compounds with an increased risk of cancer in man. However, animal studies are 

valuable in helping identify human carcinogens. Substances that caUse cancer in 

experimental animals must be considered a potential cancer risk in man. Safe 

levels of exposure to carcinogens have not been demonstrated, but lowered 

exposure to carcinogens decreases the probability of cancer development. 

NIOSH issued Current Intelligence Bulletin #Z5 (April 1978), recommending that 

ethylene dichloride (l,Z-dichloroethane) be handled in the workplace as if it were a 

human carcinogen (5). NIOSH is now distributing Bulletin #27 to advise of 

additional findings of the NCI chloroethane bioassays, other pertinent data, and 

possible implications for occupational health. Also included are "Suggested 

Guidelines for Controlling Employee Exposure to Chloroethanes." NIOSH requests 

that producers, distributors, professional associations, and unions transmit the 

information in this Bulletin to their customers, employees, associates and members. 

*to be referred to as monochloroethane in this Bulletin 

1 

(9l) 
N 

Table I. Summary of Some of the Industries and Occupations Which Use Chloroethane~. (a) 

Chemical 

monochloroethane 

I,I-dichloroethane 

l,Z-dichloroethane 

I, I, I-trichloroethane 

I,I,Z-trichloroethane 

1,1,Z,Z-tetrachloroethane 

hexachloroethane 

Industrtes (b) 

medical md other health services; automotive dealers and 

service stations; whoiesale trade; electric, gas and sanitary 

services; machinery, except electrical; special trade 

contractors; fabricated metal products; printing and 

publishing; rubber and plastid products not elsewhere 

classified; food and kindred products 

chemicals and allied products; miscellaneous business servicesr 

stone, clay and glas. products not elsewhere classified; 

petroleum and coal products 

medical and other health services; automotive dea.lers and 

service stations; machinery, e:<cept electrical; wholesale 

trade; printing and publishing; eating and drinking places; 

primary metal industries; chemicals and allied products; 

miscellaneous business services; transportation equipment; 

electrical equipment and supplies; special trade contractors; 

fabricated metal products; stone, clay and glass products; food 

and kindred products; paper and allied products; rubber and 

plastics products not elsewhere covered; communication; 

water transportation; instruments and related products 

medical and other health services; automotive dealers and 

service stations; machinery, except electrical; wholesale 

trade; transportation equipment; printing and publishing; 

primary metal industries; electrical equipment and supplies; 

fabricated metal products; communication; special trade 

contractors; chemicals and allied products; eating and drinking 

places; miscellaneous services; tra., sportntion by air; stone, 

clay and glass products; retain general merchandise; 

instruments and related products; apparal and accessory 

stores; electric, gas and sanitary services; food and kindred 

products; rubber and plastics products not elsewhere classified; 

personal services; paper and allied products 

primary metal industries; wholesale trade; auto repair, 

services and garages; transportation equipment; 

communication; electrical equipment and supplies, special 

trade contractors; miscellaneous retail stores; machinery, 

except electrical; stone, clay and glass products; chemicals 

and allied products; medical and other health services; 

instruments and other related products 

electrical equipment and supplies; chemicals and allied 

products; electric, gas and sanitary services; miscellaneous 

business services; stone, clay and glass products 

real estate; paper and allied products; lumber and wood 

products; amusement and recreation services not elsewhere 

classified 

(a) I,I,I,Z-tetrachloroethane and pentachlo~oethane were not mentioned in the NOHS survey (6) 

(b) These are standard industrial titles from the Standard Industrial Classification Manual (7) 

(c) These are standard occupational titles from the Bureau of the Census (8) 

Occupation/c) 

registered nurses; automobile mechanICS; physicians, medical 

and osteopathic; office machine mechanics and repairmen; 

garage workers and gas station attendants; not specified 

mechanics and repairmen; household appliance and accessory 

installers; assemblers; heavy equipment mechanics. including 

diesel; plum be,.. and pipe fitters 

janitors and sextons; not specified clerical workers; 

electricians; a.ssemblers; agricultural and biological technicians 

automobile me'challics; janitors and sextons; heavy equipment 

mechanics, including diesel; registered nurses; miscellaneous 

specified ma::hine operatives; miscenaneous operatives; 

assemblers; machinists; pressmen and plate printers, printing; 

cooks, except private household; garage workers and gas 

station attenc.ants; cleaners and charwomen; electricians; 

telephone installers and repairmen; vehicle washers and equipment cleaners; secretaries not elsewhere classified; nursing 

aides, orderlies and attendants; checkers, examiners and 

inspectors. manufacturing; not specified mechanics and 

repairmen; p;:tinters, manufactured articles 

auto mechanics; janitors and sextons; heavy equipment 

mechanics, inC'luding diesel; registered nurses; secretaries not 

elsewhere clas,sified; machinists; machine operatives; miscellaneous specif:,ed; assemblers; not specified clerical workers; 

cleaners and charwomen; miscellaneous operatives; 

electricians~ pressmen and plate printers, printing; garage 

workers and gas station attendants; telephone installers and 

repairmen; manufacturing checkers, examiners and inspectors; 

cooks, except private household; tool and die makers; administrators and managers, not elsewhere classified; nursing aides, 

orderlies and attendants; dishwashers; vehical washers and 

equipment cleaners; millwrights; miscellaneous mechanics and 

repairmen; office machine 

electricians; hea,·'Y equipment mechanics, including diesel; 

miscellaneous mechanics and repairmen; upholsterers; janitors 

and sextons; electrical and electronic engineering technicians; 

office machine mechanics and repairmen; radio and television; 

not speCified mechat}lcs and repairmen; air conditioning, 

heating and refrigeration; telephone installers and repairmen; 

miscellaneous operatives; assemblers; manufacturing checkers, 

examiners and inspectors; printing pressmen and plate printers 

assem bIers; janitors and sextons; not specified clerical 

workers; electricians; manufacturing checkers, examiners and 

inspectors 

cleaners and charwomen; millwrights; machine operatives, 

miscellaneous specified; plumbers and pipefitters; electricians 

-1.0 

N 

"-" 
BACKGROUND 

Chloroethanes are chlorinated organic compounds structurally related to ethane in 

which one or more of the hydrogen atoms have been replaced by a chlorine atom or 

atoms. Monochloroethane, for example, is shown to result from the replacement of 

one hydrogen atom in ethane by a chlorine atom. 

HH HH I I I I 

H-G-G-H H-G-G-GI I I I I 

HH HH 

ethane monochloroethane 

At room temperature monochloroethane is a gas, hexachloroethane is a solid, and 

the seven other chloroethanes are liquids. Some of the chloroethanes are 

manufactured on a large scale and used extensively because of their low cost and 

excellent solvent properties. They are used as solvents and in degreasing agents, 

cutting fluids, fumigants, and in the manufacture of plastics, textiles, and other 

chemicals. Table I (opposite page) summarizes the major industries and 

occupations in which workers are potentially exposed to chloroethanes. 

From 197Z-1974, NIOSH conducted the NIOSH National Occupational Hazards 

Survey (NOHS), on a sample of about 900,000 employees at 4,636 facilities, in order 

to determine the potential for worker exposure to chemicals and physical agents. 

NOHS algorithms used Bureau of the Census 1970 population counts to permit 

extrapolation from the sample to the United States worker population of 1970. A 

total of over 3 million workers were estimated to be potentially exposed to one or 

more chloroethanes. Table Z presents a summary of NOHS estimates of worker 

exposure to chloroethanes and some production figures (6,9, 40). 

Table 2 . Chloroethane Exposures and Production (6,9, 40). 

Chemical 

monochloroethane 

1,I-dichloroethane 

1,2dichloroethane 

1,1,I-trichloroethane 

1,1,2-trichloroethane 

1,1,1,2-tetrachloroethane 

1,1,2,2-tetrachloroethane 

pentach1oroethane 

hexachloroethane 

Estimated number 

of workers exposed 

113,000 

4,600 

1,900,000 

2,900,000 

112,000 

a 

11,100 

a 

1,500 

Annual 

Production quantities 

(pounds) 

670 million (1976 ) 

b 

8 billion (1976 ) 

630 million (1976) 

c 

b 

c 

b 

b,d 

:NOHS estimates not available 

does not appear to be commercially produced 1n the United States 

~direct production information not available 

730,000 kg were imported in 1976 

3 

(93) 
(94 ) 

Summaries of the current Department of Labor - Occupational Safety and Health 

Administration (OSHA) exposure standards (10) and NIOSH recommended exposure 

standards for the chloroethane compounds are given in Table 3. 

Table 3. Chloroethane Exposure Standards. 

Chemical 

monochloroethane 

1 , I-dichloroethane 

1,2-dichloroethane 

l,l,l-trichloroethane 

1,1, 2-trichloroethane 

1,1,1,2-tetrachloroethane 

1,1,2,2-tetrachloroethane 

pentachloroethane 

hexachloroethane 

OSHA 

Exposure 

Standard 

(ppm) 

1000 

100 

50 

350 

10 

none 

5 

none 

1 

NIOSH 

Recommended 

Exposure 

Standard 

(ppm) 

none 

none 

5 

350 

none 

nope 

1 

* * 

* NIOSH has tentative plans for a Criteria Document for a Recommended 

Standard for this substance 

The OSHA exposure standards and the NIOSH recommended standards and control 

measures for the chloroethanes were developed before the carcinogenic potential 

of these compounds was recognized. Therefore, an assessment of the 

carcinogenicity of these compounds was not included. The levels currently 

recommended or adopted may not provide adequate protection from potential 

carcinogenic effects. 

LABOR A TORY ANIMAL STUDIES 

Carcinogenicity 

As of July 1978, four of the eight chloroethanes selected by NCI for testing have 

been shown to be carcinogenic in laboratory animals. The results of the bioassays 

0-4,14) are summarized in Table 4. Each compound was studied separately in male 

and female Osborne-Mendel rats and male and female B6 C3F mice. Each 

experiment consisted of a high dose and a low dose group of 5d animals each. 

Twenty animals of each species/sex combination served as untreated controls and 

20 animals of each species/sex combination served as vehicle controls. The 

chloroethane compounds were administered to the test animals in a corn oil vehicle 

by gastric intubation (stomach tube) five days a week "for 78 weeks. The vehicle 

controls were intubated with pure corn oil at the same rate as the high dose 

animals. 

4 
Table 4. Summary of NCI Chlorothane Bioassay Results as of July 1978 0-4,14). 

Compound 

monocbloroethane 

1,I-dichloroethane 

1,2-dichloroethane 

1,1, I-trichloroethane 

1,1,2-trichloroethane 

1,1,1,2-tetrachloroetbane 

1,1,2,2-tetrachloroethane 

pentachloroethane 

hexachloroethane 

Species/sex Tumor site Statistically significant tumors 

no testing planned 

retesting recommended because initial results inconclusive 

rats/female 

rats/male 

mice/female 

mice/male 

mammary gland 

forestomach 

circulatory system 

subcutaneous tissue 

mammary gland 

endometrium 

lungs 

lungs 

retesting in progress 

mice/female 

mice/male 

mice 

liver 

liver 

adrenal glands 

testing in progress, no report available 

mice/female 

mice/male 

liver 

liver 

testing in progress, no report available 

mice/female 

mice/male 

liver 

liver 

adenocarcinomas 

squamous cell carcinomas 

hemangiocarcinomas 

fibromas 

adenocarcinomas 

stomal sarcomas 

adenomas 

adenomas 

hepatocellular carcinomas 

hepatocellular carcinomas 

pheochromocytomas 

hepatocellular carcinomas 

hepatocellular carcinomas 

hepatocellular carcinomas 

hepatocellular carcinomas 

The National Cancer Institute has concluded that under the conditions of the 

bioassay 1, Z-dichloroethane; 1,1, 2-trichloroethane; 1,1, Z, Z-tetrachloroethane; and 

hexachloroethane are carcinogenic in mice, inducing liver cancer in both sexes (1-

4). Additionally, results of the NCr bioassay of I,Z-dichloroethane indicate that 

this compound also causes cancer in male and female rats. In· mice 1,1,2-

trichloroethane was also· associated with increased adrenal pheochromocytoma, a 

tumor which gives rise to high blood pressure and hyperglycemia. Toxic kidney 

damage was observed in all groups of both mice and rats treated with 

hexachloroethane (4). 

Although the occurence of cancer in mice is highly significant, the results do not 

provide conclusive evidence that 1,I,Z-trichloroethane; 1,1,Z,Z-tetrachloroethane; 

or hexachloroethane cause cancer in rats. A statistically significant association 

between increased dosage and accelerated mortality was observed in rats treated 

with hexachloroethane. NCr has concluded that early mortality may have obscured 

a carcinogenic effect in these animals. 

5 

(95) 
( 96) 

The National Cancer Institute is currently conducting bioassays of 

pentachloroethane and 1,1,1,2-tetrachloroethane (14). They are also retesting 1,1-

dichloroethane and 1, 1, 1-trichloroethane because· the previous tests were 

inconclusive; low survival rates complicated the interpretation of the bioassay 

results. Monochloroethane has not yet been tested. 

Other Adverse Effects 

All of the chloroethane compounds are known to cause central nervous system 

(CNS) depression in laboratory animals. This is usually expressed as abnormal 

weakness, intoxication, restlessness, irregular respiration, muscle incoordination, 

and unconsiousness. Chloroethanes are generally irritating to the eyes and skin. 

Damage to the liver and/or kidney has been demonstrated in various animal species 

following exposure to these compounds (15). 

It has been reported that some of the chloroethanes and their metabolites are 

mutagenic in bacterial systems (3,16). Mutagenic activity, per se, should be 

considered a substantial liability. In addition, research suggests a correlation 

between mutagenicity in some bacterial strains and carcinogenicity in higher 

animals. Other adverse effects of the chloroethanes may vary from one compound 

to another. Table 5 summarizes some of the toxicological studies in animal 

systems. 

6 
Table 5. Some Adverse Effects of Chloroethanes Reported in Animal Studies (5,11-13,17-37). 

Chemicals 

monochloroethane 

1, 1 ~ichloroethane 

I,Z-dichloroethane 

1,1, I-trichloroethane 

1,I,Z-trichloroethane 

1, 1, I,Z-tetrachloroethane 

1,1, Z, Z-tetrachloroethane 

pentachloroethane 

hexachloroethane 

Species 

unspecified 

cat 

dog 

rat 

bacterium 

cat 

dog 

fruit fly 

guinea pig 

monkey 

rabbit 

rat 

cat 

dog 

guinea pig 

mouse 

monkey 

rat 

dog 

guinea pig 

rabbit 

rat 

bacterium 

dog 

guinea pig 

monkey 

mouse 

rabbit 

rat 

cat 

dog 

sheep 

cattle 

mou~ 

rat 

sheep 

Adverse Effect 

kidney damage; 

fatty changes in liver, kidney, and heart 

kidney damage 

liver injury 

liver injury; retarded fetal development 

mutagen 

retarded growth rate, fatty changes in liver; 

heart dilation; lung hyperemia 

corneal clouding; fatty changes in liver; 

liver enlargement; weight loss 

mutagen 

fatty changes in liver; liver enlargement; 

weight loss 

fatty changes in liver 

fatty changes in liver; hypotension; 

respiratory paralysis; EKG changes; anemia; 

bone marrow changes; liver dysfunction, 

hemorrhage and degeneration; kidney degeneration 

and dysfunction 

embryotoxin; pulmonary congestion; 

fatty changes in liver 

neuromuscular reflex changes 

sudden death; respiratory failure 

fatty changes in liver; lung irritation 

cardiac arrythmias; liver dysfunction; 

pulmonary congestion 

cardiac arrythmias; myocardial depression; 

respiratory failure; staggering gait; tachycardia; 

tremors 

cardiac failure; pulmonary congestion; 

pneumonitis; staggering gait; weakness; 

respiration; semiconsciousness; respiratory failure 

liver and kidney injury 

liver and kidney injury 

embryotoxin 

embryotoxin; liver dysfunction; mutagen 

mutagen 

ascites; diarrhea; jaundice; liver enlargement; 

intestinal hemorrhage 

convulsions; weight loss; death 

anorexia; diarrhea; blood cell fluctuation; 

weight loss 

staggering gait; breathing. difficulty; 

fatty degeneration of liver and kidney; death 

altered immune system; altered blood chemistry; 

liver and kidney degeneration; 

fatty degeneration of liver and kidney; 

corneal reflex changes; liver enlargement; 

paralysis; death 

blood cell changes; fatty degeneration of liver; 

liver dysfunction; death 

liver, kidney, and lung changes 

fatty degeneration of liver; kidney and lung injury 

liver dysfunction 

liver and kidney damage 

liver and kidney damage 

liver and kidney damage 

liver and kidney damage 

7 

( 97) 
(98) 

HUMAN TOXICITY 

Although chloroethanes have been associated with cancer in laboratory animals, 

NIOSH is unaware of any definitive evidence indicating that chloroethanes are 

carcinogenic in humans. However, the chloroethanes have long been known to be 

capable of producing harmful local and systemic effects. As summarized in Tables 

6 and 7, the chloroethanes may affect a variety of human organs or systems. The 

effects of chloroethane exposure vary from one compound to another, but, most are 

known to effect the central nervous system (CNS). In many instances, the clinical 

manifestations and laboratory findings associated with chloroethane toxicity are 

similar for the major routes of entry: inhalation, 'skin absorption, and ingestion. 

Liver and/or kidney injury, pulmonary irritation, and damage to the blood-forming 

system have been associated with inhalation of chloroethanes. Repeated or 

prolonged skin exposure can defat the skin and cause dermatitis. 

In addition to the toxic effects of chloroethanes and their metabolites, the 

oxidative decomposition of products produced in the presence of open flames, hot 

metals, or lighted cigarettes shOUld be taken into account. The chloroethane 

compounds may degrade to phosgene, hydrogen chloride and dichloroacetylene. 

Phosgene is considered to be dangerous to life in 30 to 60 minutes at lZ.5 ppm (37). 

* 

Table 6. Adverse Effects of Chloroethanes on Human Organs and Systems (5,11-13,39-41). 

~ Cl 

c:t 

iii 

..l 

..l ..l < ..l 

J c:t ~ < >< < 

..l < Cl ~ ~ c:t I-< 

< < ..l iii ~ Cl 0 ~ ..l U U P ..l III iii ~ Cl 0 .... ~ U >- iii 0 ..l Cl III c:t 0 I-< Iii ~ Cl ..l 0 0 0 ~ c:t III 

..l ..l < P ~ 0 0 0 g ~ 

0 g e z 0 ..l ..l ..l 

Z 0 ~ c:t ~ P 0 < < c:t 

P < 0 ~ I-< < U c:t ~ ~ iii 

~ ~ c:t ..l Z III Po. III P c:t I-< ~ 

iii < P iii < iii P iii iii Po. I-< 

CHEMICAL a II: U Po. c:t Cl ~ ~ Z 0 0 0 

monochloroethane • • • • • • • • 

1,I-dichloroethane • • • 

I,Z-dichloroethane • • • • • • • • • • 

1,1, I-trichloroethane • • • • • • • • 

1,I,Z,Z-tetrachIoroethane • • • • • • • • • 

hexachloroethane • • 

*adverse human health effects have not been reported to NIOSH for 1,I,Z-trichloroethane, 

1,1,I,Z-tetrachloroethane, and pentachIoro.ethane 

8 
Table 7. Specific Adverse Effect. of Cbloroethanes on Humans, by System (5,11-13,37-39). 

Chemical 

monochloroethaDe 

l,t-dichioroethane 

1,Z-dichloroethane 

IJ I. I-trichloroethane 

l,l,?-trichloroethane 

1, 1,1, Z-tetrachloroethane 

l,l,l,Z-tetrachnoroethane 

pentachloroethane 

hex.achloroethane 

System 

neurologic 

gastrointestinal 

respiratory 

cardiovascular 

dermatological 

other 

neUl'ologlc 

respiratot'}' 

dermalologk 

neurologic 

hepatic 

neurologic 

hepatic 

sastrointestinal 

cardiovascular 

hematologic 

dermatologic 

other 

neurologic 

hepatic 

gastrointestinal 

urologic 

respira.tory 

cardiovascular 

hematologic 

dermatologic 

other 

neurologic 

Adverse Effect 

central nervous system depression, headache, dizziness, incoordination, feeling 

inebriated, unconsciousness 

abdominal cramps 

respiratory tract irritation, relpiratory laiJUI'e 

cardiac arrhythmiae, cardiac arrest 

skin irritation, frostbite, allergic eczema 

eye irritation, death 

central nervous system depression 

respiratory tract :zritation 

skin burn 

headache, dizziness, Wlconsciousnec;s, vertigo, hand tremors, generalized weakness, sleepiness, nervousness, mental confusion 

liver function abnormalities, cellular damage, toxic chemical hepatitis, jaundice, 

liver enlarsement 

central nervous system deprl"'Ssion, headache, dizziness, incoord~tion. feeling 

inebriated, unconsciousness; impaired perceptual speed, manual dexterity and 

equilibrium; increased reaction time, lightheadeness, drowsiness, sleepiness, generalized weakness, ringing sound in ears, unsteady sait, burning and/or prickling 

sensation in hands and/or feet 

cellular damage, liver function abnormalities 

nausea, yomi ting, diarrhea 

drop in blood pressure (hypotension), decrease in heart rate (bradycardial, cardiac 

arrhythmias 

blood clotting changes 

dryness, cracking. scali ness, inflammation 

eye irritation, ratigue, death 

NIOSH is unaware of reports of adverse occupational exposure (ioce Table 5) 

NIOSH is unaware of reports of adverse occupational exposure (see Table 5) 

central nervous system depression. headache, feeling inebriated, unconsciousneSJ, 

drowsiness, unsteady gait, vertigo, hand tremors, numbness in limbs, prickling 

sensation of fingers and tows, pain in sole of feet, loss 01 knee jerk, paralysis 

of some nluscleb uf Ult: hGnds and ft-et, inflammation of the peripheral nerves 

alight paralysis of the ~oft pali't.te, loss of the gag reUes, irritability, mental confusion, delirium, convulsions, stupor, coma 

liver function abnormalities, massive cell damage toxic chemical hepatitis, jaundice, liver enlargement, sensation of pressure in the liver area 

abdominal pain, nausea, vomitins, unpleasant taste in the mouth, loss of appetite 

(anorexia), vomiting of blood (hematemesis), increased flatulence , diarrhea, constipation, pale stools 

kidney damage, presence of bile pigments, a.lbumen, and casts in the urine 

excessive fluid in the Junga (pulmonary edema), respiratory paralysis 

fatty degeneration of the heart muscle (in lab animalr) 

anemia, increase in white blood cells, (and blood platelets) 

dryn ss, cracking, scalinesst inflamation, purpuric rash 

insomnia, general malaise, fatigue, excessive sweating, weight loss 

NIOSH is unaware of reports of adverse occupational exposure (see Table 5) 

inability to close eyeJid 

eye irritation, tearing of eyes, inflamation of delicate membrane lining the eye, 

vjsual intolerance to light, (photophobia) 

9 

(99) 
(100) 

NIOSH Recommendation 

Animal studies are valuable in helping identify human carcinogens. Substances that 

cause cancer in experimental animals must be considered a potential cancer risk in 

man. Although safe levels of exposure to carcinogens have not yet been 

demonstrated, decreasing exposure to carcinogens does reduce their probability of 

initiating cancer development. 

As an interim and prudent measure while the carcinogenicity of chloroethanes is 

being further evaluated, NIOSH recommends that occupational exposure to I,Zdichloroethane; 1,I,Z-trichloroethane, 1,I,Z,Z-tetrachloroethane, and hexachloroethane be minimized. Exposures should be limited to as f~w employees as 

possible, while minimizing workplace exposure levels with engineering and work 

practice controls. Additionally, monochloroethane; 1,I-dichloroethane; 1,1,1-

trichloroethane; 1, 1, 1,Z-tetrachloroethane; and pentachloroethane should be 

treated in the workplace with caution. 

Ac~ing Director 

10 
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11 

(101) 
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/ 

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Pharmacoloica et Toxicologica Z9(5-6): 471-480, 1971. 

34. Vozovaya, M.A.: The effect of dichloroethane on the sexual cycle and 

embryogenesis of experimental animals. Akusk. Ginekol. (Moscow) Z:57-59, 

1977. 

35. Vozovaya, M.A.: The effect of small concentrations of benzene and 

dichloroethane separately and combined on the reproductive function of 

animals, Gig. Sanit. (Moscow) 6:100-10Z, 1976. 

36. Vozovaya, M.A.: The effect of small concentrations of benzene, 

dichloroethane alone and combined, on the reproductive function of animals 

and the development of the progeny. Gig. Tr. Prof. Zabol. (Moscow) 7:Z0-Z3, 

1975. 

37. Patty, F.A., Fassett, D.W., Irish, D.D., Editors: Industrial Hygiene and 

Toxicology. Second Edition. New York, Interscience Publishers, 1963. 

38. National Institute for Occupational Safety and Health. Occupational Diseases: 

A Guide to Their Recognition. U.S. Department of Health, Education, and 

Welfare, Public Health Service, Center for Disease Control, National Institute 

for Occupational Safety and Health, DHEW (NIOSH) Publication No. 77-181, 

June, 1977. 

39. Gosselin, R.E., Hodge, H.C., Smith, R.P., Gleason, M.N., Editors: Clinical 

Toxicology of Commercial Products: Acute Poisoning. Fourth Edition. 

Baltimor~, The Williams and Wilkins Co., 1976. 

40. U.S. International Trade Commission. Synthetic Organic Chemicals, United 

Production and Sales, 1976. U.S. International Trade Commission, USITC 

Publication No. 833, 1976. 

14 
SUGGESTED GUIDELINES FOR CONTROLLING EMPLOYEE EXPOSURE TO 

CHLOROETHANES 

NIOSH recommends that it would be prudent to handle 1,2-dichloroethane (ethylene 

dichloride); 1,1, 2-trichloroethane; 1,1,2, 2-tetrachloroethane; and hexachloroethane 

in the workplace as if they were human carcinogens. Exposure to these 

chloroethanes should be limited to as few employees as possible, and workplace 

exposure levels should be minimized. The areas in which they are used should be 

restricted to only those employees essential to the process or operation and these 

employees should be adequately protected. 

Additionally, NIOSH recommends that the other five chloroethane compounds: 

monochloroethane (ethyl chloride); 1,1-dichloroethane; 1,1,1-trichloroethane (methyl 

chloroform); 1,1,1,2-trichloroethane; and pentachloroethane should be treated in the 

workplace with caution because of their relation to the four chloroethanes shown to 

be carcinogenic in laboratory animals. These five chloroethanes should be closely 

monitored for carcinogenic effects in humans. 

EXPOSURE MONITORING 

Detailed sampling and analytic methods for most of the chloroethane exposure 

measurements are described in the NIOSH Manual of Analytical Methods, Second 

Edition (1). These are: 

Chemical 

monochloroethane 

1,1-dichloroethane 

1,2-dichloroethane 

1,1, i-trichloroethane 

1, 1, 2-trichloroethane 

1,1,1,2-tetrachloroethane 

1,1,2,2-tetrachloroethane 

pentachloroethane 

hexachloroethane 

NIOSH Method 

not available 

S123 

P&CAM 127 and S122 

P&CAM 127 and S328 

P&CAM 127 and S134 

not available 

S124 

not available 

S10l 

Initial and routine employee exposure surveys should be made by competent 

industrial hygiene and engineering personnel. These surveys are necessary to 

determine the extent of employee exposure and to ensure that controls are 

effective. 

15 

(105) 
(106) 

The NIOSH Occupational Exposure Sampling Strategy Manual (2) may be helpful in 

developing efficient programs to monitor employee exposures to chloroethanes. 

The manual discusses determination of the need for exposure measurements, 

selection of appropriate employees for exposure evaluation and selection of 

sampling times. 

Employee exposure measurements should primarily consist of 8-hour TWA (timeweighted average) exposure estimates calculated from personal or breathing zone 

samples (air that would most nearly represent that inhaled by the employees). In 

addition, short term samples should be taken during periods of maximum expected 

exposure by using all available knowledge regarding the area, employee work 

procedures, and process. Area and source measurements may be useful to 

determine problem areas, processes, and operations. 

CONTROLLING EMPLOYEE EXPOSURE 

There are four basic methods of limiting employee exposure to chloroethanes. 

None of these is a simple industrial hygiene or management decision and careful 

planning and thought should be used prior to implementation. 

o Product Substitution 

The substitution of an alternative material with a lower potential health risk is one 

method. However, extreme care must be used when selecting possible substitutes. 

Alternatives to chloroethanes should be fully evaluated with regard to possible 

human effects. Unless the toxic effects of the alternative have been thoroughly 

evaluated a seemingly safe replacement, possibly only after years of use, may be 

found to induce serious health effects. 

o Contaminant Controls 

The most effective control of chloroethanes, where feasible, is at the source of 

contamination by enclosure of the operation and/or local exhaust ventilation. 

Guidelines for selected processes and operations can be found in the NIOSH 

Recommended Industrial Ventilation Guidelines (3). 

If feasible, the process or operation should be enclosed with a slight vacuum so that 

any leakage will result in the flow of external air into the enclosure. 

The next most effective means of control would be a well designed local exhaust 

ventilation system that physically encloses the process as much as possible, with 

sufficient capture velocity to keep the contaminant from entering the work 

atmosphere. 

16 
To ensure that ventilation equipment is working properly, effectiveness (e.g., air 

velocity, static pressure, or air volume) should be checked at least every three 

months. System effectiveness should be checked soon after any change in 

production, process, or control which might result in significant increases in 

airborne exposure to chloroethanes. 

o Employee Isolation 

A third alternative is the isolation of employees. It frequently involves the use of 

automated equipment operated by personnel observing from a closed control booth 

or room. The control room is maintained at a greater air pressure than that 

surrounding the process equipment so that air flow is out of, rather than into, the 

room. This type of control will not protect employees who must do process checks, 

adjustments, maintenance, and related operations. 

o Personal Protective Equipment 

The least preferred method is the use of personal protective equipment. This 

equipment, which may include respirators, goggles, gloves, etc., should not be used 

as the only means to, prevent or minimize exposure during routine operations. 

Exposure to chloroethanes should not be controlled with the use of respirators 

except: 

During the time period necessary to install or implement engineering or work 

practice controls; or 

In work situations in which engineering and work practice controls are 

technically not feasible; or 

For maintence; or 

For operations which require entry into tanks or closed vessels; or 

In emergencies. 

Only respirators approved by the National Institute for Occupational Safety and 

Health (NIOSH) under the provisions of Federal regulations 30 CFR 11 should be 

used. Refer to Cumulative Supplement June 1977, NIOSH Certified Equipment (4) 

for a listing of NIOSH-approved respirators. Note that the use of faceseal 

coverlets or socks with respirators voids NIOSH approvals. 

Quantitative faceseal fit test equipment (such as sodium chloride, dioctyl 

phthalate, or equivalent) should be used. Refer to NIOSH's A Guide to Industrial 

Respiratory Protection (5) for guidelines on appropriate respiratory protection 

programs. 

17 

( 107) 
(108) 

In addition, proper maintenance procedures, good housekeeping in the work area, 

and employee education are all vital aspects of a good control program. Employees 

should be informed as to the nature of the hazard, its control, and appropriate 

personal hygiene procedures. 

REFERENCES FOR SUGGESTED GUIDELINES 

1) NIOSH Manual of Analytical Methods, 2nd Edition, Vol. 1: GPO :#017-033-

00267-3, $8.75: Vol. 2: GPO :#017-033-00260-6, $9.75; Vol. 3: GPO :#017-033-

0247-9, $9.00. 

2) NIOSH Occupational Exposure Sampling StrategyManual, GPO :#017-033-

00247-9, $2.75. 

3) NIOSH Recommended Industrial Ventilation Guidelines, GPO #017-033-00136-

7, $3.90. 

4) NIOSH Cummulative Supplement June 1977, NIOSH Certified Equipment, 

NIOSH :#77-195, no charge. 

5) A Guide to Industrial Respiratory Protection, GPO :#017-033-00153-7, $2.30. 

GPO publications must be ordered from: Superintendent of Documents 

U.S. Government Printing Office 

Washington, D.C. 20402 

Reference :#4 can be ordered from: Publications Dissemination, DTS 

NIOSH 

4676 Columbia Parkway 

Cincinnati, Ohio 45226 

18 
IDENTIFIERS AND SYNONYMS FOR CHLOROETHANE 

Chemical Abstracts Service Registry Number 75-00-3 

NIOSH RTECS Number KH75Z50 

Chemi~al Formula CZH5CI 

Aethylis 

Aethylis Chloridum 

Anodynon 

Chelen 

Chlorene 

Chlorethyl 

Chloridum 

Chloroethane 

Chloryl 

Chloryl Anesthetic 

Cloretilo 

Dubio fix 

Ethane, ChloroEther Chloratus 

Ether Hydrochloric 

Ether Muriatic 

Ethyl Chloride 

Hydrochloric Ether 

Kelene 

Monochloroethane 

Muriatic Ether 

Narcotile 

IDENTIFIERS AND SYNONYMS FOR 1,I-DICHLOROETHANE 

Chemical Abstracts Service Registry Number 75-34-3 

NIOSH RTECS Number KI01750 

Chemical Formula C ZH4CIZ 

Chlorinated Hydrochloric Ether 

1,I-Dichlorethane 

1,I-Dichloroethane 

Ethane, 1,I-DichloroEthylidene Chloride 

Ethylidene Dichloride 

NCI-C04535 

IDENTIFIERS AND SYNONYMS FOR I,Z-DICHLOROETHANE 

Chemical Abstracts Service Registry Number 107-06-Z 

NIOSH RTECS Number KI05Z50 

Chemical Formula C ZH4CIZ 

1, Z-Bichloroethane 

Brocide 

Borer Sol 

Destruxol Borer-Sol 

Di-Chlor-Mulsion 

Dichloremulsion 

1,2-Dichlorethane 

1, Z-Dichloroethane 

a,S-Dichloroethane 

19 

sym-Dichloroethane 

Dutch Liquid 

EDC 

ENT 1,656 

Ethane, I,Z-DichloroEthane Dichloride 

Ethylene Chloride 

Ethylene Dichloride 

Glycol Dichloride 

( 109) 
(11 0) 

IDENTIFIERS AND SYNONYMS FOR I,1,I-TRICHLOROETHANE 

Chemical Abstracts Service Registry Number 71-55-6 

NIOSH RTECS Number KJZ9750 

Chemical Formula CZH3Cl3 

Aerothene IT 

Chloroethene NU 

Chlorotene 

Chlorothane NU 

Chlorothene 

Chlorothene NU 

Chlorothene VG 

Chlorten 

Ethane, 1,1,1-TrichloroInhibisol 

Methyl Chloroform 

Methyltrichloromethane 

NCI-C046Z6 

Alpha-T 

Trichloroethane 

1,1, I-Trichloroethane 

a-Trichloroethane 

IDENTIFIERS AND SYNONYMS FOR I,I,Z-TRICHLOROETHANE 

Chemical Abstracts Service Registry Number 79-00-5 

NIOSH RTECS Number KJ3I500 

Chemical Formula CZH3Cl3 

Ethan Trichloride 

Ethane, 1,1, Z-TrichloroNCI-C04579 

Beta-T 

1,1, Z-Trichlorethane 

I,I,Z-Trichloroethane 

a -Trichloroethane 

Vmyl Trichloride 

Vmyltrichloride 

IDENTIFIERS AND SYNONYMS FOR I,I,I,Z-TETRACHLOROETHANE 

Chemical Abstracts Service Registry Number 63Q-ZO-6 

NIOSH RTECS Number KI8450000 

Chemical Formula CZHZCl4 

Ethane, I,I,I,Z-tetrachloroNCI-C5Z459 

I,I,I,Z-Tetrachloroethane 

20 
IDENTIFIERS AND SYNONYMS FOR 1,1,2.,2.-TETRACHLOROETHANE 

Chemical Abstracts Service Registry Number 79-34-5 

NIOSH RTECS Number KI85750 

Chemical Formula CZH2.CI4 

Acetylene Tetrachloride 

Bonoform 

Cellon 

1,1-Dichloro-2., 2.-Dichloroethane 

Ethane, 1,1,2.,2.-tetrachloroNCI-C03554 

Tetrachloroethane 

1,1,2.,2.-Tetrachloroethane 

sym-Tetrachloroethane 

TCE 

IDENTIFIERS AND SYNONYMS FOR PENTACHLOROETHANE 

Chemical Abstracts Service Registry Number 76-01-7 

NIOSH RTECS Number KI63000 

Chemical Formula CZHCl5 

Ethane Pentachloride 

Ethane, PentachloroNCI-C53894 

Pentachloroethane 

Pentalin 

IDENTIFIERS AND SYNONYMS FOR HEXACHLOROETHANE 

Chemical Abstracts Service Registry Number 61-72.-1 

NIOSH RTECS Number KI402.50 

Chemical Formula C2.CI6 

Avlothane 

Carbon Hexachloride 

Distokal 

Distopan 

Distopin 

Egitol 

Ethane Hexachloride 

Ethane, HexachloroFalkitol 

21 

Fasciolin 

Hexachlorethane 

1, 1, 1, 2., 2., 2.-Hexachloroethane 

Hexachloroethylene 

Mottenhexe 

NCI-C04604 

Perchloroethane 

Phenohep 

(111 ) 

JOINT 

NIDSH / 1J5HR 

September 21,1978 

VINYL HALIDES 

CARCINOGENICITY 

Vinyl Bromide 

Vinyl Chloride 

H, /CI 

Vinylidene Chloride /C = C, 

H CI 

U .. S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE 

Public H •• lth Servlc. 

C.nt.r for Di ••••• Control 

N.tlon."n.tlhlfe tor Occup.tlonal S., • ., .nd Health 

u. S. DEPARTMENT OF LABOR 

Occupllfion.' Safety IItId Health Administration 

( 113) 
(114 ) 

This Current Intelligence Bulletin is a joint effort of the National Institute for 

Occupational Safety and Health (NIOSH) and the Occupational Safety and Health 

Administration (OSHA) and is part of the NIOSR Current Intelligence System. The 

purpose of the Current Intelligence System is to promptly review, evaluate, and 

supplement new information received by NIOSH on occupational hazards that are 

either unrecognized or are greater than generally known. 

As warranted by this evaluation, the information is capsulized and disseminated to 

NIOSH staff, other government agencies, and the occupational health community, 

including labor, induStry, academia, and public interest groups. With respect to 

currently known hazard information this system also serves to advise appropriate 

members of the above groups of recently acquired specific knowledge which may 

have an impact on their programs or perception of the hazard. Above all, the 

Current Intelligence System is designed to protect the health of American workers 

and to allow them to work in the safest possible environment. 

FURTHER INFORMATION: 

Director 

Division of Criteria Documentation 

and Standards Development 

National Institute for .Occupational 

Safety and Health 

5600 Fishers Lane 

Rockville, Maryland ZOSS7 

(301) 443-3680 

Director 

Technical Support 

Occupational Safety and 

Health Administration 

ZOO Constitution Avenue, N.W. 

Washington, D.C. ZOZ10 

(ZOZ) 5Z3-8061 

SYNONYMS 

Identifiers and Synonyms are located on page 11. 

DHEW (NIOSH) 'Publication No. 79-102 
JOINT NIOSH/OSHA 

CURRENT INTELLIGENCE BULLETIN: VINYL HALIDES- CARCINOGENICITY 

Vinyl Bromide, Vinyl Chloride, and Vinylidene Chloride 

September 21, 1978 

The National btstitute for Occupational Safety and Health (NIOSH) and the Occupational Safety and Health Administration (OSHA) jOintly recommend that vinyl 

bromide and vinylidene chloride be considered in the workplace as potential 

carcinogens to humans and controlled with the same degree of prudence as vinyl 

chloride, another vinyl halide currently regulated as a carcinogen by OSHA. This 

recommendation is based on the results of recent studies indicating that exposure 

to vinyl bromide and to vinylidene chloride causes angiosarcoma of the liver and 

other cancers in laboratory animals. Safe levels of exposure to carcinogens have 

not been demonstrated, but lowered exposure to carcinogens may in general 

decrease the probability of cancer development. 

Vinyl chloride is lmown to cause angiosarcoma of the liver and cancers of other 

sites in laboratory animals and in hUmans. At this time, adequate carcinogenicity 

studies of vinyl bromide and vinyUdene chloride have been conducted only in 

laboratory animals. In view of the present state of lmowledge in carcinogenesis, 

substances that cause cancer in laboratory animals are considered a potential 

cancer risk to humans. 

Vinyl chloride is the only vinyl halide for which an OSHA exposure standard 

currently exists. In light of the recent laboratory animal studies demonstrating 

carcinogenicity of vinyl bromide and vinyZidene chloride, NIOSH and OSHA have 

Jointly prepared this Current Intelligence Bulletin. Its purpose is to advise the 

occupational health community of the pertinent data and implicatiOns for exposed 

workers. NIOSH and OSHA request that producers, distributors, professional 

associations, and unions transmit the information in this Bulletin to their 

customers, employees, associates, and members. 

LABORATORY STUDms 

Carcinogenici ty 

Laboratory studies have demonstrated that exposure by inhalation to vinyl chloride 

(l,Z), vinyl bromide (3), and vinylidene chloride (1,4) all caused angiosarcoma of 

(115) 
( 116) 

the liver and other cancers in animals. Angiosarcoma of the liver was induced in 

rats exposed to Z5 ppm vinyl chloride, in rats exposed to 50 ppm vinyl bromide, and 

in mice exposed to 55 ppm vinylidene chloride. 

At lower levels, exposure to vinyl chloride (1 ppm) has induced mammary 

carcinomas (5), exposure to vinyl bromide (10 ppm) has induced lymph node 

angiosarcoma (3), and exposure to vinylidene chloride (Z5 ppm) has induced 

adenocarcinomas of the kidney (4). Table 1 presents a summary of tumors in 

animals exposed to these vinyl halides. 

Table 1. Some Tumors Reported in Vinyl Halide Animal Studies. (1,3,4). 

Chemical Species Site Tumor 

vinyl rat liver angiosarcoma 

bromide zymbal gland squamous cell carcinoma 

lung metastatic angiosarcoma, 

bronchioalveolar carcinoma, 

bronchioalveolar adenoma 

breast adenocarcinoma 

mesenteric lymph 

node angiosarcoma 

lymphatic lymphosarcoma 

vinyl rat mammary gland carcinoma 

chloride skin squamous cell carcinoma 

liver angiosarcoma 

lung adenocarcinoma, angiosarcoma 

zymbal gland carcinoma 

kidney nephroblastoma 

mouse liver angiosarcoma 

mammary gland anaplastic and squamous 

metaplasia 

lung bronchioalveolar adenoma 

liver hepatic cell carcinoma 

kidney renal adenoma 

skin keratoacanthoma 

rabbit skin acanthoma 

lung adenocarcinoma 

hamster liver angiosarcoma 

skin trichoepithelioma, basalioma 

lymphatic lymphoma 

vinylidene mouse liver angiosarcoma 

chloride lung bronchioalveolar adenoma 

kidney adenocarcinoma 

rat mesenteric lymph 

node angiosarcoma 

breast mammary tumor 

zymbal gland carcinoma 
Mutagenicity 

Several investigators have reported that vinyl chloride is mutagenic in Salmonella 

typhimurium and pombe (6-11) and in Escherichia coli (lZ-14). Vinyl chloride also 

has been shown to be mutagenic in the yeast mutation assay (11), in the Drosophila 

recessive lethal test (15,16), and in the host-mediated assay (11). Studies also have 

shown vinyl chloride to be mutagenic in Tradescantia (17). Three reports bearing 

on the mutagenicity of vinyl bromide have been noted to date. Bartsch et al., (18) 

and Simmons (19) have independently reported that vinyl bromide induced 

mutations in the bacterium, Salmonella typhimurium. In addition, Sparrow (17) has 

demonstrated a significant increase in mutants in Tradescantia exposed to vinyl 

bromide vapors. Vinylidene chloride has been shown to induce mutations in 

Salmonella typhimurium (10, ZO-ZZ), in Escherichia coli (lZ), and in Tradescantia 

(17). -

Other Adverse Effects 

Other adverse health effects in animals attributed to exposure to vinyl halides 

include central nervous system (CNS) effects, cardiovascular effects, respiratory 

effects, skin effects, skeletal effects, and liver or spleen abnormalities (1). 

HUMAN STUDmS 

Carcinogenicity 

Studies of workers exposed to vinyl chloride have demonstrated an excessive risk of 

death from cancer of the lung, brain, lymphatic system, and angiosarcoma of the 

liver (1, Z3). Cancers of the same sites were previously induced in animals 

following exposure to vinyl chloride (2). 

Liver angiosarcoma in humans is a very rare malignant tumor of the blood vessels. 

Though no clinical signs or symptoms, or laboratory examinations have been found 

to be specific for the early diagnosis of this cancer, affected individuals may 

complain of fatigue, abdominal pain, weight loss, anorexia, nausea, vomiting, 

melena, indigestion, jaundice, hematemesis, or diarrhea. Other manifestations may 

include liver enlargement and liver function abnormalities. In adults, untreated 

angiosarcoma of the liver usually is fatal within 8 months. Even with treatment, 

death usually occurs within 16 months. 

To date there have been no reported cases of cancer in humans associated with 

exposure to vinyl bromide or vinylidene chloride. However, vinyl bromide has been 

in commercial production in the U.S. only since 1971. Due to the long latent period 

characteristic of occupationally-induced cancers, typically 15-40' years, no unusual 

risk of cancer among exposed workers would be expected to be be detected at this 

time. Vinylidene chloride has been in commercial production and use since the 

early 1940's. The only study (Z4) reported to date showed no excessive cancer risk 

among workers occupationally exposed to vinylidene chloride, but methodologic 

limitations of this study do not permit an adequate .evaluation of the carcinogenic 

risk of vinylidene chloride to humans. 

3 

( 117} 
( 118) 

Mutagenicity and Reproductive Effects 

Cytogenetic studies have demonstrated a significant increase in the frequency of 

chromosomal aberrations in the lymphocytes of workers exposed to vinyl chloride 

(Z5-31). Further evidence for the mutagenicity of vinyl chloride has been provided 

by investigations showing an increase in fetal wastage among wives of male 

workers following occupational .exposure to vinyl chloride (3Z,33). No studies 

addressing mutagenic or reproductive hazards among vinyl bromide or vinylidene 

chloride exposed populations have been reported. 

Other Adv:erse Effects 

Numerous other adverse health effects have been observed in humans exposed to 

vinyl chloride, as detailed in Table Z. Reports of effects on workers exposed to 

vinylidene chloride in combination with other vinyl compounds include liver 

function abnormalities, headache, vision problems, dizziness~ fatigue, weakness, 

and neurological sensory disturbances. No similar reports for vinyl bromide 

exposure were found (1). 

Table Z. Other Adverse Effects of Vinyl Chloride on Humans (1). 

System 

neurologic 

gastroin testinal 

cardiovascular 

hepatic 

respiratory 

hematologic 

dermatologic 

musculoskeletal 

other 

Adverse Effect 

dizziness, lightheadedness, dulling vision and 

hearL'"lg, drowsiness, headache, loss of memory, euphoria, 

nervousness, numbness or tingling in fingers 

or toes 

nausea, loss of appetite, abdominal distress, 

varices of esophagus or stomach, black stools, 

bloody vomitus 

increased blood pressure, Raynaud's Syndrome 

liver enlargement, liver function abnormalities, 

increased sulphbromophthalein retention, liver 

damage, serum enzyme abnormalities 

coughing and sneezing, bronchial rales, emphyzema, 

pulmonary fibrosis, decreased respiratory function, 

lung function disturbances 

anemia, reticulocytosis, leukopenia, thrombocytopenia, splenomegaly 

contact dermatitis, scleroderma-like skin changes 

calf and joint pain, acroosteolysis 

increased perspiration, cold sensation in fingers 

and hands, fatigue, weight loss, weakness, impotency 

4 
OTHER VINYL HALIDES 

There is a lack of information regarding the carcinogenicity of vinyl fluoride and 

vinylidene fluoride. However, both have been shown to be mutagenic in bacterial 

systems (1). This evidence of mutagenicity is cause for concern. 

USES, EXPOSURES, AND EXPOSURE STANDARDS 

The vinyl halides are ~f widespread industrial use, especially in the plastics 

industry. They are easily polymerized and copolymerized with various materials 

such as acrylonitrile, vinyl acetate, and styrene, to form pliable, lightweight 

plastics or thermoplastic resins. Table 3 summarizes the major industries in which 

workers are potentially exposed to vinyl halides, according to the NIOSH National 

Occupational Hazards Survey (NOHS). 

Table 3. Some Industries Which Use Vinyl Halides Based on NIOSH NOHS Data (34). 

Chemical* 

vinyl chloride 

vinyl bromide 

vinylidene chloride 

vinylidene fluoride 

Industries 

chemicals and allied products 

electrical equipment and supplies 

furniture and fixtures 

chemicals and allied products 

rubber and plastics products 

leather and leather products 

fabricated metal products 

wholesale trade 

chemicals and allied products 

special trade contractors 

fabricated ~etal products 

general building contractors 

wholesale trade 

leather and leather products 

chemicals and allied products 

machinery, except electrical 

electrical equipment and supplies 

food and kindred products 

medical and other health services 

*No NOHS information available for vinyl fluoride 

From 1972-1974, NIOSH conducted the NIOSH National Occupational Hazards 

Survey (NOHS), on a sample of about 900,000 employees at 4,636 facilities, in order 

to determine the potential for worker exposure to chemicals and physical agents. 

5 

ellg) 
( 120) 

NOHS algorithms used Bureau of the Census 1970 population counts to permit 

extrapolation from the sample to the United States worker population of 1970. 

Table 4 presents a summary of NOHS estimates of worker exposure to v~nyl halides 

(34). 

The exposure estimates include two categories. Definite estimates are 

extrapolated from actual observations of the use of the specific chemical or the 

use of a trade name product known to contain the chemical. Probable estimates 

include additional extrapolations from observations of trade name products 

suspected of containing the chemical because of generic formulations. 

Table 4. Vinyl Halide Exposures (34). 

Estimated Number of Workers Potentially Exposed 

Chemical 

vinyl chloride 

vinyl bromide 

viny lidene chloride 

viny lidene fluoride 

viny I fluoride 

Definite Probable 

Z7,OOO 

360 

6,500 

1,900 

NOT AVAILABLE 

Z,ZOO,OOO 

Z6,000 

58,000 

3Z,000 

NOT AVAILABLE 

Summaries of the current Department of Labor - Occupation,al Safety and Health 

Administration (OSHA) exposure standards and NIOSH recommended exposure 

standards for the vinyl halide compounds are given in Table 5. 

Table 5. Vinyl Halide Exposure Standards (1,35). 

Chemical 

vinyl chloride 

vinyl bromide 

viny lidene chloride 

viny lidene fluoride 

vinyl fluoride 

OSHA 

Exposure 

Standard 

(ppm) 

1 

none 

none 

none 

none 

6 

1978 NIOSH 

Recommended 

Exposure 

Standard 

(ppm) 

1 

1 

1 

1 

1 
Recommendations 

Vinyl chloride is regulated by OSHA as a demonstrated carcinogen in humans with 

an occupational exposure limit of 1 ppm. Recent evidence for vinyl bromide and 

vinylidene chloride demonstrates a pattern of tumor induction in animals similar to 

that of vinyl chloride, including angiosarcomas at low exposure levels • . Safe levels 

of exposure to carcinogens have not been demonstrated, but decreasing exposure 

may in general reduce the probability of cancer development. Therefore, as a 

prudent measure NlOSH and OSHA recommend that occupational exposure to vinyl 

bromide and vinylidene chloride be reduced to the lowest possible levels. Exposures 

should be limited to as few employees as possible, and workplace expc;>sure levels 

should be reduced with engineering and work practice controls. 

Detailed NIOSH recommendations for the control of exposure to these substances 

in the workplace are contained in the Vinyl Halides Criteria Document (1). 

7 

ch I Lane, M.D. 

ing Director 

National Institute for Occupational 

Safety and Health 

( 121) 
( 122) 

REFERENCES 

1. U.S. Department of Health, Education and Welfare, Public Health Service, 

Center for Disease Control, National Institute for Occupational Safety and 

Health. Criteria for ~ Recommended Standard .... Occupational Exposure to 

Vinyl Halides. (To be published late 1978 - Transmitted to OSHA September 

lZ, 1978). . 

Z. Maltoni, C: Predictive Value of Carcinogenesis Bioassays. N.Y. Acad. Sci. 

Z71:431-447 (1976). 

3. Huntingdon Research Center, HRC Project 7511-Z53. 18-Month Sacrifice 

Pathology Report, (Vinyl Bromide). New York. (June Z6, 1978). 

4. Maltoni, C: Recent Findings on the Carcinogenicity of Chlorinated Ole fins. 

Env. Health Perspect. Zl:1-5 (1977b). 

5. Maltoni, C: Vinyl Chloride Carcinogenicity: An Experimental Model for 

Carcinogenesis Studies. In: Origins of Human Cancer, H.H. Hiatt, J.D. 

Watson, and J.A. Winston, eds., CoJd Spring Harbor, 1:119-146 (1977a). 

6. Bartsch, H., C. Malaveille, R. Montesano: Human, Rat and Mouse LiverMediated Mutagenicity of Vinyl Chloride in S. Typhimurium Strains. Int. J. 

Cancer 1i:4Z9-437 (1975). 

7. Rannug, U., A. Johansson, C. Ramel, and C.A. Wachtmeister: The 

Mutagenicity of Vinyl Chloride After Metabolic Activation. Ambio. ~:194-197 

(1974). 

8. Garro, A.J., J.B. Guttenpaln, and P. Milvy: Vinyl Chloride Dependent 

Mutagenesis: Effects of Liver Extracts and Free Radicals. Mutat. Res. 38 

(Z):81-88 (1976). 

9. Andrews, A.W., E.S. Zawistowski, and C.R. Valentine: A Comparison of the 

Mutagenic Properties of Vinyl Chloride and Methyl Chloride. Mutat. Res. 

40:Z73 (1976). 

10. McCann, J., E. Choi, E. Yamasake, and B.N. Ames: Detection of Carcinogens 

as Mutagens in the Salmonella/Microsome Test: Assay of 300 Chemicals. 

Proc. Nat. Acad. Sci. 7Z (lZ):5135-5139 (1975). 

11. Loprieno, N., R. Barale, and S. Baroncelli: Evaluation of the Genetic Effects 

Induced by Vinyl Chloride Monomer (VCM) Under Mammalian Metabolic 

Activation: Studies In Vitro and In Vivo, Mutat. Res. 40:85-95 (1976). 

8 
lZ. Greim H., G. Bonse, Z. Radwan, D. Reichert, and D. Henschler: Mutagenicity 

In Vitro and Potential Carcinogenicity of Chlorinated Ethylenes as a Function 

of Metabolic Oxirane Formation. Biochem. Pharmacol. Z4:Z013-Z017 (1975). 

13. Henschler D: Metabolism and Mutagenicity of Halogenated Ole fins-A 

Comparison of Structure and Activity. Unpublished Report Submitted to 

National Institute for Occupational Safety and Health by Henschler, D., 

University of Wurzburg, Institute for Toxicology and Pharmacology, Wurzburg, 

West Germany, 19 pp. (April 1977). 

14. Henschler D., G. Bonse, and H. Greim: Carcinogenic Potential of Chlorinated 

Ethylenes-··Tentative Molecular Rules. INSERM 5Z:171-175 (1976). 

15. Bartsch H., and R. Montesano: Mutagenic and Carcinogenic Effects of Vinyl 

Chloride. Mutat. Res. 3Z:93-U3 (1975). 

16. Magnusson J., and C. Ramel: Mutagenic Effects of Vinyl Chloride in 

Drosophila Melanogaster. Mutat. Res. 38:115 (1976). 

17. Personal Communication dated May 6, 1976 from Mr. Arnold H. Sparrow, 

Brookhaven National Laboratory, to Dr. Peter Infante National Institute for 

Occupational Safety and Health (NIOSH). 

18. Bartsch, H., C. Malaveille, A. Barbin, G. Planche, and R. Montesano: 

Alkylating and Mutagenic Metabolites of Halogenated Olefins Produced by 

Human and Animal Tissues. Proc. Amer. Assoc. Cancer Res. 17 March (1976). 

19. Correspondence, May ZI, 1976, Ethyl Corporation to National Institute for 

Occupational Safety and Health (NIOSH). 

ZOo Bartsch, H., C. Malaveille, R. Montesano, and L. Tomatis: Tissue Mediated 

Mutagenicity of Vinylidene Chloride and Z-Chlorobutadiene in Salmonella 

Typhimurium. Nature ill:641-643 (1975). 

ZI. Baden, J., R. Whurton, B. Hitt, M. Brinkenhoff, V. Simmons, and R. Mazze: 

Mutagenicity of Volatile Anesthetics. Fed. Proc. 35:410 (1976). 

ZZ. Barsch, H., C. Malaveille, and R. Montesano: The Predictive Value of TissueMediated Mutagenicity Assays to Assess the Carcinogenic Risk of Chemicals 

In: Screening Tests in Chemical Carcinogenesis. IARC Scientific Publications 

No. lZ., eds., Montesano, R., H. Barsch, and L. Tomatis, Lyon, France, World 

Health Organization, International Agency for Research on Cancer 467-491 

(1976). . 

Z3. Reinl, W., H. Weber, E. Greiser: Epidemiologische Studies Uber Die 

Sterblichkeit Vinylchlorid(VC)-Exponierter Arbeiter in der Bundesrepublik. 

Deutschland Medichem. (September 1977). 

9 

( 123) 
(124) 

Z4. Ott, M.G., W.A. Fishbeck, J.C. Townsend, E.J. Schneider: A Health Study of 

Employees Exposed to Vinylidene Chloride. J. Occup. Med.1!:735-738 (1976). 

25. Leonard A., G. Decat, E.D. Leonard, M.J. Lefevre, L.J. Decuyper, C. Nicaise: 

Cytogenetic Investigations on Lymphocytes from Workers Exposed to Vinyl 

Chloride. J. Toxicol. Environ. Health. ~:1135-1141 (1977). 

26. Heath, C.W. Jr., C.R. Dumont, J. Gamble, R.J. Waxweiler: Chromosomal 

Damage in Men Occupationally Exposed to Vinyl Chloride Monomer and Other 

Chemicals. Environ. Res. 14:68-72 (1977). 

27. Ducatman, A., K. Hirschhorn, I.J. Selikoff: Vinyl Chloride Exposure and 

Human Chromosome Aberrations. Mutat. Res. g:163-168 (1975). 

28. Funes-Cravioto, F.B. Lambert, J. Lindsten, L. Ehrenberg, A.T. Natarajan, and 

S. Osterman-Golkar: Chromosome Aberrations in Workers Exposed to Vinyl 

Chloride. Lancet .!.:459 (1975). 

29. Purchase, I.F.H., C.R. Richardson, and D. Anderson: Chromosomal and 

pominant Lethal Effects of Vinyl Chloride. Lancet ~:41O-11 (1975). 

30. Szentesi, I., E. Hornyaki, G. Ungvary, A Gzeizel, Z. Bognar, and M. Timar: 

High Rate of Chromosomal Aberration in PVC Workers. Mutat. Res. 37:313-

316 (1976). 

31. Purchase, I.F.H., C.R. Richardson, D. Anderson, G.M. Paddle, and W.G.F. 

Adams: Chromosomal Analyses in Vinyl Chloride-Exposed Workers. Mutat. 

Res. 57: 325-334 (1978). 

32. Infante, P.F., J.K. Wagoner, A.J. McMichael, R.J. Waxweiler, and H. Falk: 

Genetic Risks of Vinyl Chloride. Lancet 1:734-735 (1976). 

33. Infante, P.F., J.K. Wagoner, and R.J. Waxweiler: Carcinogenic, Mutagenic and 

Teratogenic Risks Associated with Vinyl Chloride. Mutate Res. 41:131-142 

(1976). 

34. Personal Communications dated August 1978 from Mr. David P. Sundin, 

Division of Surveillance, Hazard Evaluations and Field Studies, National 

Institute for Occupational Safety and Health (NIOSH), to Leonard J. Bahlman, 

Office of Extramural Coordination and Special Projects (NIOSH). 

35. United States Department of Labor, Occupational Safety and Health 

Administration: General Industry Standards, OSHA Publication 2206, 29 CFR 

1910.1017 (January 1976). 

10 
IDENTIFIERS AND SYNONYMS FOR VINYL CHLORIDE 

Chemical Abstracts Service Registry Number 75-01-4 

NIOSH RTECS Number KU96Z50 

Chemical Formula CZH3CI 

Chlorethene 

Chlorethy lene 

Chloroethene 

Chloroethylene 

Ethene, ChloroEthylene, ChloroEthylene Monochloride 

Monochloroethene 

Monochloroethylene 

Trovidur 

VC 

VCM 

Vinyl Chloride 

Vinyl Chloride Monomer 

Vinyl CMonomer 

IDENTIFIERS AND SYNONYMS FOR VINYL BROMIDE 

Chemical Abstracts Service Registry Number 593-60-Z 

NIOSH RTECS Number KU84000 

Chemical Formula CZH3Br 

Bromoethene 

Bromoethylene 

Ethene, BromoEthylene, BromoNCI-C50373 

Vinyl Bromide 

IDENTIFIERS AND SYNONYMS FOR VINYLIDENE CHLORIDE 

Chemical Abstracts Service Registry Number 75-35-4 

NIOSH RTECS Number KV9Z750 

Chemical Formula CZHZCIZ 

l,l,-DCE 

1,1,-Dichloroethene 

l,l,-Dichloroethylene 

Ethene, l,l,-DichloroEthylene, l,l,-Dichloro 

11 

NCI-C54Z6Z 

Sconatex 

Vinylidene Chloride 

Viny lidene Chloride (II) 

(125) 

( 127) 

NlaSM 

e~ 9~ StiItetUe 29 

OCTOBER 12, 1978 

GLYCIDYL ETHERS 

U. S.DEPARTMENT OF HEALTH,EDUCATION, AND WELFARE 

Public H.alth S.r~/c. 

C.nt., lor Dis.a .. Control 

National Institut. lor Occupational Sal.ty and H.alth 
( 12B) 

The NIOSH Current Intelligence Bulletin is the primary product of the Current 

Intelligence System. The purpose of the Current Intelligence System is to promptly 

review, evaluate, and supplement new information received by NIOSH on occupational hazards that are either unrecognized or are greater than generally known. 

As warranted by this evaluation, the information is capsulized and disseminated to 

NIOSH staff, other government agencies, and the occupational health community, 

including labor, industry, academia, and public interest groups. With respect to 

currently known hazard information this system also serves to advise appropriate 

members of the above groups of recently acquired specific knowledge which may 

have an impact on their programs or perception of the hazard. Above all, the 

Current Intelligence System is designed to protect the health of American workers 

and to allow them to work in the safest possible environment. 

IDENTIFIERS, SYNONYMS, AND CHEMICAL STRUCTURES FOR SEVERAL GLYCIDYL 

ETHERS ARE TABULATED IN THE REAR PORTION OF THIS BULLETIN 

Mention of company names or products does not constitute 

endorsement by the National Institute for Occupational 

Safety and Health. 

DHEW (NIOSH) Publication No. 79-104 

ii 
CURRENT INTELLIGENCE BULLETIN 

GLYCIDYL ETHERS 

October 12, 1978 

The National Institute for Occupational Safety and Health (NIOSH) would like to 

inform the occupational health community of the possibility of adverse effects to 

the testes and the hemopoietic (blood forming) system in workers exposed to 

glycidyl ethers. 

During development of a NIOSH criteria document on glycidyl ethers, a pattern of 

research findings emerged which indicates that some of the glycidyl ethers may be 

capable of produCing testicular atrophy and hemopoietic abnormalities in various 

species of laboratory animals. Additionally, after the issuance of the June 1978 

NIOSH criteria document, a 1957 study was released to NIOSH reporting testicular 

atrophy in laboratory rats exposed to !!~butyl glycidyl ether. While none of the 

individual research reports are conclusive with respect to the ability of glycidyl 

ethers to produce permanent changes to the testes or hemopoietic system in 

laboratory animals, some of the changes observed may act as predisposing factors 

to systemic problems. NIOSH is not aware of any studies investigating the 

possiblity of occurrence of testicular atrophy or hemopoietic abnormalities 

occurring in humans exposed to glycidyl ethers. The possibility of these effects 

occurring in humans is reason for concern. Therefore, NIOSH requests that any 

information regarding testicular atrophy or hemopoietic abnormalities observed in 

workers exposed to glycidyl ethers be reported to the NIOSH Division of 

SUrveillance, Hazard Evaluations, and Field Studies, Industry-Wide Studies Branch, 

Medical Section, Telephone: (513) 684-3593 . 

NIOSH advises strict adherence to the detailed recommended occupational standard 

described in the glycidyl ethers criteria document. Particular attention should be 

given to appropriate medical surveillance in order to detect testicular atrophy or 

hemopoietic abnormalities in exposed workers. NIOSH requests that producers, 

distributors, users, professional associations, and unions transmit this information 

to their customers, employees, associates and members. 

BACKGROUND o 

I /\ 

Glycidyl ethers are synthetic compounds characterized by the -C-O-CHZ-CH-CHZ 

group and find their major use as components of epoxy resin systems. The 

"diglycidyl ether of bisphenol A" has been a traditional basic active ingredient of 

( 129) 
( 130) 

epoxy resins; other glycidyl ethers are frequently incorporated into epoxy resin 

systems as reactive diluents. The epoxy group of the glycidyl ethers reacts during 

the curing process and glycidyl ethers are therefore generally no longer present in 

completely cured products. Epoxy resins containing glycidyl ethers are used in a 

variety of applications including protective coatings, reinforced plastics, as ·well as 

bonding materials and adhesives. 

Much occupational exposure to glycidyl ethers results from the use of proprietary 

or trade name products which do not disclose the presence of toxic agents in their 

formulations. This complicates efforts to take appropriate precautionary measures 

for the prevention of occupational disease. For example, unrecognized hazardous 

situations can occur where protective coatings containing epoxy resins are sprayed, 

thereby facilitating the inhalation of even non-volatile materials, and where there 

is skin contact with epoxy resins containing glycidyl ethers. 

Data collected by the NIOSH National Occupational Hazards Survey (NOHS) have 

been used to estimate the number of people having potential occupational exposure 

to glycidyl ethers, as well as in identifying the industries in which the exposures 

occur. Pertinent data from NOHS are presented in Tables 1 and Z. NIOSH has 

previously estimated that approximately 1,000,000 workers are exposed to epoxy 

resins (1). 

Table 1. NIOSH National Occupational Hazard Survey Estimates of Occupational 

Exposure to Glycidyl Ethers 

Glycidyl Ether 

Glycidyl Ethers** 

Diglycidyl Ether of Bisphenol A 

n-Butyl Glycidyl Ether 

Phenyl Glycidyl Ether 

Resorcinol Diglycidyl Ether 

Allyl Glycidyl Ether 

Octyl-Decyl Glycidyl Ether 

Diglycidyl Ether 

Isopropyl Glycidyl Ether 

Triglycidyl Glycerol Ether 

Estimated Number of Workers 

Potentially Exposed* 

71,000 

36,000 

13,000 

8,000 

3,000 

Z,OOO 

ZOO 

150 

100 

70 

* A worker may be exposed to more than one glycidyl ether, thus the exposure 

estimates are not additive. Due to the difficulty of obtaining data regarding the 

composition of trade name products, these estimates may be low. 

**Exposures were entered into the NOHS data base either under the specific 

glycidyl ether (when the information was available) or under the general term 

"glycidyl ethers" (when more specific information was not available). To the extent 

that an exposure to a specific glycidyl ether was reported as exposure to "glycidyl 

ethers," the data may underestimate occupational exposure to individual glycidyl 

ethers. 

Z 
Table 2. Industries Where the Majol'ity of Occupational Exposures to Glycidyl 

Ethers Occur* 

Transportation Equipment 

Instruments and Related ·Products 

Chemicals and Allied Products 

Electrical Equipment and Supplies 

Special Trade Contractors 

Automotive Dealers and Service Stations 

Transportation by Air 

Miscellaneous Repair Services 

Machinery, except electrical 

Stone, Clay, and Glass Products 

Medical and Other Health Services 

Fabricated Metal Products 

Building Materials and Farm Equipment 

Food and Kindred Products 

Rubber and Plastic Products 

Furniture and Fixtures 

Amusement and Recreation Services 

Leather and Leather Products 

Communication 

*These are standard industrial titles from the Standard Industrial Classification 

Manual (2). 

The National Occupational Hazard Survey, conducted between 1972 and 1974, was 

based on a sample of businesses selected by the Bureau of Labor Statistics and 

consisted of approximately 5,000 establishments employing nearly 900,000 workers 

in 67 standard metropolitan areas throughout the United States. This sample was 

representative of non-agricultural businesses covered under the Occupational 

Safety and Health A.ct of 1970. 

NIOSH is not aware of any studies investigating the possible occurrence of 

testicular atrophy or hemopoietic abnormalities in humans exposed to glycidyl 

ethers. However, other effects observed in humans include dermatitis, irritation, 

and allergic reactions. The NIOSH glycidyl ethers criteria document (1) provides a 

detailed evaluative review of reported adverse effects resulting from exposure to 

glycidyl ethers. 

LABORATORY ANIMALS -- Testicular Atrophy and Hemopoietic Abnormalities 

Studies in several different research laboratories indicate that some of the glycidyl 

ethers are capable of producing adverse effects to the testes and hemopoietic 

system in various species of laboratory animals. Reported testicular abnormalities 

(including testicular atrophy with decreased spermatogenic activity) following 

exposure to glycidyl ethers are presented in Table 3. Table 4 summarizes reported 

hemopoietic abnormalities following exposure to glycidyl ethers, including 

alteration of the leukocyte count, atrophy of lymphoid tissue, and bone marrow 

cytotoxicity. These abnormalities were usually observed along with pneumonia 

and/or toxemia, and therefore may be secondary effects. However, especially in 

light of the generalized reduction in leukocytes and the atrophy of lymphoid 

tissues, the observed hemopoietic abnormalities may have been predisposing factors 

to pneumonia. While none of the individual research reports are conclusive with 

respect to the ability of glycidyl ethers to produce permanent changes to the testes 

or hemopoietic system in laboratory animals, the pattern of effects displayed in 

Tables 3 and 4 is reason for concern. 

The NIOSH glycidyl ethers criteria document (1) contains an evaluative review of 

the literature on effects of exposure to glycidyl ethers. Reported adverse effects 

in laboratory animals include sensitization, and skin and eye irritation, as well as 

mutagenic and tumorigenic activity. 

3 

(131) 
(132) 

Table 3. Reported Testicular Disorders Following Exposure to Glycidyl Ethers 

Reported 

Agent (reference) Animal Exposure Testicular Disorder 

Allyl Glycidyl Ether (3) Rat 400 mg/kg intramuscular focal necrosis of 

injections on days 1,2,8, the testis in 1 of 2 

and 9 of the 3 surviving 

animals sacrificed on rats 

day 12 

n-Butyl Glycidyl Ether (4) Rat 38 ppm, 75 ppm, 150 ppm, atrophic testes in 

300 ppm by inhalation, 5 of 10 at 300 ppm; 

'seven hours/day, five very small testes in 

days/week for a total of 1 of 10 at 300 ppm; 

50 exposures slight patchy atrophy 

of the testes in 1 of 

10 animals at 75 ppm 

Diglycidyl Ether (5) Rat 125 mg/kg, 250 mg/kg focal necrosis of the 

cutaneous daily appli- testes 

cation, 5 days/week, 

total of six applications 

3 ppm by inhalation necrosis of the tubules 

4 hours/day, 5 days/week of the testes in 1 of 15 

total of 19 exposures animals 

0.3 ppm by inhalation, poorly defined focal 

4 hours/day,S days/week degeneration of the 

total of 60 exposures germinal epithelium 

in 5 of 10 animals 

Rabbit single 24 hour inhalation greatly atrophied testes 

exposure of 24 ppm in two animals which 

died on the evening of 

the fifth day 

Phenyl Glycidyl Ether (6) Rat 1.75 ppm, 5.84 ppm, Initial Report: 

11.20 ppm by inhalation focal degenerative 

6 hours/day for 19 changes involving the 

consecutive days seminiferous tubules 

in bo th gonads in 

1 of 8 at 1.75 ppm, 

1 of 8 at 5.84 ppm, and 

3 o~ 8 11.20 ppm 

Supplemental 

Examination: 

1 of 8 in each of 1.75, 

5.84, and 11.20 ppm 

groups had a marked 

degree of gonad change 

Triethylene Glycol Mouse 7208 mg/kg total testular atrophy with 

Diglycidyl Ether (7) dose administered in decreased spermatogenic 

12 intraperitoneal activity 

injection, 3 per week 

for four weeks, animals 

sacrificed 39 weeks after 

the first injection 

4 
Table 4. Reported Hemopoietic Abnormalities in Animals Following Exposure to Glycidyl Ethers (133) 

Reported 

Agent (reference) Animal Exposure Abnormality 

Allyl Glycidyl Ether (3) Rat 400 mg/kg intramuscular atrophy or loss of 

injections on days 1,2,8, lymphoid tissue in 

and 9 2 of 3 rats 

animals sacrificed decreased leukocyte 

on day 12 count 

~-Butyl Glycidyl Ether (3) Rat 400 mg/kg intramuscular increased leukocyte 

injections for 3 consecu- count 

tive days 

Butanediol Diglycidyl Rat 100 mg/kg, 200 mg/kg bone marrow 

Ether (8) single intraperitoneal cytotoxicity 

injection 

Diethylene Glycol Rat 100 mg/kg, 200 mg/kg, bone marrow 

Diglycidyl Ether (8) 400 mg/kg cytotoxicity 

single intraperitoneal 

injection 

Diglycidyl.Ether (5) Rat single application of 0.5 g/kg, decreased leukocyte 

1 g/kg to shaved backs count 

daily skin application of decreased leukocyte 

125 mg/kg, 5 days/week count 

for 4 weeks; skin application increase in percentage 

on days 1,2,3,4,5, and 8 of of polymorphonuclear 

250 mg/kg, 500 mg/kg cells 

fewer nucleated 

cells of the bone 

marrow 

enlarged myeloid 

cells in 250 and 500 

mg/kg groups. 

lymphoid atrophy of 

the thymus at 500 mg/kg. 

3 ppm by inhalation, decreased leukocyte 

4 hours/day,S days/week, count 

total of 19 exposures 

Rabbit Single application of 1.13 g/kg decreased leukocyte 

to shaved back count 

Single intravenous injection decreased leukocyte 

of 50 mg/kg, 100 mg/kg, count 

200 mg/kg 

23 nucleated erythrocytes 

per 100 leukocytes in 

100 mg/kg group 

Dog 25 mg/kg intravenous injection, decreased leukocyte 

2 injections, six days apart, in count 

two dogs 

3 weekly injections in one dog 

Phenyl Glycidyl Ether (3) Rat 400 mg/kg intramuscular increased leukocyte 

injections for 3 consecutive count 

days 

.. 
(134) 

NIOSH RECOMMENDATION 

Reports from different laboratories present a pattern of findings indicating that 

some of the glycidyl ethers may be capable of producing testicular atrophy and 

hemopoietic abnormalities in various species of laboratory animals. While none of 

the individual research reports are conclusive with respect to the ability of glycidyl 

ethers to produce permanent changes to the testes or hemopoietic system in 

laboratory animals, some of the changes observed may act as predisposing factors 

to systemic problems. NIOSH is not aware of any studies investigating the possible 

occurrence of testicular atrophy or hemopoietic abnormalities in humans exposed 

to glycidyl ethers. The possibility of these effects occurring in humans is reason 

for concern. Therefore, the occupational health community is advised of the 

possibility of these effects appearing in workers exposed to glycidyl ethers. 

The "NIOSH Criteria for a Recommended Standard ••.. Occupational Exposure to 

Glycidyl Ethers" was transmitted to the Occupational Safety and Health Administration (OSHA), Department of Labor, on June 30, 1978 (1). This criteria 

document contains detailed recommendations regarding maximum exposure levels, 

medical surveillance, labeling and posting, personal protective clothing and 

equipment, informing employees of hazards, work practices, sanitation, monitoring, 

and recordkeeping requirements as well as sampling and analytical procedures. 

Existing occupational exposure limits for specific glycidyl ethers are listed in 

Table 5. 

Table 5. Existing Occupational Exposure Limits for Specific Glycidyl Ethers 

Present OSHA 

Exposure Standard (9) 

NIOSH Recommended 

Exposure Standard (1) 

(Ceiling) 

Allyl Glycidyl Ether 10 

!!-Butyl Glycidyl Ether 50 

Diglycidyl Ether 0.5 

Isopropyl Glycidyl Ether 50 

Phenyl Glycidyl Ether 10 

*Ceiling 

**8-hour time-weighted average 

ppn (45 

ppn (270 

ppn (2.8 

ppn (240 

ppn (60 

6 

rrg/cu m) * 

rrg/cu m) ** 

rrg/cu m) * 

rrg/cu m) ** 

rrg/cu m)** 

45 Ill5/cu m 

30 Ill5/cu m 

1 ng/cu m 

240 ng/cu m 

5 rrg/cu m 

(9.6 

(5.6 

(0.2 

(50 

(1 

ppn) 

ppn) 

ppn) 

ppn) 

ppn) 
NIOSH advises strict adherence to this detailed recommended occupational 

standard for glycidyl ethers described in the NIOSH criteria document. 'Particular 

attention should be given to appropriate medical surveillance in order to detect 

testicular atrophy or hemopoietic abnormalities in exposed workers. 

NIOSH requests that any information regarding testicular atrophy or hemopoietic 

abnormalities in workers exposed to glycidyl ethers be reported to the NIOSH 

Division of Surveillance, Hazard Evaluations, and Field Studies, Industry-Wide 

Studies Branch, Medical Section, Telephone: (513) 684-3593. 

chael Lane, M.D. 

Acting Director 

7 

( 135) 
( 136) 

REFERENCES 

1. NIOSH Criteria for a Recommended Standard •..• Occupational Exposure to 

Glycidyl Ethers. United States Department of Health, Education, and 

Welfare. Public Health Service, Center for Disease Control, National 

Institute for Occupational Safety and Health, Cincinnati (1978), in press. 

Z. Standard Industrial Classification Manual 1967. Executive Office of the 

President, Bureau of the Budget, Washington (1967). 

3. Kodama, J. K., R. J. Guzman, M. K. Dunlap, G. S. Loquvam, R. Lima and 

C. H. Hine: Some Effects of Epoxy Compounds on the Blood. Arch. Environ. 

Health Z: 56-67 (1961). 

4. Anderson, H. H., C. H. Hine, R. J. Guzman and J. S. Wellington: Chronic 

Vapor Toxicity of n-Butyl ' Glycidyl Ether. Confidential Report to Shell 

Development Company, Emeryville, California from Department of 

Pharmacology and Experimental Therapeutics, University of California School 

of Medicine, San Francisco, U. C. Report No. 270, February 4, 1957. 

5. Hine, C" H., J. K. Kodama, R. J. Guzman, M. K. Dunlap, K. Lima and G. S. 

Loquvwam: Effects of Diglycidyl ,Ether on Blood of Animals. Arch. Environ. 

Health, 2: 37-50 (1961). 

6. Terrill, J. B. and H. J. Trochimowicz: A Two-Generation Reproduction and 

Mutagenic Study in Rats. E. I. du Pont de Nemours and Company, Haskell 

Laboratory for Toxicology and Industrial Medicine, Haskell Laboratory Report 

No. 163-75, Wilmington, Delaware, April 7, 1975. 

7. Shimkin, M. B., J~ H. Weisburger, E. K. Weisburger, N. Gubareff and V. 

Suntzeff: Bioassay of 29 Alkylating Chemicals by the Pulmonary-Tumor 

Response in Strain A Mice. J. Nat. Cancer Inst. 36: 915-935 (1966). 

8. Hendry, J. A., R. F. Homer, F. L. Rose and A. L. Walpole: Cytotoxic Agents: 

II, Bis-Epoxides and Related Compounds. Brit. J. Pharmacol. 6: 235-255 

(1951). 

9. Occupational Safety and Health General Industry Standards. United States 

Department of Labor, Occupational Safety and Health Administration, OSHA 

Publication 2206, Washington (1976). (29 CFR 1910.1000) 

8 
IDENTIFIERS AND SYNONYMS FOR ALLYL GL YCIDYL ETHER 

Chemical Abstracts Service Registry Number 106-9Z-3 

NIOSH RTECS Number RR0875000 

Chemical Formula C6H100 Z 

AGE 

Allyl Z,3-Epoxypropyl Ether 

Allyl Glycidyl Ether 

l-Allyloxy-Z,3-epoxypropane 

1, Z-Epoxy-3-allyoxypropane 

Ether, Allyl Z,3-epoxypropyl 

Glycidyl Allyl Ether 

Oxirane, [(Z-Propenyloxy)methyl]-

Propane, 1-(Allyloxy)-Z,3-epoxy-

~~~

IDENTIFIERS ~~~~~~~~~~~~~~~~=-~~~~~~~~ AND SYNONYMS FOR n-BUTYL GL YCIDYL ETHER 

Chemical Abstracts Service Registry Number 2426-08-6 

NIOSH RTECS Number TX4Z00000 

Chemical Formula C7H140 Z 

BGE 

I-Butoxy-2,3-epoxypropane 

3-Butoxy-l,2-epoxypropane 

Butyl Glycidyl Ether 

!l-Butyl Glycidyl Ether 

Z,3-Epoxypropyl Butyl Ether 

ERL 0810 

Ether, Butyl Z,3-Epoxypropyl 

Ether, Butyl Glycidyl 

Glycidyl Butyl Ether 

Oxirane, (Butoxymethyl)-

Propane, I-Butoxy-Z,3-epoxyIDENTIFIERS AND SYNONYMS FOR DIGL YCIDYL ETHER 

Chemical Abstracts Service Registry Number 2238-07-5 

NIOSH RTECS Number KNZ350000 

Chemical Formula C 6HlO0 3 

Bis(Z,3-Epoxypropyl) Ether 

DGE 

Di(Z,3-epoxy)propyl Ether 

Diglycidyl Ether 

Ether, Bis(2,3-epoxypropyl) 

Ether, Diglycidyl 

Glycidyl Ether 

NSC 54739 

Oxirane, 2,2'- pxybis(methylene)]bis9 

(137) 
(138) 

IDENTIFIERS AND SYNONYMS FOR DIGLYCIDYL ETHER OF BISPHENOL A 

Chemical Abstracts Service Registry Number 1675-54-3 

NIOSH RTECS Number TX3800000 

Chemical Formula CZ1HZ404. 

4,4'-Bis(Z,3-epoxypropoxy)diphenyldimethylmethane 

Z,Z-Bis f2-(Z,3-epoxypropoxy)phenyl]propane 

Z,Z-Bis P,-(Z,3-epoxypropoxy)phenyl]propane 

Bis(4-glycidyloxyphenyl)dimethylmethane 

Z, Z-Bis (£"glycidy loxypheny l)propane 

Z,Z-Bis(4-glycidyloxyphenyl)propane 

Bis(4-hydroxyphenyl)dimethylmethane Diglycidyl Ether 

Z,Z-Bis(E.-hydroxyphenyl)propane Diglycidyl Ether 

Z,Z-Bis(4-hydroxyphenyl)propane Diglycidyl Ether 

Bisphenol A Diglycidyl Ether 

D.E.R.33Z 

Dian Diglycidyl Ether 

Diglycidyl Bisphenol A 

Diglycidyl Bisphenol A Ether 

Diglycidyl Diphenylolpropane Ether 

Diglycidyl Ether of Z,Z-Bis(E-hydroxyphenyl)propane 

Diglycidyl Ether of Z,Z-Bis( 4-hydroxyphenyl)propane: 

Diglycidyl Ether of Bisphenol A 

Diglycidyl Ether of 4,4'-Isopropylidenediphenol 

4,4'-Dihydroxydiphenyldimethylmethane Diglycidyl Ether 

E,E'-Dihydroxydiphenyldimethylmethane Diglycidyl Ether 

Diomethane Diglycidyl Ether 

EPI-REZ 510 

Epoxide A 

ERL-Z774 

4,4'-Isopropy lidene bis[ 1-(Z ,3-epoxypropoxy)benzene] 

4,4'-Isopropylidenediphenol Diglycidyl Ether 

Z,Z' KI-Methylethylidene)bis(4, 1-phenyleneoxymethylene)] bisoxirane 

Oxirane, Z,Z' R1-Methylethylidene)bis(4,1-phenyleneoxymethylene~ bisPropane, Z, Z-Bis [(E-(Z ,3-epoxypropoxy) pheny U -

IDENTIFIERS AND SYNONYMS FOR ISOPROPYL GL YCIDYL ETHER 

Chemical Abstracts Service Registry Number 4016-14-Z 

NIOSH RTECS Number TZ3500000 

Chemical Formula C 6H1ZOZ 

1 ,Z-Epoxy-3-isopropoxypropane 

Glycidyl Isopropyl Ether 

IGE 

3-Isopropoxy-l , Z-epoxypropane 

(Isopropoxymethyl)oxirane 

Isopropyl Glycidyl Ether 

[(l-Methylethoxy) methyl] oxirane 

Oxirane, RI-Methylethoxy) methyl]-

Propane, 1,Z-Epoxy-3-isopropoxy10 
IDENTIFIERS AND SYNONYMS FOR PHENYL GLYCIDYL ETHER 

Chemical Abstracts Service Registry Number lZZ-60-1 

NlOSH RTECS Number TZ3675000 

Chemical Formula C9H100 Z 

Benzene, (Z,3-Epoxypropoxy)-

1, Z-Epoxy-3-phenoxypropane 

Z,3-Epoxypropyl Phenyl Ether 

Z,3-Epoxypropylphenyl Ether 

Ether, Z,3-Epoxypropyl Phenyl 

Glycidol Phenyl Ether 

Glycidyl Phenyl Ether 

Oxirane, (Phenoxymethyl)-

PGE 

Phenol Glycidyl Ether 

I-Phenoxy-Z,3-epoxypropane 

3-Phenoxy-I, Z-epoxypropane 

3-Phenoxy-I, Z-propy lene Oxide 

(Phenoxyme thy 1) oxirane 

Phenoxypropene Oxide 

Phenoxypropylene Oxide 

y-Phenoxypropylene Oxide 

Phenyl Z,3-Epoxypropyl Ether 

Phenyl Glycidyl Ether 

Phenylglycidyl Eth('r 

3-Pheny loxy-l , Z-epoxypropane 

Propane, I,Z-Epoxy-3-phenoxyIDENTIFIERS AND SYNONYMS FOR RESORCINOL DlGL YCIDYL ETHER 

Chemical Abstracts Service Registry Number 101-90-6 

NlOSH RTECS Number VHI050000 

Chemical Formula CIZH1404 

Araldite ERE 1359 

Benzene, m-Bis(Z,3-epoxypropoxy)-

Diglycidyl Resorcinol Ether 

,!!!.-Bis (Z ,3-epoxypropoxy) benz,ene 

1,3-Bis(Z,3-epoxypropoxy)benzene 

NCl - C54966 

Oxirane, Z,Z'- o.,3-Phenylenebis(oxymethylenen bis2.,Z- b.,3-Phenylenebis(oxymethylene))bisoxirane 

RDGE 

Resorcinol Bis(Z,3-epoxypropyl) Ether 

Resorcinol Diglycidyl Ether 

Resorcinol Glycidyl Ether 

Resorcinyl Diglycidyl Ether 

11 

(139) 
(140) 

CHEMICAL STRUCTURES 

OF SOME GL YCIDYL ETHERS 

all yl glycidyl ether 

~-butyl glycidyl ether 

di glycidyl ether 

diglycidyl ether of bisphenol A 

isopropyl glycidyl ether 

phenyl glycidyl ether 

resorcinol diglycidyl ether 

CH2=CHCH20CH2C~ - 5H2 

o 

CH3CH2CH2CH20CH2C~-5H2 

o 

12 
( 141) 

NlaSM . 

(3ePtMHt 9~ 1/t4etue SO 

OCTOBER 12, 1978 

EPICHlOROHYDRIN 

U. s. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE 

Public Health Serlf/ce 

Center for Disease Control 

National Institute for Occupational Safety and Health 
( 142) 

The NIOSH Current Intelligence Bulletin is the primary product of the Current 

Intelligence System. The purpose of the Current Intelligence System is to promptly 

review, evaluate, and supplement new information received by NIOSH on occupational hazards that are either unrecognized or are greater than generally known. 

As warranted by this evaluation, the information is capsulized and disseminated to 

NIOSH staff, other government agencies, and the occupational health community, 

including labor, industry, academia, and public interest groups. With respect to 

currently known hazard information this system also serves to advise appropriate 

members of the above groups of recently acquired specific knowledge which may 

have an impact on their programs or perception of the hazard. Above all, the 

Current Intelligence System is designed to protect the health of American workers 

and to allow them to work in the safest possible environment. 

IDENTIFIERS AND SYNONYMS FOR EPICHLOROHYDRIN ARE USTED 

IN THE REAR PORTION OF THIS BULLETIN 

Mention of company names or products does 

not constitute endorsement by the National 

Institute for Occupational Safety and 

Health. 

DHEW (NIOSH) Publication No. 79-105 

ii 
CURRENT INTELLIGENCE BULLETIN 

EPICHLOROHYDRIN 

October lZ, 1978 

The National Institute for Occupational Safety and Health (NIOSH) recommends 

that as a prudent measure, epichlorohydrin be handled in the workplace as if it 

were a human carcinogen. This recommendation is based primarily on two recent 

studies: a long term epidemiologic study showing a significant increase in 

respiratory cancer deaths of exposed workers, and an inhalation study showing an 

increase in nasal carcinomas in rats. In addition, cytogenic studies of human 

peripheral lymphocytes hav~ shown a highly significant increase in chromosome 

abnormalities in exposed workers. Pending further evaluation of its carcinogenic 

potential, NIOSH believes it would be prudent to minimize occupational exposure to 

epichlorohydrin. 

NIOSH has prepared this Bulletin to advise you of these recent studies, their 

implications for occupational health, and precautions for handling products 

containing epichlorohydrin. We request that producers, distributors, and users 

transmit this information to their customers and employees, and that professional 

associations and unions inform their members. 

EXPOSURE STANDARDS 

The current Department of Labor, Occupational Safety and Health Administration 

(OSHA) standard for occupational exposure to epichlorohydrin is 5 ppm (19 

mg/cu m) as an 8-hour time-weighted average (1). Studies of carcinogenicity were 

not available when this standard was developed. 

In September 1976, NIOSH recommended an occupational exposure limit of 2 

mg/cu m of air (approximately 0.5 ppm) determined as a time-weighted average 

(TW A) concentration for up to a 10 hour work day in a 40 hour work week, and a 

ceiling concentration standard of 19 mg/cu m (approximately 5 ppm) as determined 

by a sampling time of 15 minutes (2). Aft~r a comprehensive review of the 

literature, NIOSH concluded that risks from exposure to epichlorohydrin may 

include carcinogenesis, mutagenesis and sterility, as well as damage to the kidneys, 

liver, respiratory tract, and skin. Since most of the available evidence on adverse 

effects of epichlorohydrin was obtained from animal experiments which were 

inadequate to determine scientifically acceptable exposure limits, the 1976 NIOSH 

recommendation was based on professional judgement which quantitatively 

considered the cumulative toxic effects. 

(143) 
(144 ) 

PRODUCTION, USES, AND OCCUPATIONAL EXPOSURES 

Epichlorohydrin is a liquid at room temperatures. In 1978, domestic annual 

production capacity was 470 million pounds. An important constituent of epoxy 

resin is synthesized by alkylating bisphenol A with epichlorohydrin (2). 

Epichlorohydrin is used in the manufacture of epoxy resins, surface active agents, 

pharmaceuticals, insecticides, agricultural chemicals, textile chemicals, coatings, 

adhesives, ion-exchange resins, solvents, plasticizers, glycidyl esters, ethynylethylenic alcohol and fatty acid derivatives. 

According to the NIOSH National Occupational Hazard Survey (NOHS) (3), an 

estimated 85,000 workers are potentially exposed to epichlorohydrin in the 

workplace. Table 1 lists occupations and industries in which a potential exists for 

exposure to epichlorohydrin. The NOHS survey data were collected during 1972 to 

1974 from a sample of approximately 5,000 businesses employing nearly 900,000 

workers. 1970 Census figures were used in extrapolating the sample data to the 

working population employed in industries covered by the Occupational'Safety and 

Health Act of 1970. The potential exposure estimates include data on actual 

observations of the use of the specific chemical or the use of a trade name product 

known to contain the chemical as well as additional observations of generic 

formulations (trade name products suspected of containing the chemical). 

Table 1. Some 'Occupations and Industries Which Use Epichlorohydrin 

Occupations (a) assemblers; miscellaneous specified machine operatives; aircraft 

machinists; construction and maintanance painters; miscellaneous 

operatives; chemists; mining operatives; painters of manufactured 

articles; sheetmetal workers and tinsmiths; pattern and model 

makers, except paper 

Industries (b) chemicals and allied products; transportation equipment; instruments and related products; transportation by air; electrical 

equipment and supplies; special trade contractors; miscellaneous 

repair services; rubber and plastics not elsewhere classified; 

machinery, except electrical; stone, clay, and glass products 

(a) Standard occupational titles from the Bureau of the Census (4) 

(b) Standard industrial titles from the Standard Industrial Classification Manual 

(5). 

HUMAN CARCINOGENICITY 

A statistically significant (p < .05) increase in deaths due to respiratory cancer has 

been observed in a long-term epidemiologic study conducted on workers exposed to 

epichlorohydrin at two facilities of the Shell Chemical Company (6). The data were 

analyzed by Dr. Philip Enterline of the University of Pittsburgh (7, 8). There were 

2. 
864 workers identified as having been occupationally exposed to epichlorohydrin for 

6 months or more, before January 1, 1966. Ninety-eight percent of the workers 

were traced as of December 31, 1976. For men estimated to have had moderate to 

heavy exposure who were followed for 15 years or more, observed deaths were also 

greater than those expected for the categories of all cancers, leukemia, and 

suicide, although those differences were not statistically significant. Information 

was not available for most worke.rs on smoking history, or the extent of exposure to 

other chemicals (9). NIOSH feels that the study results are suggestive of a 

carcinogenic effect of epichlorohydrin on humans, and deserve attention. 

The Dow Chemical Company has informed NIOSH that it is currently conducting a 

mortality study of workers engaged in the manufacture and conversion of 

epichlorohydrin (10). Dow estimates that the results will be made available 

November, 1978. 

ANIMAL CARCINOGENICITY 

In ongoing inhalation studies, rats exposed to epichlorohydrin have shown a 

statistically significant increase in nasal cancer (p < .05) (11). In experiments 

initiated under Dr. Sidney Laskin and continued under Dr. Norton Nelson at the 

New York University Institute of Environmental Medicine, 140 rats have been 

exposed to 100 ppm epichlorohydrin for 6 hours/day,S days/week, for 30 days, with 

subsequent lifetime observation. Fifteen of the animals have died with 

pathologically confirmed squamous cell nasal cancinoma (11). Another animal 

developed a nasal papilloma. No spontaneous nasal cancer was seen in a group of 

50 controls. Of another group of 100 animals exposed to 30 ppm of epichlorohydrin 

for 6 hours/day, 5 days/week, in a chronic lifetime study one animal has developed 

a papilloma of the larynx, another has developed a nasal squamous cell carcinoma 

(12). In contrast, no spontaneous nasal carcinomas were seen in the 50 animal 

control group. 

Further information on previous studies that investigated the other evidence 

relating to carcinogenicity of epichlorohydrin can be found in the NIOSH 

epichlorohydrin criteria document (2, 13). 

HUMAN MUTAGENICITY 

Epichlorohydrin has been shown to induce a significant increase in chromosomal 

aberrations found in the white blood cells of workers occupationally exposed to 

epichlorohydrin. In 1977, Kucerova et al. (14) conducted a prospective cytogenetic 

study of 35 workers occupationally exposed to epichlorohydrin. Each worker served 

as his own control. After exposure for one year, these workers showed a significant 

increase in chromosomal aberrations. After two years of exposure to 

epichlorohydrin, the increase in chromosomal aberrations was significant at the 

p < .0001 level. 

3 

(145) 
( 146) 

In 1976, Sram et al. (15) found chromosome abnormalities in human peripheral 

lymphocytes exposed in vitro to epichlorohydrin. They concluded that a genetic 

risk for man exists following exposure to epichlorohydrin. A quantitative risk was 

not estimated. 

OTHER TOXIC EFFECTS 

Epichlorohydrin is a highly toxic substance which is easily absorbed through the 

skin. Skin contact with epichlorohydrin can cause severe chemical burns, although 

the effects may not appear until sometime after exposure. The latent period can 

range from several minutes to several days, depending on the duration and intensity 

of exposure. Allergic response has been noted (16). Exposure to epichlorohydrin 

vapor induces transient burning of the eyes and nasal passages at concentrations as 

low as ZO ppm. Exposure to high concentrations (100 ppm) leads to pulmonary 

edema (fluid accumulation in the lung) and kidney problems in laboratory animals. 

A comprehensive discussion of the toxic effects is found in the NIOSH 

epichlorohydrin criteria document (2). Table Z summarizes the reported toxic 

effects in humans at varying exposure levels. 

Table Z. Other Toxic Effects of Epichlorohydrin on Humans (Z). 

Route of 

Exposure 

dermal 

inhalation 

Effect 

burning sensation, redness, swelling, red papules, itching, blisters, 

skin erosion, enlarged lymph nodes 

burning of the eyes, nose and throat; cough; chest congestion; running nose; eye tenderness; headache followed by nausea; vomiting; 

facial swelling; dyspnea 

Exposure to epichlorohydrin has been shown to induce sterility in rats (2), and a 

fertility study has been conducted in male workers exposed to epichlorohydrin (17). 

While the study concluded that exposure to epichlorohydrin did not decrease sperm 

counts or affect hormonal activity in the workers, the data were not analyzed 

statistically. 

4 . 
NIOSH RECOMMENDATIONS 

In light of the statistically significant increase in respiratory cancer seen in 

workers exposed to epichlorohydrin, and the statistically significant increase in 

nasal carcinomas seen in rat inhalation studies, as well as the chromosomal 

aberrations seen in the peripheral lymphocytes of exposed workers, NIOSH 

recommends that epichlorohydrin be treated in the workplace as if it were a human 

carcinogen. Pending further evaluation of its carcinogenic potential, NIOSH 

believes it would be prudent to minimize occupational exposure to epichlorohydrin. 

Exposures should be limited to as few employees as possible while workplace 

exposure should be minimized with engineering and work practice controls. In 

particular, skin exposure should be avoided. 

·

u"

, &~ ') 

/ • lchael Lane, M.D. J' · 'ting Director 

( 147) 
( 148) 

REFERENCES 

1. U.S. Department of Labor, Occupational Safety and Health Administration: 

Occupational Safety and Health General Industry Standards. 

Publication 2206, 29 CFR 1910.1000, Washington, D.C. (1976) 

2. U.S. Department of Health, Education, and Welfare, Public Health Service, 

Center for Disease Control, National Institute for Occupational Safety and 

Health. Criteria for ~ Recommended Standard .... Occupational Exposure to 

Epichlorohydrin. Washington, D.C. (1976). 

3. NIOSH National Occupational Hazard Survey (NOHS): Personal 

communication to the NIOSH Technical Evaluation and Review Branch, 

Office of Extramural Coordination and Special Projects (1978). 

4. U.S. Bureau of the Census: 1970 Census of Population, Alphabetical Index of 

Industries and Occupations. Washington, D.C. (1971). 

5. Bureau of the Budget: Standard Industrial Classification Manual. 

Washington, D.C. (1967). 

6. Enterline, P.: Letter from P. Enterline, Ph.D., Department of Biostatistics, 

University of Pittsburgh to R. E. Joyner, M.D., Corporate Medical Director, 

Shell Oil Company, July 31, 1978. 

• 

7. Enterline, P.: Updated Mortality in Workers Exposed to Epichlorohydrin, 

unpublished report to the Shell Oil Company, July 31, 1978. 

8. Enterline, P.: Mortality in Workers Exposed to Epichlorohyd~in, unpublished 

report to the Shell Oil Company, August 31, 1977. 

9. Joyner, R.E.: Letter from R.E. Joyner, M.D., Corporate Medical Director, 

Shell Oil Company to J. Michael Lane, M.D., Acting Director, NIOSH, 

August 7, 1978. 

10. Walker, R.C.: Letter from R.C. Walker, Manager, The Dow Chemical 

Company, to Vernon E. Rose, Ph.D., Director, Division of Criteria 

Documentation and Standards Development, NIOSH, August 29, 1978. 

11. New York University Institute of Environmental Medicine: Personal 

communication to the NIOSH Technical Evaluation and Review Branch, 

Office of Extramural Coordination and Special Proj ects, (1978). 

12. Nelson, N.: Letter to the Office of the Director, NIOSH, June 23, 1978, 

updating the letter of March 28, 1977. 

13. Van Duur en , B.B., B. M. Goldschmidt, C. Katz, I. Seidman, and J. S. Paul: 

Carcinogenic Activity of Alkylating Agents. Journal of the National Cancer 

Institute 53: 695-700 (1974). 

6 
14. Kucerova, M., V. S. Zurkov, Z. Polvkova, and J. E. Ivanova: Mutagenic Effect 

of Epichlorohydrin. n. Analysis of Chromosol Aberrations in Lymphocytes of 

Persons Occupationally Exposed to Epichlorohydrin. Mutation Research, 48: 

355-360 (1977). 

15. Sram, R.J., M. Cerna, and M. Kucerova: The Genetic Risk of Epichlorohydrin 

as Related to the Occupational Exposure. Biologisches Zentralblatt 95: 451-

462 (1976). 

16. u.s. Department of Health, Education, and Welfare, Public Health Service, 

Center for Disease Control, National Institute for Occupational Safety and 

Health: Occupational Diseases: A Guide to Their Recognition. Washington, 

D.C. (1977). 

17. Whorton, D., T.H. Milby, and R.L. Davis: Testicular Function Among ECH 

Workers at Shell Deer Park and Norco Facilities. Unpublished report to the 

Shell Oil Company from Environmental Health Associates, August 22, 1978. 

(149) 
('50) 

SUGGESTED GUIDELINES FOR MONITORING AND CONTROLLING EMPLOYEE 

EXPOSURE TO EPICHLOROHYDRIN 

NIOSH recommends that it would be prudent to handle epichlorohydrin in the 

workplace as if it were a human carcinogen. Exposure to epichlorohydrin should be 

limited to as few employees as possible, and workplace exposure levels should be 

minimized. The area in which it is used should be restricted to only those 

employee~ essential to the process or operation and these employees should be 

adequately protected. 

EXPOSURE MONITORING 

A detailed sampling, and analytical method for epichlorohydrin exposure 

measurements is described in the NIOSH Manual of Analytical Methods, Second 

Edition (1) as NIOSH method #S118 in Volume 2. 

Initial and routine employee exposure surveys should be made by competent 

industrial hygiene and engineering personnel. These surveys are necessary to 

determine the extent of employee exposure and to ensure that controls are 

effective. 

The NIOSH Occupational Exposure Sampling Strategy Manual (2), may be helpful in 

developing efficient programs to monitor employee exposures to epichlorohydrin. 

The manual discusses determination of the need for exposure measurements, 

selection of appropriate employees for exposure evaluation and selection of 

sampling times. 

Employee exposure measurements should primarily consist of 8-hour TWA (timeweighted average) exposure estimates calculated from personal or breathing zone 

samples (air that would most nearly represent that inhaled by the employees). In 

addition, short term samples should be taken during periods of maximum expected 

exposure by using all available knowledge regarding the area, employee work 

procedures, and process. Area and source measurements may be useful to 

determine problem areas, processes, and operations. 

CONTROLLING EMPLOYEE EXPOSURE 

There are four basic met1;lods of limiting employee exposure to epichlorohydrin. 

None of these is a simple' industrial hygiene or management decision and careful 

planning and thought should be used prior to implementation. 

8 
o Product Substitution 

The substitution of an alternative material with a lower potential health risk is one 

method. However, extreme care must be used when selecting possible substitutes. 

Alternatives to epichlorohydrin should be fully evaluated with regard to possible 

human effects. Unless the toxic effects of the alternative have been thoroughly 

evaluated a seemingly safe replacement, possibly only after years of use, may be 

found to induce serious health effects. 

o Contaminant Controls 

The most effective control of epichlorohydrin where feasible, is at the source of 

contamination by enclosure of the operation and/or local exhaust ventilation. 

Guidelines for selected processes and operations can be found in the NIOSH 

Recommended Industrial Ventilation Guidelines (3). 

If feasible, the process or. operation should be enclosed with a slight vacuum so that 

any leakage will result in the flow of external air into the enclosure. 

The next most effective means of control would be a well Ciesigned local exhaust 

ventilation system that physically encloses the process as much as possible, with 

sufficient capture velocity to keep the contaminant from entering the work 

atmosphere. . 

To ensure that ventilation equipment is working properly, effectiveness (e.g., air 

velocity, static pressure, or air volume) should be checked at least every three 

months. System effectiveness should be checked soon after any change in 

production, process, or control which might result in significant increases .in 

airborne exposure to epichlorohydrin. 

o Employee Isolation 

A third alternative is the isolation of employees. It frequently involves the use of 

automated equipment operated by personnel observing from a closed control booth 

or room. The 'control room is maintained at a greater air pressure than that 

surrounding the process equipment so that air flow is out of, rather than into, the 

room. This type of control will not protect those employees that must do process 

checks, adjustments, maintenance, and related operations. 

o Personal Protective Equipment 

The least preferred method is the use of personal protective equipment. This 

equipment, which may include respirators, goggles, gloves, etc., should not be used 

as the only means to prevent or minimize exposure d~ing routine operations. 

9 

(151 ) 
(152) 

Exposure to epichlorohydrin should not be controlled with the use of respirators 

except: 

During the time period necessary to install or implement engineering or work 

practice controls; or 

In work situations in which engineering and work practice controls are technically not feasible; or 

For maintenance; or 

For operations which require entry into tanks or closed vessels; or 

In emergencies. 

Only respirators approved by the National Institute for Occupational Safety and 

Health (NIOSH) under the provisions of Federal regulations 30 CFR 11 should be 

used. Refer to c;u~:ulative Supple~ent June _1977, NIOSH Certified Equipment (4) 

for a listing of NIOSH-approved respirators. Note that the use of faceseal 

coverlets or socks with respirators voids NIOSH approvals. 

Qu~titative faceseal fit test equipment (such as sodium chloride, dioctyl 

phthalate, or equivalent) should be used. Refer to NIOSH's A Guide to Industrial 

Respiratory Protection (5) for guidelines on appropriate respiratory protection 

programs. 

In addition, proper maintenance procedures, good housekeeping in the work area, 

and employee education are all vital aspects of a good control program. Employees 

should be informed as to the nature of the hazard, its control, and appropriate 

personal hygiene procedures. 

REFERENCES FOR SUGGESTED GUIDELINES 

1) NIOSH Manual of Analytical Methods, Znd Edition, Vol. 1: GPO #017-033-

00Z67-3, $8.75: Vol. Z: GPO #017-033-00Z60-6, $9.75: Vol. 3: GPO #017-

033-0Z47-9, $9.00. 

Z) NIOSH Occupational Exposure Sampling Strategy Manual, GPO #017-033-

00Z47-9, $Z.75. 

3) NIOSH Recommended Industrial Ventilation Guidelines, GPO #017-033-00136-

7, $3.90. 

4) NIOSH Cumulative Supp'lement June 1977, NIOSH Certified Equipment, 

NIOSH #- 77-195, no charge. 

5) A Guide to Industrial Respiratory Protection, GPO #017-033-00153-7, $Z.30. 
GPO publications must be ordered from: Superintendent of Documents 

U.S. Government Printing Office 

Washington, D.C. 20402 

Reference :ft;4 can be ordered from: Publications Dissemination, DTS 

NIOSH 

4676 Columbia Parkway 

Cincinnati, Ohio 45Z26 

11 

( 153) 
(154 ) 

IDENTIFmRS AND SYNONYMS FOR EPICHLOROHYDRIN 

Chemical Abstracts Service Registry Number: 106-89-8 

NIOSH RTECS Number: TX4900000 

Chemical Formula: C3HSOCI 

l-Chloro-Z,3-epoxypropane 

3-Chloro-l, Z-epoxypropane 

3-Chloro-l,Z-propylene oxide 

(Chloromethy!)ethy!~ne oxide 

(Chloromethyl)oxirane 

Z-Chloromethyl oxyrane 

3-Chloropropene-l, Z-oxide 

Chloropropylene oxide 

y-Chloropropylene oxide 

ECH 

ECHH 

lZ 

Epichlorohydrin 

Q,-Epichlorohydrin 

1, Z-Epoxy-3-chloropropane 

Z,3-Epoxypropyl chloride 

Glycerol epichlorohydrin 

Glycidyl chloride 

Oxirane, (chloromethyl)-

Oxirane, Z-(Chloromethyl)-

Propane, l-chloro-Z,3-epoxySKEKhG 
(155) 

CUMMULA TIVE UST OF NIOSH CURRENT INTELUG ENCE BULLETINS 

1- Chloroprene - January 20, 1975 

2. Trichloroethylene (TCE) - JWle 6, 1975 

3. Ethylene Dibromide (EDB) - July 7, 1975 

4. Chrome Pigment - JWle 24, 1975 

- October 7, 1975 

- October 8, 1976 

5. Asbestos - Asbestos Exposure during Servicing - August 8, 1975 

of Motor Vehicle Brake and Clutch Assemblies 

6. Hexamethylphosphoric Triamide (HMPA) - October 24, 1975 

7. Polychlorinated Biphenyls (PCBs) - November 3, 1975 

- August 20, 1976 

8. 4,4'-Diaminodiphenylmetbane (DDM) - January 30, 1976 

9. Chloroform - March 15, 1976 

10. Radon Daughters - May'l1, 1976 

11. Dimethy1carbamoyl Chloride (DECC) - July 7, 1976 

Revised 

12. Diethy1carbamoyl Chloride (DEC C) - July 7, 1976 

13. Explosive Azide Hazard - August 16, 1976 

14. Inorganic Arsenic - Respiratory - September 27,1976 

Protection 

15. Nitrosamines in Cutting Fluids - October 6, 1976 

16. Metabolic Precursors of a Known Human - December 17,1979 

Carcinogen, Beta-Naphthylamine 

17. 2-Nitropropane - April 25, 1977 

18. Acrylonitrile - JUly 1, 1977 

19. 2,4-Diaminoanisole in Hair and Fur Dyes - January 13, 1978 

20. Tetrachloroethylene (Perchloroethylene) - January 20, 1978 

21. Trimellitic Anhydride (TMA) - February 3, 1978 

22. Ethylene Thiourea (ETU) - April 11, 1978 

23. Ethylene Dibromide and, Disulfiram - April 11, 1978 

Toxic Interaction 

24. Direct Black 38, Direct Blue 6, and - April 17, 1978 

Direct Brown 95 Benzidine Derived Dyes 

25. Ethylene Dichloride (1,2-Dichloroethane) - April 19, 1978 

26. NIAX· Catalyst ESN - May 22, 1978 

27. Chloroethanes - Review of Toxicity - August 21, 1978 

28. Vinyl Halides - Carcinogenicity - September 21,1978 

29. Glycidyl Ethers - October 12, 1978 

30. Epichlorohydrin - October 12, 1978 

,,' u.s. GOVERNr.;ENT PRINTING OFFICE, 1979 -651-061/5820 


DEPARTMENT OF 

HEALTH, EDUCATION, AND WELFARE 

PUBLIC HEALTH SERVICE 

CENTER FOR DISEASE CONTROL 

NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH 

ROBERT A. TAFT LAB')RATORIES 

4676 COLUMBIA PARKWAY. C I NCINNATI. OHIO 45226 

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PENALTY FOR PRIVATE USE. $300 

SPECIAL FOURTH -CLASS BOOK P05TAGE AND FEES PAlO 

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HEW 396 

DHEW (NIOSH) Publication No. 79-146·