The effects of inhalation exposure to sulfuryl fluoride on fetal development in rats and rabbits.

Sulfuryl fluoride is a fumigant insecticide used for soils and permanent structures. Pregnant Fischer 344 rats and New Zealand White rabbits were exposed to 0, 25, 75, or 225 ppm of sulfuryl fluoride vapor via inhalation for 6 hr/day on Days 6-15 and 6-18 of gestation, respectively. Among rats, maternal water consumption was increased in the 225 ppm exposure group, but there were no indications of embryotoxicity, fetotoxicity, or teratogenicity in any of the exposed groups. Among rabbits, maternal weight loss during the exposure period (Days 6-18) was observed in the 225 ppm group. Decreased fetal body weights, considered secondary to maternal weight loss, were also observed at 225 ppm. However, no evidence of embryotoxicity or teratogenicity was observed among rabbits in any exposure group. Thus, inhalation exposure to sulfuryl fluoride was not teratogenic in either rats or rabbits exposed to levels of up to 225 ppm, and fetotoxic effects (reduced body weights) were observed among fetal rabbits only at an exposure level that produced maternal weight loss.

Methylene chloride: a 2-year inhalation toxicity and oncogenicity study in rats.

Male and female Sprague-Dawley rats were exposed to 0, 50, 200, or 500 ppm methylene chloride for 6 hr/day, 5 days/week for 2 years. Blood carboxyhemoglobin levels were elevated in a dose-dependent (less than linear) manner in rats exposed to 50-500 ppm methylene chloride. Histopathologic lesions related to methylene chloride exposure were confined to the liver and mammary tissue of rats. An increased incidence of hepatocellular vacuolization was observed in male and female rats exposed to 500 ppm methylene chloride. Female rats exposed to 500 ppm methylene chloride also had an increased incidence of multinucleated hepatocytes and number of spontaneous benign mammary tumors/tumor-bearing rat (adenomas, fibromas, and fibroadenomas with no progression toward malignancy); the incidence of benign mammary tumors in female rats exposed to 50 or 200 ppm methylene chloride was comparable to historical control values. No increase in the number of any malignant tumor type was observed in rats exposed to concentrations as high as 500 ppm methylene chloride. Additional groups of female rats were exposed to 500 ppm methylene chloride for the first 12 months or the last 12 months of the 24-month study. The response observed in female rats exposed to 500 ppm for the first 12 months was the same as that observed in female rats exposed to 500 ppm for 2 years. Conversely, the response observed in female rats exposed to 500 ppm during the last 12 months of the study was similar to that observed in control animals. Based upon the results of this study, the no-adverse-effect level for chronic inhalation exposure of Sprague-Dawley rats was judged to be 200 ppm methylene chloride.

Hazard communication: the case for category IV "cancer information".

Chemical hazard labeling is changing in order to convey information to a broad spectrum of the public. In addition to standard hazard warnings, supplemental information which includes the enumeration of a wide range of possible adverse effects which may occur under conditions of overexposure is also appropriate. With regard to cancer hazard warnings, known human carcinogens and even confirmed animal carcinogens are fairly easy to identify. The new American National Standards Institute, Inc., guidelines are recommending that cancer hazard warnings be limited to these known human and animal carcinogens. It seems appropriate, however, to extend cancer label statements to encompass information about certain animal tests which are indicative of some degree of carcinogenic activity, but which are not believed to be relevant to human risk in the classical sense when consideration is given to all of the data. This information concerning carcinogenicity test results and their relevance to humans can be added to label text but need not be in the form of a warning.

Acute, pharmacokinetic, and subchronic toxicological studies of 2,4-dichlorophenoxyacetic acid.

The single-dose oral LD50 values in Fischer 344 rats for technical-grade, 2,4-dichlorophenoxyacetic acid (2,4-D), esters, and salts ranged from 553 mg/kg (isobutyl ester in females) to 1090 mg/kg (dimethylamine salt in males). The LD50 values for the acid, esters, or salts, when expressed as acid equivalents, were consistent which suggests that the acute toxicity was due to 2,4-D per se. Acute dermal LD50 values in rabbits for the acid, esters, and salts were greater than 2000 mg/kg. Overall, these results indicate that the acute oral and dermal toxicity of 2,4-D are low. Pharmacokinetics were evaluated in male Fischer 344 rats given single oral doses of 10, 25, 50, 100, or 150 mg 2,4-[14C]D/kg. The amount of 2,4-D in the plasma, kidney, and urine 6 hr postdosing indicated that the urinary elimination of 2,4-D was saturated in male rats given oral doses in excess of 50 mg/kg. Subchronic dietary studies in male and female Fischer 344 rats used dose levels of 0, 15, 60, 100, or 150 mg/kg/day of purified or technical-grade 2,4-D acid for 13 weeks. Body weight gains were decreased for both sexes at the higher dose levels of purified and technical-grade 2,4-D acid. Kidney weights were increased in all treated male rats and in females given the higher three dose levels of purified 2,4-D. Treatment-related cytoplasmic alterations were present in the renal proximal tubules of most rats given 60 mg/kg/day and higher of purified or technical-grade 2,4-D; a few females given 15 mg/kg/day also had slight alterations in the cytoplasm of the proximal tubules. A dose-related degenerative change was identified in the descending proximal renal tubules of all male rats given the highest three dose levels of either test material and some given 15 mg/kg/day. Dose levels of 100 or 150 mg/kg/day of either compound for both sexes produced minimal swelling and increased staining homogeneity in the liver cells and were associated with a slight elevation of liver weight and serum glutamic pyruvic transaminase activity. Higher dose levels of technical-grade and purified 2,4-D decreased total serum tetraiodothyronine levels in female rats, however, the morphology of the thyroid gland was normal. The no-observed-effect level (NOEL) was less than 15 mg/kg/day for both purified and technical-grade 2,4-D acid.

Evaluation of global literature for definition of dose-response relationship for hexachlorobenzene toxicity.

Numerous research groups have generated data that can be collated to define the hexachlorobenzene (HCB) dose-response relationship for subchronic/chronic target-organ toxicity, oncogenicity and reproductive toxicity. Subchronic toxicity studies in rats are typified by Kuiper-Goodman et al. (1977) and Mollenhauer et al. (1975) in which the lowest-observed-effect-level was 0.25-2.0 mg/kg per day and the no-observed-effect-level was 0.05-0.5 mg/kg per day. In the pig, den Tonkelaar et al. (1978) defined the subchronic lowest-observed-effect-level and the no-observed-effect-level as 0.5 and 0.05 mg/kg per day, respectively. In a 12-month dog study by Gralla et al. (1977) the lowest-observed-effect-level was 10 mg/kg per day and the no-observed-effect-level was 1 mg/kg per day. Rozman et al. (1978) reported a no-observed-effect-level of 0.033 mg/kg per day in a study of 18 months' duration in the monkey. Oncogenic assessment of HCB has been carried out in studies using the hamster (Cabral et al., 1977), the mouse (Cabral et al., 1979) and the rat (Arnold et al., 1978; Smith & Cabral, 1980), with responses obtained at doses of approximately 2-4 up to greater than 24 mg/kg per day, but no response at doses of approximately 0.4-0.8 up to 6 mg/kg per day. Reproductive toxicity studies of HCB have used the cat (Hansen et al., 1979a), the pig (Hansen et al., 1979b) and the rat (Grant et al., 1977), obtaining no-observed-effect-levels of 1.0, greater than 0.025-0.5 and 1-2 mg/kg per day respectively, for the three species. Overall, the substantial amount of toxicity data from these studies can be collated into a cohesive pattern that defines the dose-response relationship for HCB toxicity.

Chronic toxicity and oncogenicity bioassay of inhaled ethyl acrylate in Fischer 344 rats and B6C3F1 mice.

Male and female Fischer 344 rats and B6C3F1 mice were exposed to 0, 25 or 75 ppm (0, 0.10 or 0.31 mg/l) ethyl acrylate vapors, 6 hours per day, 5 days per week, for a total of 27 months. Additional rats and mice were exposed to 225 ppm (0.92 mg/l) for 6 months and then held for 21 additional months post-exposure. Histopathologic changes in olfactory portions of the nasal mucosa were present in animals in all of these three exposure groups. These microscopic exposure-related changes were concentration-dependent, primarily in terms of distribution of the lesions within the nasal cavity. Generally those areas of the nasal mucosa normally lined by olfactory epithelium were altered, while the regions lined by respiratory epithelium were relatively unaffected. There was no indication of an oncogenic response in any organ or tissue in either rats or mice. A follow-up study in which Fischer 344 rats and B6C3F1 mice were exposed to 5 ppm (0.02 mg/l) for 24-months revealed no treatment-related changes in the nasal mucosa.

Subchronic oral toxicity, tissue distribution and clearance of hexachloroethane in the rat.

Hexachloroethane (HCE) was fed to Fischer 344 rats at approximate doses of 0, 1, 15 or 62 mg/kg/day for 16 weeks. Selected tissues were assayed at termination for HCE content. Histopathological examination identified the kidney as the primary target organ with male rats more sensitive than female rats. The kidney concentration of HCE increased proportionately with dose in the males, but there were disproportionately small increases with dose in females. A group of male rats was given 62 mg/kg/day for 8 weeks to estimate tissue clearance. Clearance of HCE from fat, liver, kidney and blood occurred in an apparent first-order manner with a half-life of approximately 2.5 days. The apparent first-order elimination suggests that HCE metabolism and excretion were not saturated in rats given up to 62 mg/kg/day and suggests that, in the range of doses given, toxicity should be proportional to exposure concentration. The no-observable-effect level (NOEL) for toxicity was 1 mg/kg/day for male and female rats.

Immunotoxicologic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rabbits.

Male white New Zealand rabbits were exposed orally to 0, 0.01, 0.1, 1 and 10 micrograms/kg/wk of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for a period of 8 weeks. After 4 and 6 weeks of first TCDD administration, the rabbits were inoculated with a mixture of tetanus toxoid and Freund's adjuvant. TCDD exposure reduced the serum antitoxin titers, skin sensitivity to tuberculin, and the number of antibody producing cells in popliteal lymph nodes. At the end of the treatment period serum IgG levels were increased at the lowest dose of TCDD treatment while a marked depression was noticed at the highest dose level. An increase in the thymidine uptake by splenic lymphocytes in culture was noted at all levels of TCDD treatment whereas the response of these cells to phytomitogens was decreased at high levels of TCDD exposure. All different immunologic effects were not altered at the lowest TCDD treatment but both humoral and cell-mediated immune responses were depressed at the highest level of TCDD exposure.

Toxicity of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD).

In summary, the toxicity of TCDD has been comprehensively examined in multiple acute, subchronic, and chronic studies. Acute toxicity studies have shown marked species differences, with up to a 10,000-fold difference between the single oral LD50 dose for the guinea pig and hamster. TCDD is capable of causing an acnegenic response in man and a similar skin response in certain animals. It is also a potent inducer of microsomal enzymes in some but not all species. A dose-related suppression of cell-mediated immunity has been observed at higher dose levels in laboratory animals but not in humans manifesting TCDD-induced acnegenic response. TCDD causes a dose-related teratogenic response in mice, with the no-adverse-effect level of 0.1 micrograms TCDD/kg/day. In rats, TCDD causes embryo- and fetotoxicity above the no-adverse-effect level of 0.03-0.125 micrograms/kg/day. Dose-related reproductive effects have also been noted in monkeys at doses that elicit maternal toxicity, and additional long-term studies are presently underway. A multigeneration reproduction study as well as a lifetime chronic toxicity study have been completed with TCDD in rats; in both studies, the no-adverse-effect level was found to be 0.001 microgram TCDD/kg/day. Numerous mutagenic studies have been performed using in vitro plant and microbial test systems as well as in vivo tests in mammals and man. A mutagenic response was noted in a few of the vitro test systems, but there are no definitive in vivo correlates of TCDD mutagenicity in higher mammals or man. TCDD has been studied for carcinogenic potential in rats and mice. There is good correlation of the results, with a carcinogenic response noted in both species only after long-term ingestion of higher dose levels that induce toxicity. No carcinogenic response occurred at continuous dose levels of 0.001-0.0014 micrograms/kg/day in rats and 0.001-0.03 micrograms/kg/day in mice. Data presently available are more supportive of a nongenetic (?promotor) rather than a genetic mechanism of carcinogenesis. The most recent research, some of which is still underway, indicates that the biologic uptake and toxicity of TCDD may be significantly decreased if the TCDD is adsorbed onto carbon or soil particles. This information is helpful in hazard assessment of exposure to TCDD.

Subchronic toxicity study of 1,2,4-trichlorobenzene in the rat, rabbit and beagle dog.

Male rats, rabbits and dogs were exposed to 0, 30 or 100 ppm of 1,2,4-trichlorobenzene (TCB) for 7 hours/day, 5 day/week for 30 exposures in 44 days. In all 3 species, there were no significant effects on body weight gain, hematologic and serum biochemical tests or gross and histopathologic appearance of tissues. At 100 ppm TCB, both rats and dogs had increased liver weights, and the rats also had increased relative kidney weight at this higher exposure level. Urinary excretion of porphyrins were increased in rats exposed to 30 or 100 ppm TCB, most likely as a result of hepatic induction by TCB. In view of the reversibility of this porphyrin induction noted in a companion study, and the absence of other indications of discernible toxicity, this increased urinary excretion of porphyrins is best considered more of a compound-specific physiologic effect rather than a toxic effect.