OSHA comments from the January 19, 1989 Final Rule on Air Contaminants Project extracted from 54FR2332 et. seq. This rule was remanded by the U.S. Circuit Court of Appeals and the limits are not currently in force.
CAS: 61-82-5; Chemical Formula: C2H4N4
OSHA had no former PEL for amitrole; the Agency proposed a TWA limit of 0.2 mg/m3, which is also the limit recommended by the ACGIH (1986/Ex. 1-3, p. 25) on the basis of positive carcinogenicity studies conducted in rats and mice. OSHA is establishing these limits in the final rule. NIOSH recommends a 10-hour TWA of 0.3 mg/m3 for amitrole, which is a crystalline solid; however, NIOSH specifically concurred with the limit for this substance being established by the final rule (Ex. 8-47, Table N6A). Amitrole is used as an herbicide and plant growth regulator.
Amitrole is a potent antithyroid agent and has been shown to cause tumors, particularly of the thyroid and pituitary glands, in experimental animals (ACGIH 1986/Ex. 1-3, p. 25). Its tumor-producing activity is thought to be related to its goitrogenic effects, which cause an increase in thyroid-stimulating hormone (TSH). Other antithyroid agents that cause TSH stimulation, such as propylthiouracil, have also been shown to produce thyroid tumors (Guyton 1981/Ex. 1-1002). Amitrole has not been shown to be mutagenic in the Ames bacterial mutation assay, a dominant lethal test in male mice, or in assays that measure recessive sex-linked lethal mutations in Drosophila melanogaster (ACGIH 1986/Ex. 1-3, p. 25).
An excess incidence of tumors has been reported to occur among pesticide workers exposed to amitrole alone or in combination with phenoxy herbicides. Although these studies indicate the possible association of increased tumor incidence with exposure to amitrole, confounding factors, such as smoking and concurrent exposure to other pesticides, complicate the interpretation of these data.
The Swedish National Board of Occupational Safety and Health ordered an epidemiological evaluation to assess the incidence of cancer among railroad workers exposed to herbicides (Axelson and Sundell 1974/Ex. 1-812). Amitrole was among the pesticides utilized by these workers. Cohorts were separated into groups according to whether they were exposed to amitrole and combinations of other herbicides, phenoxy acids and combinations of other herbicides, or other herbicides alone. A statistically significant increase in the incidence of total tumors and lung tumors was found among workers exposed to amitrole and combinations of other herbicides. Smoking frequency among members of this group was reported to be similar to the frequency of smoking in the general Swedish population.
In a 1980 follow-up to the Axelson and Sundell (1974/ Ex. 1-812) study, Axelson and co-workers (Ex. 1-242) combined data from the earlier study with data on workers exposed from 1972 to 1978. Cohorts were divided into the following exposure groups: amitrole alone, phenoxy acids alone, and amitrole and phenoxy acids combined. The reanalyzed data did not show a statistically significant increase in cancer incidence among the workers exposed to amitrole alone; however, the incidence of tumors among workers exposed to amitrole and phenoxy acids together was significantly increased (Axelson, Sundell, Andersson et al. 1980/Ex. 1-242).
Amitrole has been found to be carcinogenic in laboratory animals following dietary exposure to relatively high doses. Attempts to induce tumors by dermal application and subcutaneous injection have been unsuccessful. Studies investigating the carcinogenic potential of amitrole in laboratory animals are reviewed below.
The effects of lifetime exposure to amitrole were investigated in rats, mice, and hamsters fed diets containing 1, 10, or 100 ppm amitrole (Steinhoff, Weber, Mohr, and Boehme 1983/Ex. 1-208). There was a significant increase in the incidence of thyroid tumors in male and female rats and in the incidence of pituitary tumors in female rats exposed to 100 ppm. An excess incidence of tumors was not found in male or female rats exposed to 1 or 10 ppm. The results of this experiment are presented in Table C15-3. Tumor induction was not observed in male or female mice or hamsters. Another study reported negative results for rats fed diets containing 10, 50, or 100 ppm amitrole (Jukes and Schaffer 1960/Ex. 1-213).
Dermal applications of 0.1 or 10 mg of amitrole produced no increased incidence of tumors in mice (IARC 1982a/Ex. 1-1112).
In contrast to the negative results obtained in mice following lifetime dietary exposure to 1, 10, or 100 ppm amitrole (Steinhoff, Weber, Mohr, and Boehme 1983/Ex. 1-208), positive results were observed in male and female mice following dietary exposure to higher levels (2192 ppm) of amitrole for one year (Innes, Ulland, Valerio et al. 1969/ Ex. 1-270). Carcinomas of the thyroid were observed in 89 percent (64/72) of the exposed animals (tumor incidence in controls was not reported).
Positive results were also observed in mice exposed to 1 percent (10,000 ppm) amitrole in the diet in a lifetime study (exposure for four weeks followed by one week with no exposure) (Feinstein, Fry, and Staffeld 1978a/Ex. 1-281). Liver tumors developed in 100 percent of the exposed mice; however, the incidence of tumors in unexposed controls was not reported. A small number of thyroid tumors was also reported. The authors hypothesized that the reason more thyroid tumors were not seen was because the animals died of the high toxic doses before such tumors were expressed.
Chronic dietary administration of amitrole in dogs (10, 50, 100, or 500 ppm) and in rainbow trout (1200 or 4800 ppm) did not result in the development of tumors (IARC 1982a/Ex. 1-1112), but these experiments were not long enough to allow for evaluation of the carcinogenicity of the chemical.
Risk estimate for amitrole. The study by Steinhoff et al. (1983/Ex. 1-208) provides sufficient information to estimate quantitatively the excess cancer risk associated with exposure to amitrole in the workplace. The linearized multistage model was chosen to estimate risk. The incidence of malignant thyroid tumors in female rats was used because these tumors demonstrate a clear monotonic response. Female rats were assumed to weigh 250 g and to consume 25 g of food per day. Human risks were estimated at exposure levels corresponding to the proposed PEL of 0.2 mg/m3, as well as for exposure levels of 0.4 mg/m3 and 1.0 mg/m3. OSHA has revised the risk estimates presented in the NPRM on amitrole to correct an overestimate in the calculation of lifetime dose (Ex. 110). The revised excess estimated cancer risk, in terms of excess deaths per 1,000 employees, is shown in Table C15-4.
Exposure to 0.2 mg/m3 of amitrole for an occupational lifetime (45 years) is associated with an estimated 3 excess cancer deaths per 1,000 employees (0.3 percent). This rate is based on the maximum likelihood estimate (MLE). The 95-percent upper-bound estimate of risk corresponding to this dose is about 4 excess cancer deaths per 1,000 workers. By comparison, the maximum likelihood estimates of risk for lifetime exposure to 0.4 mg/m3 or 1.0 mg/m3 are 5 or 13 excess deaths per 1,000 employees, respectively.
NIOSH (Ex. 8-47, Table N6A) concurred with OSHA's 0.2 mg/m3 TWA limit for amitrole. Two other rulemaking participants commented on OSHA's assessment (Ex. 3-894; Tr. pp. 3-13 to 3-14). The American Industrial Health Council (AIHC) (Ex. 3-894) urged OSHA to use a different risk assessment procedure for amitrole that incorporates information on the mechanism by which amitrole induces thyroid tumors:
- Where, as in the case of amitrole, the data indicate that the
tumors in the experimental animals are in endocrine sensitive tissue and
the mechanism is a secondary hormonal action, a risk assessment
procedure incorporating these mechanistic data should be used (Ex.
3-894, p. I-8).
The AIHC cites a draft EPA report on thyroid follicular cell carcinogenesis (EPA/625/3-88/014A, EPA 1988), which indicates that the steps leading to thyroid follicular cell tumors are expected to show a threshold effect. The AIHC also cites an FDA report (General Principles for Evaluating the Safety of Compounds Used in Food-Producing Animals, issued in conjunction with 52 FR 49572, FDA 1988), in which FDA concludes that, for the group of "endogenous sex steroids that have been adequately tested," the oncogenic response is related to overstimulation of the hormonal system and no cancer hazard is perceived to exist if the hormonal system is not overstimulated (Ex. 3-894, p. I-8).
Dr. Isadore Rosenthal, Corporate Director for Safety and Health at the Rohm and Haas Company, also testified on the mechanism of amitrole's carcinogenicity:
- There is much scientific evidence on threshold effects in regard
to the generation of thyroid cancers by goiterogenic agents. In fact,
the EPA has proposed using a new threshold risk assessment method for
evaluating thyroid carcinogens (Tr. pp. 3-13 to 3-14).
OSHA recognizes the possibility that a threshold effect level may exist for the development of tumors induced by this special class of substances that act on endocrine-sensitive tissues. OSHA notes that EPA's preliminary findings and proposed threshold risk assessment model are still under review by the Science Advisory Board, and the Agency eagerly awaits EPA's final conclusions on this issue. OSHA points out, however, that amitrole has produced liver tumors in mice (Innes, Ulland, Valerio et al. 1969/Ex. 1-270; Feinstein, Fry, and Staffeld 1978a/Ex. 1-281) and, in one instance (Feinstein, Fry, and Staffeld 1978a/Ex. 1-281), the liver tumors appeared at an earlier age and at a higher incidence than did thyroid tumors. It is not clear from the present data that the mechanism for the development of these liver tumors is the same as that for thyroid tumors. OSHA also notes that the proposed 0.2 mg/m3 PEL is, according to the ACGIH's calculations, only a factor of 10 lower than the demonstrated effect level for amitrole-induced effects of thyroid function; even assuming that amitrole-induced carcinogenesis follows a dose-threshold pattern, use of a tenfold safety margin when the risk involved is related to a disease as serious as cancer cannot be viewed as unreasonable.
Occupational exposure to amitrole has been shown to be associated with an increased incidence of thyroid and pituitary tumors in experimental animals. Although human studies have not demonstrated conclusively that amitrole is carcinogenic, the studies by Axelson and Sundell (1974/Ex. 1-812) and Axelson, Sundell, Andersson et al. (1980/Ex. 1-242) provide evidence that amitrole may increase the risk of cancer among exposed workers. The Agency concludes that the adverse effects resulting from exposure to amitrole constitute material impairment of health and functional capacity. OSHA's risk assessment, based on the animal data, shows that this significant excess cancer risk can be substantially reduced for employees who are currently exposed above the final rule's 0.2 mg/m3 limit. Therefore, OSHA is establishing a 0.2 mg/m3 TWA exposure limit for amitrole.
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