Environmental and toxicological planning in polymer production and disposal.

There is neither a prescribed format nor a rigid sequence of testing to follow for the assessment of health and environmental effects of chemicals. Conventional animal toxicity tests plus medical surveillance and monitoring of exposed human populations will provide knowledge of the biological effects of chemicals and assurance that they can be handled safely. Useful information also can be derived from other test procedures. These include extraction studies to measure the amounts of additives which can leach from polymers, toxicity tests using aquatic organisms and birds, and determination of the biodegradability of materials and their potential for accumulation and magnification in biological systems. Current concern over pyrolysis products of polymers points up the need for defining the variables involved and development of test procedures by which meaningful evaluations of potential health hazards can be made.

A review of toxicology studies on cyanurate and its chlorinated derivatives.

Chlorinated cyanurates are added to swimming pools as disinfectants. In the presence of water, these materials hydrolyze to yield cyanurate and hypochlorous acid. To evaluate the safety of exposure to these materials, a comprehensive testing program was undertaken. This review summarizes the results of acute and subchronic tests on chlorinated isocyanurates. Findings from acute, subchronic, reproduction, metabolism, mutagenicity, and chronic/carcinogenicity tests on cyanurate are also summarized. Results from these tests indicate that chlorinated isocyanurates are safe for use in swimming pools.

Hepatic involvement of two chlorinated propenes following repeated oral exposure in the rat.

The comparative toxicity of two chlorinated propene isomers, 1,2,3-trichloropropene (TRCP) and 1,1,2,3-tetrachloropropene (TECP), was investigated via subchronic oral administration to rats for 4 weeks. Test groups, each consisting of 5 male and 5 female rats, were exposed to 0, 3, 10, 30, 100 or 300 mg/kg/d TRCP or TECP by gavage. A separate corn oil control group was used for each chloropropene. While all rats of both sexes given 300 mg/kg/d TRCP died, only 1 female exposed to 300 mg/kg TECP died. Mean body weights were reduced in male rats given 100 mg/kg/d TRCP. With TECP, dose-related reductions in mean body weight and food consumption were seen at 100 and 300 mg/kg/d. Moderate fatty changes in the livers of high-dose TRCP-treated rats which died during the first study week were probably related to chloropropene exposure. Treatment-related necrotic/degenerative lesions of the liver were seen in both male and female rats administered 300 mg/kg/d TECP.

Effects of formaldehyde in the rat and dog following oral exposure.

Formaldehyde was administered orally (p.o.) to groups of rats and dogs at dosages up to 150 and 100 mg/kg/day, respectively, for 91 consecutive days. Significant body weight changes were observed at the higher dosages tested in both species. Decreased water consumption was observed in a dose-related pattern in all treated groups of rats. Food consumption and feed efficiency were decreased at higher dosage levels in dogs. Results of other clinical studies and microscopic pathology revealed no specific, treatment-related effects on any organ or tissue examined. These findings suggest that formaldehyde possesses little subacute toxicity following oral exposure.

Subchronic toxicity of tetramethylsuccinonitrile.

The acute rat oral LD50 for tetramethylsuccinonitrile (TMSN) is 38.9 +/- 7.4 mg/kg. A series of three 90-day subchronic toxicity studies were conducted with Sprague-Dawley-derived albino rats. In each study, rats were administered corn oil solutions of TMSN by intubation. In the first study, groups of 15 male and 15 female rats were given 0, 1, 3, or 10 mg/kg TMSN. Significant reductions in weight gain were observed at 10 and 3 mg/kg/day. Survival, demeanor, food consumption, hematology, and urinalysis were not affected. Except for a reduction in fasting blood glucose in the 10 mg/kg test group, no effects were observed in clinical pathology parameters. Absolute and relative liver weights were increased at 10 mg/kg (both sexes) and 3 mg/kg (males). Both absolute and relative kidney weights were increased and treatment-related morphological lesions, characterized as tubular nephrosis, were observed in all test groups of males, but not in females. Other TMSN-related microscopic observations were limited to liver changes in both sexes at 10 mg/kg. Two subsequent 90-day studies, each conducted with 15 male rats per group, used levels of 0, 0.001, 0.01, 0.1, 0.3, or 1.0 mg/kg/day TMSN. Renal weight increases were observed at 1.0 mg/kg TMSN. Microscopic renal lesions similar to those seen in the first study were observed down to 0.1 mg/kg TMSN. A no-effect level was established at 0.01 mg/kg TMSN. No treatment-related microscopic lesions of the kidney were observed in groups of male rats given 3.0 mg/kg TMSN by gavage for 90 days and then removed from treatment for 14 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationships between toxicity and structure of aliphatic nitriles.

A retrospective structure-activity relationship (SAR) comparison was undertaken of several of the toxicological properties (acute and subchronic toxicity, teratogenicity, and biochemical mechanism studies) of a series of structurally similar aliphatic nitriles based on available published data. Members of this chemical class included several mononitriles (aceto-, propio-, butyro-, and acrylonitrile), dinitriles (succino- and adiponitrile), and cyanohydrin derivatives (lactonitrile and acetone cyanohydrin). Broadly defined, retrospective SAR analysis suggested that the toxicological profiles of this group of aliphatic nitriles were similar; however, unique differences were observed within each of the toxicity categories and nitrile subclasses as the toxicological focus narrowed. Additionally, the toxicological properties associated with acetonitrile, the first of this chemically similar series, were unique and quite different from others within the homologous series. Finally, knowledge regarding the mechanism of toxicological action provided valuable information in relating toxicological properties among the aliphatic nitriles.

Oral toxicity of trichlorobenzyl chloride and its acid derivative.

The acute rat oral LD50 of 2,4,6-Trichlorobenzyl chloride (TCBC) was determined to be 3075 mg/kg. When male and female rats were administered 1500 and 3000 ppm TCBC in the diet for 3 weeks, marked retardation in weight gain was observed. Reductions in food consumption were noted in both groups of treated male, but not female, rats. All blood chemistry and urinalysis parameters including those indicative of liver injury, were within the range of normal limits. Gross necropsy revealed pale livers in all high-dose rats and the majority of low-dose animals. Gross observations correlated with observation of degenerative hepatic changes (irregularity of cell and nuclear size, cord pattern, edema and cytoplasmic alterations) following microscopic evaluation. Rats and dogs administered up to 100 ppm trichlorobenzoic acid (TCBA) in the diet for 90 days exhibited no effects considered related to treatment.

Acute and subchronic toxicity of tetramethylcyclohexanes.

The acute oral toxicity in rats was estimated for seven isomers or isomeric ratios of tetramethylcyclohexane (TMCH). Lack of sufficient mortality at the highest dosage test (15.8 g/kg) precluded evaluation of an LD50 for mixed cis, trans-isomers of 1,2,3,4-TMCH, 1,2,3,5-TMCH, 1,2,4,5-TMCH and 1,1,2,3-TMCH, for the separate cis- or trans-forms of 1,1,3,5-TMCH or a 1:1 mixture of c,t-1,1,3,5-TMCH and c,t-1,2,3,4-TMCH. Mixed (c,t-combined) isometric TMCH was administered orally to rats (30/group) and dogs (8/group) for 90 days at dietary levels of 0, 3000, 10,000 and 30,000 ppm TMCH and 0, 100, 300 and 1000 ppm TMCH, respectively. Administration of up to 30,000 TMCH to rats produced no discernible effects on survival, behavior, growth, food consumption, clinical blood picture or urine analysis. Absolute kidney weights of male but not female rats were elevated at all test levels. TMCH-related microscopic lesions were confined to the kidney of male rats in all treated groups. These histopathologic changes were characteristic of tubular nephrosis. No treatment-related effects were observed in groups of dogs fed up to 1000 ppm TMCH for 90 days.

Toxicological profile of orally administered 1,6-hexane diamine in the rat.

The industrial chemical 1,6-Hexane Diamine, or hexamethylenediamine (HMD), has an acute oral LD50 of 980 mg kg-1 in rats. Dietary administration of HMD to groups of rats for 3 months at dosages of 0, 50, 150, and 500 mg kg-1 resulted in a modest retardation in weight gain at the two higher test levels. No other obvious signs of toxicity or changes in the peripheral blood picture or selected clinical pathology parameters were found at any test level throughout the study. Evaluation of absolute and relative weights of 10 selected organs, as well as complete necropsies and microscopic evaluation of over 30 selected tissues and organs, revealed no changes considered related to treatment. The administration of HMD by gavage to pregnant rats at 0, 112, 184 and 300 mg kg-1 day-1 on days 6-15 of pregnancy (day 1 = day sperm detected) did not induce any teratogenic effects. Signs of maternal toxicity were observed only at 300 mg kg-1 day-1. Embryotoxicity was observed at both the 300 and 184 mg HMD kg-1 day-1 dosage levels. No treatment-related effects were observed at 112 mg HMD kg-1 day-1.

Teratogenic response of dimethylacetamide in rats.

Pregnant CD rats (25/group) were used to determine the teratogenic potential of dimethylacetamide (DMAC). DMAC was administered in deionized water once a day by gavage on Days 6 through 19 of gestation at dosages of 0, 65, 160, and 400 mg/kg/day. Cesarean sections were performed on all females on Gestation Day 20. No treatment-related effects were observed in survival, appearance, or behavior at necropsy. Mean maternal body weight gain was reduced significantly only at the 400 mg/kg/day level. Fetotoxicity manifested by increased postimplantation loss was seen at the 400 mg/kg/day level while reduction in mean fetal body weights was noted at the 160 and 400 mg/kg/day test levels. Developmental variations (reduced ossification and unossified skeletal variations) were increased at the 400 mg/kg/day test level and corresponded to the reduced fetal body weights which were observed. Treatment-related malformations of the heart, major vessels and oral cavity, and anasarca were seen at the 400 mg/kg/day DMAC level. No teratogenic effect of DMAC treatment was observed at or below dosage levels of 160 mg/kg/day.

The mortality experience of workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin in a trichlorophenol process accident.

Epidemiologic studies on dioxin, specifically 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), have not consistently found an increased cancer risk. This study examines mortality rates for 754 employees at a chemical plant after an accident in 1949 in which 122 workers developed chloracne from high exposure to TCDD. We also examined exposure to 4-aminobiphenyl, a potential bladder carcinogen. Although the numbers are small, and confounding factors cannot be ruled out, workers exposed to 4-aminobiphenyl who developed chloracne from the accident had increased mortality rates from soft tissue sarcoma, bladder cancer, and respiratory cancer. All soft tissue sarcomas occurred among workers with potential 4-aminobiphenyl exposure, whereas no soft tissue sarcomas occurred among workers with TCDD exposure alone. In these workers, exposure to TCDD alone at levels great enough to cause chloracne was not associated with increased cancer rates.

Subchronic inhalation toxicity and reproductive assessment in rats of three chlorinated propenes.

Groups of 15 male and 15 female Sprague-Dawley rats were exposed to 1 of 3 chloropropene (2,3-Di = DCP; 1,2,3-Tri = TRCP; and 1,1,2,3-Tetra = TECP) vapors to provide information on repeated exposures and the potential for reproductive impairment by the most likely route of occupational exposure. Target exposure concentrations were 0, 1, 5, and 15 ppm, 6 h/d, 5 d/wk for 13 wk. The following parameters were evaluated: pharmacotoxic signs, survival, body weights, hematology, clinical blood chemistry, urine analysis, gross and histopathology (over 40 tissues/rat), organ weights, and selected weight ratios. Signs of nasal irritation were noted in rats exposed to 15 ppm of either DCP or TRCP but not TECP. Small decreases in overall body weight were observed in female rats exposed to 15 ppm TCP. An increase (approximately 15%) in spleen weight, with no corresponding histopathological or clinical findings, was observed in 15 ppm DCP-treated male rats. No other effects considered related to treatment were observed following exposure to any of the three chlorinated propenes. Additional groups of 10 male and 20 female Sprague-Dawley rats were exposed to DCP, TRCP, or TECP vapors at target concentrations of 0, 1, or 5 ppm for 6 h/d, 5 d/wk for a 10-wk premating period, a mating period, and the first 14 d (females only) of gestation. Females were allowed to deliver litters and the offspring were evaluated during a 21-d lactation period. Mating, pregnancy, and fertility indices were generally comparable among all test groups, although female mating and pregnancy indices of both DCP-treated females were lower than expected in the regular and postrecovery reproduction phase. No effects were seen on pup survival, sex distribution, body weights, organ weights, and ratios. A modest reduction in pup body weights was observed following TECP exposure but was attributed to large litter size. No treatment-related effects were seen following necropsy of adults or weanlings, nor were such effects noted following microscopic evaluation of gonads from parental animals.

Subchronic inhalation toxicity of p-nitroaniline and p-nitrochlorobenzene in rats.

For evaluation of subchronic toxicity of the two single-ring nitroaromatics, p-nitroaniline (PNA) and p-nitrochlorobenzene (PNCB), groups of 10 male and 10 female Sprague-Dawley rats were exposed to an aerosol/vapor of PNA in isopropanol at target concentrations of 0, 10, 30, or 90 mg/m3 or to PNCB vaporized from a solution in ethylene glycol monoethyl ether at target concentrations of 0, 5, 15, or 45 mg/m3 for 6 hr/day, 5 days/week for 4 weeks. Clinical signs of toxicity, body weights, results of ophthalmoscopic exam, hematology and clinical chemistry tests, organ weights, gross and histopathological changes were recorded. Exposure to PNA or PNCB resulted in a dose-related increase in blood methemoglobin levels. Mean red blood cell counts, hematocrit, and hemoglobin were significantly decreased in mid and high level animals exposed to PNCB. Mean spleen weights (absolute and relative to body weight) were significantly increased at the high dose levels in the two studies. A slight increase in spleen weights was also observed at the low concentration level in the PNA study. Absolute and relative liver weights also were increased among animals exposed to 45 mg/m3 PNCB. Microscopic changes were observed mainly in the spleen and included an increase in intensity of extramedullary hematopoiesis and hemosiderosis with both compounds. Spleens of animals exposed to PNCB also exhibited congestion. Neither PNA nor PNCB exhibited significant toxicological effects other than those of methemoglobinemia, anemia, and splenic changes classically associated with nitroaromatics at levels significantly above presently accepted occupational standard. Our data suggest that the current TLV for PNA which is 3 mg/m3 will provide adequate protection to the workers. OSHA's PEL of 1 mg/m3 for PNCB is to be preferred over the current TLV of 3 mg/m3 to provide a comparable margin of safety.

Evaluation of the teratogenic potential of three aliphatic nitriles in the rat.

Acetonitrile (ACN), adiponitrile (ADN), and propionitrile (PN), were evaluated for embryotoxic and teratogenic potential in rats. Mated Sprague-Dawley rats were administered one of the three nitriles by gavage on gestation Days 6-19, inclusive. Daily dosage levels (mg/kg body wt) were: ACN at 0, 125, 190, and 275; ADN at 0, 20, 40, and 80; PN at 0, 20, 40, and 80. There was evidence of maternal toxicity in each of the high dose groups treated with ACN, ADN, or PN. Some maternal effects also were seen with ADN at the middle dosage. Embryotoxic effects were observed at the highest dosage tested for ACN and middle and high dose levels for PN. Slight fetotoxicity was observed at the highest dosage for ADN. No teratogenic effects were observed at any dosage level with ACN, ADN, or PN.

Assessment of toxicity of o-nitrochlorobenzene in rats following a 4-week inhalation exposure.

o-Nitrochlorobenzene (ONCB) is a chemical intermediate used for the synthesis of various industrial chemicals. To evaluate the subchronic toxicity of this compound, three groups of 15 male and 15 female Sprague-Dawley rats were exposed to ONCB vapor 6 hr/day, 5 days/week for 4 weeks at target concentrations of 10, 30, or 60 mg/m3. A control group of 15 animals/sex was exposed to room air in a separate inhalation chamber. Concentrations of ONCB in the chambers were determined at least three times a day using a uv spectrophotometer. Parameters monitored in this study included observation for signs of toxicity, body weights, ophthalmoscopic exam, hematology, and clinical chemistry. At necropsy, selected organ weights were recorded and over 35 tissues/animal were examined microscopically for all control and high-exposure level animals. No mortality was observed in this study. Mean body weights of all groups were comparable to controls. Animals exposed to the mid and high concentrations of ONCB showed a significant increase in blood methemoglobin and a significant decrease in hemoglobin, hematocrit, and red blood cell counts. Spleen and liver weights (absolute and relative to body weight) were significantly increased for these two groups. Microscopic changes, observed only in the spleen, included increased degree of extramedullary hematopoiesis and hemosiderosis. These data suggest that the toxicity of ONCB is comparable to that of its structural analog, p-nitrochlorobenzene. Thus these two compounds should have similar work-place exposure limits.

A review of the subchronic toxicity of butyl benzyl phthalate.

This review compares the subchronic toxicity of butyl benzyl phthalate (BBP) across several species. Data from the published literature as well as previously unpublished studies sponsored by Monsanto are presented. BBP-induced toxicity occurs only at relatively high levels of exposure and is dependent on the species, age and strain of test animals used. These factors should be considered in extrapolating findings from animal toxicology studies to humans when assessing the safety of BBP.

Subchronic inhalation toxicity of hexamethylenediamine in rats.

Four groups of 15 male and 15 female Sprague-Dawley-derived (CD) rats each were exposed to aqueous hexamethylenediamine (HMD) aerosols for 6 hr/day, 5 days/week for 13 weeks at mean analytical concentrations of 0, 12.8, or 51 mg/m3. Because of exposure-related deaths in a group of male and female rats similarly exposed to 215 mg/m3 HMD, this group was terminated during the seventh week of the study. Signs of respiratory and conjunctival irritation were observed in rats at both the 51 and 215 mg/m3 HMD test levels. Body weight gain was significantly reduced in both sexes exposed to 215 mg/m3 HMD. At the 5-week study interval, slight hemopoietic stimulation of peripheral blood parameters was observed in rats of both sexes exposed to 215 mg/m3 HMD. Treatment-related microscopic lesions were seen only in rats exposed to 215 mg/m3 MD and were confined to the trachea, nasal passages, and lungs. The no-effect level in this study is considered to be 12.8 mg/m3 HMD.

Teratogenicity studies of alkylaryl phosphate ester plasticizers in rats.

Santicizer 141 plasticizer (2-ethylhexyldiphenyl phosphate) and Santicizer 148 plasticizer (isodecyldiphenyl phosphate) were tested for teratogenic activity in Charles River COBS CD rats. Groups of 25 mated females were given 0, 300, 1000, or 3000 mg/kg/day by gavage on Days 6 through 15 (Santicizer 141) or 6 through 19 (Santicizer 148) of gestation. Mean maternal body weight gains were slightly and severely reduced at the mid- and high-dose levels of Santicizer 141, respectively. Body weights were not affected by treatment with Santicizer 148. Most malformations found in groups treated with either plasticizer occurred as single incidences and have been observed in historical controls. Thus, no teratogenic response was observed in rats after treatment with either of these two alkylaryl phosphates during the period of organogenesis.

Teratology and multigeneration reproduction studies with maleic anhydride in rats.

These studies were initiated to evaluate the effects of maleic anhydride on development and reproduction in CD rats. In the teratology study, pregnant rats (19-23/group) received 0, 30, 90, or 140 mg/kg/day maleic anhydride in corn oil orally from Days 6-15 of gestation and fetuses were examined for gross soft tissue and skeletal defects. A reduced weight gain or weight loss was observed in all maleic anhydride-treated groups between Days 6 and 9; however, mean weights of all groups were within 5% of control on Days 15 and 20. No treatment-related effects on fetal development were observed. In the multigeneration study, rats (10 males and 20 females/group) received 0, 20, 55, or 150 mg/kg/day maleic anhydride in corn oil orally and were mated to produce two generations, each with two litters. Groups of the same size from the second litter were used for subsequent generations and were given the same dose of maleic anhydride as were their parents. The high-dose group was terminated during the second generation due to treatment-related mortality in adults. Renal cortical necrosis occurred in high-dose Fo males and females. Increased kidney weights were observed in low- and mid-dose adult F1 females. No treatment-related effects on reproduction were observed with maleic anhydride at doses up to 55 mg/kg/day over two generations.

Evaluation of the subchronic and reproductive effects of a series of chlorinated propanes in the rat. I. Toxicity of 1,2,3-trichloropropane.

Repeated inhalation exposure and 1-generation reproduction studies have been conducted in the rat to address the adequacy of the 10 ppm occupational exposure limit established for 1,2,3-trichloropropane (TriCP). Groups of 5 rats per sex were exposed for 6 h/d, 5 d/wk up to 4 wk to target TriCP concentrations of 0-900 ppm. Nine of 10 rats died after a single exposure at 900 ppm. Additional deaths were seen in the 300 (1 death) and 600 (3 deaths) ppm test groups. Mean body weights for all TriCP-treated groups were lower than control values. Liver weights were increased in animals of both sexes at 600 ppm and lower. For females ovary weights for the 300 and 600 ppm groups and spleen weights for the 300 ppm group were lower than those of controls. Males exhibited decreased testes weights only at the 600 ppm TriCP level (not evaluated at 900 ppm). Results of a 13-wk exposure, 6 h/d, 5 d/wk of 15 rats/sex.group to TriCP target vapor concentrations of 5, 15, or 50 ppm also resulted in liver weight increases at all test levels. Histopathologic examination showed hepatocellular hypertrophy in male rats at all TriCP levels. Other microscopic findings related to treatment in rats exposed to 15 ppm and to 5 ppm TriCP included lung hyperplasia (both sexes) and splenic extramedullary hematopoiesis (females only) and parallel observed organ weight increases. No treatment-related deaths were observed in this study, nor were there apparent effects on the hematology or clinical chemistries. Group mean body weights at 50 ppm (both sexes) and 15 ppm (females only) TriCP were reduced when compared to controls. In a 13-wk follow-up study in rats at 0, 0.5, and 1.5 ppm TriCP, no gross or microscopic findings related to treatment were found. Groups of 10 male and 20 female rats were exposed 6 h/d, 5 d/wk to 0, 5, or 15 ppm TriCP vapor during premating and mating. Females also were exposed during gestation. Low mating performance was observed in all groups of female rats including the controls, although fewer females in the 15-ppm group mated than in other study groups. Mating and fertility indices of male rats in both treated and control groups were generally low. All measured progeny indices appeared unaffected by treatment. A follow-up study of the same design was conducted at levels of 0, 0.5, and 1.5 ppm TriCP.(ABSTRACT TRUNCATED AT 250 WORDS)