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: 95-53-4; Chemical Formula: CH3C6H4NH2
OSHA’s former 8-hour TWA for o-toluidine was 5 ppm, with a skin notation. OSHA proposed to revise this limit to 2 ppm as an 8-hour TWA, with a skin notation. NIOSH (Ex. 8-47, Table N6A) concurs with the selection of this limit and notes that o-toluidine meets the OSHA definition of a potential human carcinogen. The ACGIH identifies o-toluidine as a suspected human carcinogen and has accordingly placed it in the A2 category (ACGIH 1986/Ex. 1-3, p. 586). The International Agency for Research on Cancer (IARC 1982b, as cited in ACGIH 1986/Ex. 1-3, p. 586) classifies o-toluidine as a probable carcinogen (category 2A) based on sufficient evidence of its carcinogenicity in rats and mice following oral administration (IARC 1982b, as cited in ACGIH 1986/Ex. 1-3, p. 586). IARC judged the evidence inadequate to establish o-toluidine’s carcinogenicity in humans. In the final rule, OSHA has determined that it is appropriate to retain both the existing 5-ppm exposure limit and the skin notation for this substance. o-Toluidine is a light yellow liquid that rapidly darkens on exposure to air and light.
o-Toluidine is mutagenic in short-term tests, inducing sister chromatid exchanges and unscheduled DNA synthesis in mammalian cells in vitro and chromosomal anomalies in yeast. o-Toluidine was negative in the micronucleus test in mice in vivo, but induced cell transformations in the BHK (baby hamster kidney) assay. IARC considers these data to be sufficient evidence of o-toluidine’s activity in short-term tests (IARC 1982b, as cited in ACGIH 1986/Ex. 1-3, p. 586).
There are a number of studies that report an excess of bladder tumors in dyestuff workers exposed to o-toluidine and other chemicals; however, there are no studies that examine a population of workers exposed to o-toluidine alone. Workers exposed to toluene, o-nitrotoluene, o-toluidine, and 4,4-methylene bis (2-methylaniline) in manufacturing were observed to have an excess of bladder tumors. However, the concurrent exposures of these workers to these other potential carcinogens make these data inappropriate for use in the quantitative assessment of o-toluidine’s carcinogenic risk in human populations. A few reports of bladder tumors in persons exposed primarily to o-toluidine have been reported, but insufficient follow-up time and incomplete data have prevented the establishment of a clear quantitative association between o-toluidine exposure and cancer in humans. For this reason, IARC considers the data from human studies inadequate to establish an association between exposure to o-toluidine and cancer (IARC 1982b, as cited in ACGIH 1986/Ex. 1-3, p. 586).
o-Toluidine has been determined to be carcinogenic in rats and mice following oral administration. In rats, statistically significant increases in subcutaneous fibromas, fibrosarcomas, and cancers of the urinary bladder have been reported. Studies in mice have resulted in statistically significant increases in hemangiosarcomas and hepatocellular carcinomas.
The National Cancer Institute (NCI 1979c, as cited in ACGIH 1986/Ex. 1-3, p. 586) conducted long-term carcinogenicity studies with o-toluidine in rats and mice. Both of these studies were positive for carcinogenicity. The mouse study used groups of 50 female and 50 male B6C3F1 mice fed o-toluidine hydrochloride in the diet at levels of 1000 ppm or 3000 ppm for 102 to 103 weeks. There was no excess mortality in the tested animals. At the 3000 ppm dose level, there was a statistically significant increase in hemangiosarcomas at all sites in males and a statistically significant increase in hepatocellular carcinomas and adenomas in females.
The National Cancer Institute also conducted a two-year feeding study with 50 male and 50 female Fischer 344 rats. There was a dose-related trend in mortality (which was not caused by cancer); all the males in the high-dose group died by 100 weeks. However, the females at both dose levels were observed to have significant increases in transitional-cell carcinomas or papillomas of the urinary bladder, and the high-dose females developed fibroadenomas of the mammary gland. The males at both dose levels showed significant increases in fibromas of the subcutaneous tissue and mesotheliomas in multiple organs (NCI 1979c, as cited in ACGIH 1986/Ex. 1-3, p. 586). The high mortality in the males complicates the interpretation of these latter findings.
Weisburger, Russfield, Homburger et al. (1978/Ex. 1-535) reported positive findings for o-toluidine in long-term feeding studies in rats and mice. The study in rats was conducted with two groups of 25 male CD rats fed o-toluidine in the diet via one of two regimens: 8000 ppm for three months and then 4000 ppm for an additional 15 months; or 16,000 ppm for three months and then 8000 ppm for an additional 15 months. Statistically significant increases in the incidence of subcutaneous fibromas and fibrosarcomas were observed in both dose groups. In addition, there was a non statistically significant increase in the incidence of transitional-cell carcinomas of the urinary bladder in these animals.
Weisburger, Russfield, Homburger et al. (1978/Ex. 1-535) also reported the results of a long-term study in mice. Groups of 25 male and 25 female CD-1 mice were fed diets containing toluidine at two dose levels: 16,000 ppm for three months and then 8000 ppm for an additional 15 months; or 32,000 ppm for three months and then 8000 ppm for an additional 15 months. There was a statistically significant, dose-related increase in the incidences of vascular tumors (hemangiosarcomas and hemangiomas of the abdominal viscera) in both sexes of treated mice, compared with results in control mice.
Risk estimate for o-toluidine. Four of these carcinogenicity studies of o-toluidine have yielded sufficient and adequate data for quantitative risk estimation: the two NCI studies (NCI 1979c, as cited in ACGIH 1986/Ex. 1-3, p. 586) and the two Weisburger et al. (1978/Ex. 1-535) studies. OSHA has used the NCI (1979c) study in rats as the basis for its quantitative risk assessment because it provides the most appropriate data. Table C15-7 presents the Maximum Likelihood Estimates (MLEs) of excess deaths per 1,000 employees predicted to result from exposure to o-toluidine at the current OSHA PEL of 5 ppm and at the proposed PEL of 2 ppm. These data were calculated using a multistage model, GLOBAL83.
Table C15-7 shows an excess MLE estimate of risk of 1.4 per 10,000 workers exposed over their working lifetimes at the current PEL. This risk would be reduced to 0.5 per 10,000 exposed workers after promulgation of the final rule’s limit of 2 ppm. This level of risk is lower than the levels OSHA has regulated for some carcinogens, such as ethylene oxide, arsenic, and benzene. George M. Talley and Michael C. Garcia, Industrial Hygienists for the Los Alamos National Laboratory, commented that OSHA’s risk assessment does not support a reduction in the PEL for o-toluidine (Ex. 3-1095).
Lawrence Hecker of Abbott Laboratories (Tr. p. 9-149) commented that OSHA’s skin notation for o-toluidine is not supported by the available evidence. As described in Section VI.C.18 of the preamble regarding OSHA’s general policy for establishing skin notations in this rulemaking, OSHA has determined that removal of an existing skin notation is not warranted unless human data are available that demonstrate the absence of a significant health risk from dermal contact with the hazardous substance in question. No such data exist for o-toluidine; therefore, OSHA is retaining the skin notation for o-toluidine in the final rule.
OSHA has concluded that further reduction in the exposure limit for o-toluidine would require a detailed analysis of the levels at which significant risk is eliminated. Both because of the scope of this rulemaking and because there were few comments on this issue, OSHA has not directed its limited resources to conduct a detailed analysis of this issue at this time. Accordingly, OSHA has concluded that it is appropriate to retain both the existing 5-ppm PEL and the skin notation for o-toluidine in this proceeding. OSHA is not making any final determination on either the general policy issue or what its conclusion might be in a single-substance rulemaking involving extensive public comment and detailed analysis.