Health and Environmental Effects Profile for Pentachloronitrobenzene

Autor: Harlal Choudhury, C.T. De Rosa, J. Coleman, J.F. Stara, F.L. Mink
Rok vydání: 1987
Předmět:
Zdroj: Toxicology and Industrial Health. 3:5-69
ISSN: 1477-0393
0748-2337
DOI: 10.1177/074823378700300102
Popis: Pure pentachloronitrobenzene (PCNB) is a colorless crystalline solid (Worthing, 1983). The commercial product may have a light- yellow to cream color with a musty odor (Hartley and Kidd, 1983). It is practically insoluble in a number of organic solvents. The compound is reasonably stable but may undergo hydrolysis in a strong alkaline medium (Hartley and Kidd, 1983). In 1983, Olin Corp., Leland, MS, was the only manufacturer of PCNB in the United States (SRI, 1984; Hartley and Kidd, 1983). No data for U.S. production volume for this chemical are available, but recent production source data (USITC, 1985; SRI, 1985) suggest that this chemical is no longer commercially produced in the United States. The primary usage of PCNB is as a soil fungicide for a wide variety of crops and in seed treatment (Worthing, 1983; Hartley and Kidd, 1983). The fate of PCNB in water has not been comprehensively studied. Only qualitative data regarding fate and transport in water are available. The half-life of PCNB in the water phase was estimated to be 1.8 days. The two processes reported to be most responsible for the rapid decrease in PCNB concentration in water were volatil ization and sorption to seston and biota, followed by sedimentation as detritus (Schauerte et al., 1982). Neither biodegradation nor photolysis appears to be a significant process for the loss of PCNB from water (Crosby and Hamadmad, 1971; Schauerte et al., 1982). The BCFs for PCNB in the golden orfe, Leucisens idus melanotus, and in rainbow trout, Salmo gairdneri, were reported to be 950- 1130 and 260-590, respectively (Korte et al., 1978; Oliver and Niimi, 1985). It therefore appears that PCNB will moderately bioaccumulate in aquatic organisms. Pertinent data regarding the fate and transport of PCNB in air could not be located in the available literature as cited in the Appendix. Based on its physical properties and its behavior in other media, it would appear that PCNB will persist in the atmo sphere because no known chemical/photochemical processes signif icantly degrade this chemical. Precipitation of particulate PCNB, especially of larger particle size and higher particle density, may remove some PCNB from the atmosphere. PCNB is persistent in soils. The two processes that are important in the loss of PCNB from soils are volatilization and biodegradation; biodegradation is more rapid in soils under anaerobic conditions than under aerobic conditions (Ko and Farley, 1969; Casley, 1968; Gile and Gillett, 1979; Cole and Metcalf, 1977). The average half- life of PCNB in a variety of field soils was reported to be 434 days (Beck and Hansen, 1974). Another study reported the half-lives for PCNB in sandy loam, clay and peaty muck soils as 4.7, 7.6 and 9.7 months, respectively (Wang and Broadbent, 1972). PCNB is expected to be moderately mobile in soils (Gile and Gillett, 1979). Evidence of very restricted (∼ 3% on the average) translocation of PCNB and its metabolites from the roots to foliar tissue in plants was reported by Cairns et al. (1983). Pertinent data regarding the levels of PCNB in ambient and drink ing water could not be located in the available literature as cited in the Appendix. U. S. EPA's STORET database contains 120 entries on the analysis of PCNB in ambient water and aqueous effluent samples. Maximum and minimum PCNB concentrations in these samples were 1.0 and 0.01 μg/l, respectively, with a mean value of 0.4 μg/l. Pertinent data regarding the ambient atmospheric level of PCNB could not be located in the available literature as cited in the Appendix. The concentration of PCNB in the ambient air of a commercial pest control building was reportedly 1.56 μg/m3 (Yeboah and Kilgore, 1984). In the foods consumed by U.S. adults, infants and toddlers, PCNB residues have been detected mainly in the oils, fats and shortening group of foods (Johnson et al., 1981a,b, 1984a; Johnson and Manske, 1976; Manske and Johnson, 1975; 1984a,b). Occasionally, PCNB has been detected in sugar and adjuncts, fruits and potatoes (Manske and Johnson, 1977; Johnson and Manske, 1977; Podre barac, 1984a). On the basis of the assumption of a maximum PCNB content of 0.006 mg/kg (Johnson et al., 1984a) in oil, fats and shortening composite and a daily adult consumption of 0.070 kg/day of this category of food (Johnson et al., 1984a), the maxi mum daily adult intake of PCNB in the United States has been estimated to be 0.4 μg. The Canadian daily PCNB intake has been reported to vary between 0 and 0.4 μg (McLeod et al., 1980). Little pertinent information is available concerning toxicity of PCNB to aquatic organisms in the available literature. PCNB tox icity to carp increased with increasing temperature, with 24-hour LC50 values ranging from 40 mg/l at 15° C to 1 mg/l at 35° C (Hashimoto and Nishiuchi, 1981). The lowest concentration at which toxic effects were reported for any species was 1 mg/l. PCNB and its metabolites can apparently accumulate to a signifi cant extent in fish and other aquatic biota. In the species that have been studied, PCNB metabolism involves denitrification but not dechlorination (Bahig et al., 1981; Murphy et al., 1982). Pharmacokinetic and metabolism studies of PCNB indicate that it is rapidly and extensively absorbed from the gastrointestinal tract of rabbits, rats and monkeys (Betts et al., 1955; Korte et al., 1978; Koegel et al., 1979a,b). Following absorption by monkeys and rats, PCNB is rapidly metabolized and the metabolites are widely dis tributed to tissues but do not accumulate (Koegel et al., 1979a,b; Borzelleca et al., 1971). Courtney et al. (1976) demonstrated that PCNB and its metabolites can cross the placental barrier of mice. Major metabolites in urine and feces of monkeys and rats include pentachloroaniline, pentachlorothionanisole, pentachlorobenzene, pentachlorophenol, pentachlorothiophenol and mercapturic acid conjugates (Borzelleca et al., 1971; Koegel et al., 1979c). Metabolic pathways in monkeys involve reduction of the nitro group to pen tachloroaniline and conjugation with glutathione. Conjugation twice with the same molecule of PCNB can lead to bis methylmercapto-tetrachlorobenzene and other tetrachlorometabo lites. Conjugation and nitro reduction combined can lead to tetrachloroaminometabolites. Similar pathways may operate in rats. The metabolites are excreted in the urine and bile. Biliary excretion accounts for the fecal metabolites. Unchanged PCNB was excreted only in the feces of monkeys. The rate of excretion of PCNB and metabolites was dose-dependent: 50% was excreted in 24 hours following a dose of 0.5 mg/kg; and 50% was excreted in 4 days following a dose of 91 mg/kg. There have been five chronic bioassays involving dietary adminis tration of PCNB. BRL (1968a) administered an average concentra tion of 1298 ppm PCNB to 18 male and 18 female B6C3F1 and B6AKF1 mice for 77 weeks. Courtney et al. (1976) later confirmed that the sample was contaminated with 11% hexachlorobenzene (HCB). The only positive neoplastic results were increased inci dences of hepatomas in female B6C3F1 and male B6AKF1 mice (p < 0.001), compared with negative controls. Cabral et al. (1977, 1978), however, noted increased incidences of this tumor type in hamsters treated with 50-200 ppm and mice treated with ≥ 100 ppm HCB alone in the diet. NCI (1978) administered 97% PCNB to 50 male and 50 female Osborne-Mendel rats and B6C3F1 mice for 78 weeks, at two die tary levels. Average concentrations for the low-dose rats were 5417 ppm (males) and 7875 ppm, (females), and for the high-dose rats were 10, 064 ppm (males) and 14,635 ppm (females). Average con centrations for the low-dose mice were 2606 ppm (males) and 4093 ppm (females), and for the high-dose mice were 5213 ppm (males) and 8187 ppm (females). Compared with control groups of 20 rats each, the treated rats showed no significant increases in tumor inci dence. Among the mice, low-dose males and high-dose females did not show any significant (by the Fisher exact test) elevations in hepatocellular carcinomas over control rats. These results were especially difficult to evaluate because of the small number of male mice that survived to terminal sacrifice and the large number of tissue sites that were autolyzed in female mice. In a repeat study by NTP (1986) that used highly purified PCNB (> 99% PCNB, 0.07 ± 0.01% HCB), B6C3F1 mice were given the compound in the diet at 2500 or 5000 ppm for 103 weeks. No evidence of carcinogenicity was found, although high mortality in the treated female mice decreased the sensitivity of the study. Two oral chronic bioassays using technical grade PCNB were per formed in Swiss mice (Van der Heijden and Til, 1974) and albino rats (Anonymous, n.d.). The compound was administered for 80 weeks (mice) and 104 weeks (rats), at 0, 100, 400 or 1200 ppm. In high-dose female mice there were increased (p < 0.001) incidences of fibrosarcomas and combined fibromas/fibrosarcomas (p < 0.001), relative to control values. By employing Cochran-Armitage trend tests, statistically significant (p < 0.001) differences were observed in female mice for these tumor types. In male mice, there was suggestive evidence of a treatment-related increase in liver nodules, which was probably a hyperplastic rather than a neoplas tic effect. In rats of either sex, there appeared to be no treatment- related increase in tumorigenesis. An analysis of the possible influence of the technical grade contam inant HCB shows there to be a reasonably close numerical relation ship between the HCB level and the estimated carcinogenic potencies of the technical grade PCNB compared with the HCB alone. A similar relationship seems to exist for the tumor response. In view of the available data, it is reasonable to observe that the technical grade contaminant, HCB, may be influential in the observed carcinogenic activity of PCNB. Using weight of evidence criteria from the U.S. EPA (1984) proposed guidelines, PCNB is considered to have limited evidence for human carcinogenicity; thus it can be classified as an EPA Group C compound. PCNB has been found to initiate carcinogenic activity in initiation- promotion studies (Searle, 1966), but not when given as a single subcutaneous injection to B6C3F1 or B6AKF1 mice (BRL, 1968b). In vitro, PCNB was not mutagenic in reverse mutation assays using S. typhimurium (Waters et al., 1982; Haworth et al., 1983) or E. coli (Shirasu et al., 1976; Waters et al., 1982; Moriya et al., 1983) with or without metabolic activation. It did cause reverse muta tions in an E. coli WP-2 repair-deficient strain (Clarke, 1971). In an assay for forward mutations in E. coli (Mohn, 1971), the rec assay in Bacillus subtilis (Shirasu et al., 1976) and mitotic recombination in Saccharomyces cerevisiae (Waters et al., 1982), PCNB was not genotoxic. The compound also had no effects in sex-linked reces sive lethal assays in Drosophila melanogaster (Waters et al., 1982; Vogel and Chandler, 1974), a dominant lethal assay in mice (Jor genson et al., 1976), unscheduled DNA synthesis in human fibro blasts (Waters et al., 1982) or in host-mediated assays in S. typhimurium and Serratia marcescens (Buselmaier et al., 1972). In a 3-generation study in CD rats, there were no effects on repro ductive indices or terata in any generation that were due to the con tinual administration of up to 500 ppm PCNB in the diet (Borzelleca et al., 1971). No microscopic anomalies were found in the tissues of treated third-generation weanlings. Oral treatment of rats with 200 mg/kg PCNB on gestation days 6-15 led to losses in maternal body weight gain and decreased numbers of liveborn fetuses/litter (Khera and Villeneuve, 1975). There were no dose- related effects on the appearance of terata or postnatal fetal devel opment at < 125 mg/kg (Jordan et al., 1975). In C57BL6 (but not AKR) mice, oral administration of 215 or 464 mg/kg PCNB (con taminated with 11% HCB) on days 6-15 of gestation increased the incidences of renal agenesis and, to a lesser extent, microphthalmia, in fetuses (BRL, 1968b). The effects on kidney development were also observed when administration was on gestation days 6-10 but not on days 10-15. Courtney et al. (1976) conducted a series of studies that were designed to pinpoint the causative factors of the reported renal teratogenicity. Administration of 500 mg/kg PCNB contaminated with 11% HCB to C57B16 mice on gestation days 7-11 increased the incidence of renal and eye malformations and cleft palates in exposed fetuses. There were no teratogenic effects in pups of CD rats dosed with 500 mg/kg contaminated PCNB on a longer treat ment schedule. In CD-1 mice dosed daily throughout organogene sis with either 500 mg/kg contaminated PCNB or 100 mg/kg HCB, there were statistically significant increases in the incidences of cleft palate and renal malformations, respectively. Dosing with 500 mg/kg pure PCNB increased the incidence of clubfoot and fetal mortality. This regimen did not, however, provoke renal agenesis in the offspring and only slightly increased the incidence of cleft palate. The authors concluded that HCB was the etiological agent in renal ophthalmological terata. Two-year administration of 0, 5, 30, 180 or 1080 ppm 97.8% PCNB to three male and three female beagles/group, in the diet, had no consistent effect on the body weights, clinical signs, urinalysis results or blood biochemistries (Borzelleca et al., 1971). At the high concentration, the investigators found slightly elevated relative hepatic weights in the high-dose dogs and cholestatic hepatosis and secondary bile nephrosis at 108 and 1080 ppm. In a long-term study, Swiss mice were exposed to 0, 100, 400 or 1200 ppm PCNB (Van der Heijden and Til, 1974). After 80 weeks, males showed a treatment-related increase in hyperplastic hepatic nodules that was slightly elevated at 100 ppm but markedly increased at 400 and 1200 ppm; this effect was accompanied by hepatomegaly at 400 and 1200 ppm. The appearance of hepatic nodules was not observed in females, although high-dose females were shown to have increased kidney weights. In another study, Wistar rats were given dietary PCNB at 0, 100, 400 or 1200 ppm for 104 weeks (Anonymous, n.d.). At 1200 ppm, relative kidney and liver weights were higher than control values. In both sexes, indications of hepatotoxicity, including enlarged centrilobular hepatocytes, fatty centrilobular metamorphosis and single cell necrosis were slightly elevated at the 100 ppm level and markedly elevated at the higher concentrations. Female albino rats given technical grade PCNB as a 20% powder for 2 years, up to dietary levels of 23,500 ppm, had sporadic inhibition in growth rates (Fin negan et al., 1958). There were no treatment-related effects upon mortality rates, hematologies or incidences of tissue damage. These investigators also found hepatocellular enlargement and pale- staining cytoplasm in groups of three dogs exposed for 1 year to 25-1000 ppm PCNB in the diet. Two strains of mice given 1298 ppm "contaminated" PCNB in the diet for 77 weeks had increased incidences of pneumonia and lymphoid infiltration, relative to con trols (BRL, 1968a). In a more comprehensive bioassay, the NCI (1978) found that TWA concentrations of 10,064-14,635 ppm die tary PCNB led to a "hunched" appearance and abdominal urine stains in male and female rats. At these dietary levels and at lower levels (5417-7875 ppm), there were inhibitions in weight gain rela tive to controls. The hunched appearance also occurred in treated mice, and female mice treated with up to 9000 ppm (TWA = 8187 ppm) PCNB showed an inhibition of weight gain. No treatment- related effects or nonneoplastic tissue pathology were noted. In a repeat study using B6C3F1 mice, there was a dose-related decreased body weight gain, increased mortality and increased incidence of ovarian abscesses in females given 2500 and 5000 ppm in the diet for 103 weeks (NTP, 1986). The increased mortality was attributed to a combination of the toxicity of PCNB and the ovar ian infections. It was suggested that the PCNB treatment predis posed the female mice to infection. Fytizias-Danielidou (1975) administered a 75% pure suspension of PCNB to Wistar rats by gavage, 6 days/week for up to 32 weeks. Serial sacrifices were made every 8 weeks. Exposure to 400 mg/kg, and to a lesser extent 200 mg/kg led to increases in mortality, tran sient inhibitions in weight gain, polyuria, hepatocellular necrosis, hepatomegaly and degeneration of the renal tubular epithelium. There were no changes in hematological parameters. A number of animal studies involving subchronic oral exposure to PCNB have been conducted. Koegel et al. (1979b) found no effects of 2 ppm dietary PCNB, given over 70-80 days, on four rhesus monkeys, relative to historic controls. In a 13-week oral dosing experiment, Finnegan et al. (1958) noted mortality and morbidity in rats given a dietary concentration of 5000 ppm PCNB (as a 20% dust), and inhibition in growth rate in males given 2500 ppm. At lower concentrations, there were increases in relative liver and kid ney weights. The NCI (1978) observed body weight gain depres sions and mortality in rats exposed to ≥ 21,500 ppm or greater PCNB and in mice exposed to 4640 (males) or 10,000 (females) ppm for a 6-week period. NTP (1986) found significantly increased relative liver weights in male mice treated at ≥ 2500 ppm and females at ≥ 5000 ppm PCNB in the diet for 13 weeks. Mice of both sexes were emaciated at ≥ 20,000 ppm. The 40,000 ppm level was fatal to female mice and resulted in lymphoid depletion. Finally, Kawano et al. (1979) noted evidence of increased hepatic microsomal activity in rats given 2000 ppm PCNB, of an unknown purity, for 3 weeks. Acute oral LD50 values for PCNB in rodents range from 1.65 to > 12 g/kg. The technical grade material has been found to be more hazardous than the wettable powder (Finnegan et al., 1958; Renner, 1980; Cholakis et al., 1981). Schumann and Borzelleca (1978) reported methmoglobinemia in rats after oral administration of PCNB, an effect not observed by Koegel et al. (1979b) in rhesus monkeys. Dose and species differences were the two most likely reasons for these discrepancies. Although the evidence indicates that relatively pure PCNB (< 1% HCB) did not induce hepatomas in B6C3F1 mice (NCI, 1978; NTP, 1986), albino Swiss female mice fed relatively pure PCNB with HCB contamination of 2.7% developed statistically significant increased incidences of subcutaneous fibromas and fibrosarcomas. From these data a q1* for humans of 3.93 × 10-2 (mg/kg/day) -1 was derived. Another bioassay with 11% HCB contamination shows a hepatoma response in male B6AKF1 and female B6C3F1 mice. These data were used to derive a human qi* of 0.26 (mg/kg/day) -1. Since the potency of the tested PCNB compounds seems related at least in part to the level of HCB contaminant, any statements about risk levels derived from the available data must be referenced to the purity of PCNB. Arbitrarily, the bioassay with the highest level of PCNB contamination will be used to derive drinking water levels and RQ "F" factors. The concentrations in water associated with risk levels of 10-5, 10-6 and 10-7 are 1.33 × 10-3, 1.33 × 10-4 and 1.33 × 16-5 mg/l. An F factor of 1.4 (mg/kg/day)-1 was also derived. The limited evidence in animals and lack of evidence in humans indicate that PCNB is an EPA Group C chemical. Therefore, PCNB has a LOW hazard ranking under CERCLA. At 180 ppm (2.7 mg/kg/day), dogs had choles tatic hepatosis and bile nephrosis. An RQ of 1000 was also derived based on the liver pathology in dogs at 180 ppm in the study by Borzelleca et al. (1971).
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