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 site-specific 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.
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 report1 based on data from a case-control study of 25,416 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
24 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.
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, 294-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 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 , 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 294-diaminoanisole must be avoided in the
workplace.
There are reports indicating that 2,4-diaminoanisole is mutagenic in
bacterial systems9 and in drosophila.10 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.
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 2,4-diaminoanisole is being further evaluated,
the National Institute for Occupational Safety and Health recommends, as
an interim and prudent measure, that occupational exposure to 2,4-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 2,4-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.
[signature]
Edward J. Baier
Deputy Director
Notes
*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). [return to text]
**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. [return to text]
References
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.
Garfinkel J., Selvin, S. and Brown, S. M., "Possible Increased Risk of
Lung Cancer Among Beauticians," J. National Cancer Institute, 58, 141,
1977.
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.
Kinlen, L. J. et al., "Use of Hair Dyes by Patients with Breast Cancer: Case-Control Study," British Medical Journal, 2, 366, 1977.
Menck, H. R. et al., "Lung Cancer Risk Among Beauticians and Other Female Workers," J. National Cancer Institute, 59, 1423, 1977.
Shafer, N., and Shafer, R. W., "Potential of Carcinogenic Effects of Hair Dyes," New York State Journal of Medicine, 76, 394, 1976.
Burnett, C. et al., "Long-Term Toxicity Studies on Oxidation Hair Dyes," Food and Cosmetics Toxicology, 13, 353, 1975.
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.
Ames, B.N. et al., "Hair Dyes Are Mutagenic: of a Variety of Mutagenic Ingredients," Proceedings National Academy of Sciences USA, 72, 2423, 1975.
Blijleven, W. G. H., "Mutagenicity of Four Hair Dyes in Drosophila
Melanogaster," Mutation Research, 48, 181, 1977.
Copies of this and other NIOSH documents are available from: