p-NITROCHLOROBENZENE
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: 100-00-5; Chemical Formula: NO2C6H4Cl
OSHA formerly had an 8-hour TWA limit of 1 mg/m3, with a skin notation, for p-nitrochlorobenzene (PNCB). The ACGIH’s new TLV-TWA of 0.6 mg/m3 (0.1 ppm), with a skin notation for this substance was recently reduced from a TLV-TWA of 3 mg/m3 (0.5 ppm). The Agency proposed to retain its limit and the skin notation, and the final rule includes these limits. para-Nitrochlorobenzene takes the form of yellow crystals and has a sweet odor.
The primary hazards associated with exposure to PNCB include systemic toxicity to the liver, spleen, bone marrow, and kidneys, as well as methemoglobinemia and DNA damage. The Monsanto Company (1977, as cited in ACGIH 1986/Ex. 1-3, p. 432.2) reported an oral LD(50) in rats of 530 mg/kg and a dermal LD(50) in rabbits of greater than 3040 mg/kg; PNCB was absorbed through rabbit skin to produce methemoglobinemia (Kubota 1960, as cited in ACGIH 1986/Ex. 1-3, p. 432.2), although application to the skin or eyes did not produce irritation (Monsanto Company 1977, as cited in ACGIH 1986/Ex. 1-3, p. 432.2). Rusakov, Korotkova, and Bikbulatov (1973/Ex. 1-660) described the development of sensitization in guinea pigs after dermal application of PNCB.
A four-hour inhalation exposure of rats (heads only) showed that the lethal concentration was approximately 16.1 mg/L (E.I. du Pont de Nemours & Co., Inc. 1981, as cited in ACGIH 1986/Ex. 1-3, p. 432.2). Head-only exposures at 0.05, 0.29, or 0.64 mg/L PNCB for six hours/day, five days/week for two weeks resulted in spleen-weight increases and blood effects in all groups. In addition, there were dose-related effects in blood methemoglobin levels (i.e., decreased hemoglobin, hematocrit, and red blood cell count values). Microscopic changes in the spleen, bone marrow, and kidneys were seen in the two higher-dose groups, and both pathological degeneration of the seminiferous tubules and abnormal epididymal sperm contents were also observed in these groups (E.I. du Pont de Nemours & Co., Inc. 1984, as cited in ACGIH 1986/Ex. 1-3, p. 432.2).
The Monsanto Company (1981, as cited in ACGIH 1986/Ex. 1-3, p. 432.2) reported that a 90-day gavage administration of PNCB at daily doses of 0.3, 10, or 30 mg/kg to male and female rats produced hemolytic effects and spleen changes at all levels, kidney and liver effects at mid- to high-level doses, and hyperplasia of bone marrow and testicular atrophy at the highest dose (30 mg/kg/day). In 1985, Monsanto reported the results of another gavage study in rats. After two years of PNCB feeding at 0.1, 0.7, or 5.0 mg/kg/day, animals in the mid- and high-dose groups exhibited hemolytic effects; in addition, mid- and high-dose groups showed microscopic spleen, kidney, and liver changes and, at the highest dose, bone marrow hyperplasia and testicular atrophy (Monsanto Company 1985, as cited in ACGIH 1986/Ex. 1-3, p. 432.2).
Rats fed PNCB at doses of 0, 0.1, 0.7, or 5 mg/kg/day for up to two years showed methemoglobinemia at the two highest levels, and animals in the 5-mg/kg/day group had indications of anemia and pigment accumulation in spleen cells. No treatment-related increase in tumors was observed (Monsanto Company 1985, as cited in ACGIH 1986/Ex. 1-3, p. 432.2). In a dietary cancer bioassay, rats and mice were given PNCB at unspecified levels for two years (Weisberger, Russfield, Homburger et al. 1978/Ex. 1-535). Only mice were affected, with mice of both sexes showing an increase in vascular tumors at the highest dose and male mice showing an increase in liver tumors at the lowest dose (Weisberger, Russfield, Homburger et al. 1978/Ex. 1-535).
Maternal toxicity was seen in rats given PNCB by gavage at doses of 15 and 45 mg/kg/day on days nine through 16 of gestation; at the 45-mg/kg level, fetotoxicity and teratogenicity were also observed (Nair, Johannsen, and Schroeder 1985/Ex. 1-752). At 15 mg/kg, maternal toxicity but no fetotoxicity or teratogenic effects occurred; at the lowest dose, the only effect was a small increase in maternal spleen weight. A two-generation reproductive study resulted in a reduced mating index in rats given 0.7 or 5.0 mg/kg/day (Monsanto Company 1984, as cited in ACGIH 1986/Ex. 1-3, p. 432.2). Positive responses were observed in a mutation assay of L5178Y TK mouse lymphoma cells (both with and without metabolic activation) and in a microbial assay of Salmonella strain AT 1535 (in the absence of metabolic activation); however, no evidence of mutagenicity was noted in assays of three other Salmonella strains or in assays of Chinese hamster ovary cells, rat hepatocyte primary culture/DNA repair, or rat bone marrow cell clastogenesis (Monsanto Company 1980-1984, as cited in ACGIH 1986/Ex. 1-3, p. 432.2). PNCB produced DNA damage in the liver, kidney, and brain cells of rats after a single intraperitoneal dose of 30 to 1000 mg/kg (Cesarone, Bolognesi, and Santi 1983/Ex. 1-542) and in cultured hepatocytes at 1.5 hours after a three-hour treatment (Cesarone, Fugassa, Galle et al. 1984/Ex. 1-541).
p-Nitrochlorobenzene may be absorbed through the lungs and skin in humans to produce methemoglobinemia. Reports of industrial exposures indicate that overexposure causes cyanosis, weakness, and headache (Saita and Moreo 1958/Ex. 1-930; Renshaw and Ashcroft 1926/Ex. 1-522). In a study of workmen exposed to average concentrations of PNCB at 55, 125, or 143 ppm and to a 23-ppm concentration of a PNCB-nitrophenol mixture, the authors concluded that the mixed exposure did not produce chronic intoxication, but did cause increased methemoglobin, the appearance of Heinz bodies, headache, vertigo, and occasional eczema; these effects could not be attributed definitely either to skin absorption or to the level of PNCB in the mixture (Pacseri, Magos, and Batskor 1958/Ex. 1-521). No data are reported for the p-nitrochlorobenzene exposures only (Pacseri, Magos, and Batskor 1958/Ex. 1-521).
Only NIOSH commented on p-nitrochlorobenzene. NIOSH (Ex. 8-47, Table N6B and Tr. III, pp. 97-98) notes that this substance is a potential occupational carcinogen and that the risk remaining at the PEL is substantial; NIOSH therefore regards p-nitrochlorobenzene as a candidate for a full Section 6(b) rulemaking. OSHA is aware both of the recent toxicological data on this substance and of the ACGIH’s recent lowering of the TLV to 0.6 mg/m3. OSHA will carefully monitor the literature on PNCB and will revise the PEL in the future if such action is warranted.
In the final rule, OSHA is retaining its former 8-hour TWA limit of 1 mg/m3 for p-nitrochlorobenzene, with a skin notation. The Agency concludes that these limits are necessary to protect workers from the significant risks of methemoglobinemia and changes in the spleen, liver, and kidney possible at higher exposure levels. OSHA is retaining the skin notation because dermal absorption of PNCB has been shown to cause systemic effects in humans and animals. The Agency finds that methemoglobinemia and spleen, kidney, and liver damage constitute material impairments of health.