Short-term and subchronic repeated exposure studies with 5-ethylidene-2-norbornene vapor in the rat.

5-Ethylidene-2-norbornene (ENB) is an industrial chemical whose physical properties indicate a likelihood for vapor exposure to humans. The potential for target organ or cumulative toxicity was investigated in rats exposed for 6 h per day for 9 days over an 11-day period, or 66 or 67 days over 14 weeks; 4- week recovery animals were added to the 14-week study. Mean analytically measured ENB vapor concentrations (+/-SD) were 52 +/- 1.5, 148 +/- 2.3 and 359 +/- 4.2 ppm for the 9-day study and 4.9 +/- 0.14, 24.8 +/- 1.23 and 149 +/- 4.40 ppm for the subchronic study. There were no mortalities, and clinical signs were limited to periocular swelling and/or encrustation, and urogenital area wetness. Body weight gain was decreased in the 9-day 359 ppm females and in the subchronic 24.8 and 149 ppm males. A minimal macrocytic anemia was present in subchronically exposed males, which resolved during the recovery period. In the 9-day study increased liver weight was associated with minimal centrilobular hepatocytomegaly and cytoplasmic basophilia with no degenerative or serum biochemical liver function changes, suggesting an adaptive response. Only relative liver weights were increased in the subchronic 149 ppm males, and no histopathological findings were observed. Principal target organ effects were to the thyroid gland, which showed an exposure concentration-related, but not exposure time-related, depletion of follicular colloid that resolved during the recovery period, together with light microscopic evidence for a hypertrophic and hyperplastic response in the follicular epithelium that resolved more slowly. The thyroid colloid depletion was a graded effect without a clear no-effect concentration, but was not accompanied by any clinical or clear biochemical evidence for thyroid dysfunction. A no-effect concentration of 4.9 ppm was established for the follicular cytological effects.

Comparative acute toxicity and primary irritancy of the ethylidene and vinyl isomers of norbornene.

The acute toxicity and primary irritancy of the industrial chemicals 5-ethylidene-2-norbornene (ENB) and 5-vinyl-2-norbornene (VNB) were studied. They are of moderate acute peroral toxicity in the rat, with LD50 values for ENB of 2.54 (male) and 5.66 (female) ml kg(-1), and for VNB of 5.90 (male) and 11.9 (female) ml kg(-1). Percutaneous toxicity is slight in the rabbit by 24-h occluded contact, with no mortalities for ENB up to 8.0 ml kg(-1) and only one mortality (male) at 16.0 ml kg(-1) VNB. Dynamically generated saturated vapor atmosphere LT50 values for ENB in the rat were 75 (male) and 125 (female) min, and for VNB they were 28 (male) and 37 (female) min. The 4-h LC50 values for ENB were 2717 (male) and 3015 (female) ppm, and for VNB they were 2231 (male) and 2518 (female) ppm. Intravenously, the ENB LD50 ranged from 0.09 (male rabbit) to 0.11 ml kg(-1) (female); corresponding LD50 values for VNB were 0.10-0.05 mg kg(-1). Acute neurotoxic signs were seen by the intravenous and inhalation routes of exposure, including tremors, ataxia and convulsions; the latter were sufficient to cause vertebral column luxation or fracture, producing spinal cord compression and resultant hindlimb paralysis. Both ENB and VNB are moderately irritating to the skin (rabbit), causing erythema and edema, but not necrosis. Both materials cause slight conjunctival hyperemia and chemosis in rabbits, but not corneal injury.

Developmental toxicity study in Fischer 344 rats by whole-body exposure to N,N-dimethylethanolamine vapor.

Timed-pregnant Fischer 344 rats were exposed whole body to N,N-dimethylethanolamine vapor for 6 h per day on gestational days 6-15 at mean (+/- SD) analytically measured concentrations of 10.4 +/- 0.86, 29.8 +/- 2.14 and 100 +/- 4.9 ppm. Dams were sacrificed on gestational day 21. There was no maternal mortality in any exposed groups. Maternal toxicity observed in the 100 ppm group included reduced body weight during and after exposures, reduced weight gain during exposure and ocular changes (darkened, cloudy and hazy eyes, slight corneal vascularization and fixed, dilated pupils). Ocular effects were also noted in the other two exposure groups; the effects were quite marked at 30 ppm but only minimal and transient at 10 ppm. There were no effects of treatment on any gestational parameters, including pre- and postimplantation loss or sex ratio. Fetal body weights per litter were statistically significantly increased at 100 ppm relative to controls. There were no increases in the incidences of total malformations by category (external, visceral or skeletal) or individually. The incidence of six skeletal variations out of 120 noted differed in exposed groups relative to that of control. Four of these variations were decreases in incidence; only one fetal variation, the split (bipartite) cervical centrum, was elevated at 100 ppm relative to controls. In the absence of any other indications of delayed ossification or fetal body weights, the observed fetal variation does not suggest a consistent pattern of fetal toxicity. Hence, the no-observed-adverse-effect level is around 10 ppm for maternal toxicity and at or above 100 ppm for embryofetal toxicity and teratogenicity.

Evaluation of the developmental toxicity of ethylene glycol aerosol in CD-1 mice by nose-only exposure.

Ethylene glycol (EG; CAS No. 107-21-1) is teratogenic to mice by whole-body (WB) exposure to aerosol (1000-2500 mg/m3). The WB results were confounded by possible exposure from ingestion after grooming and/or from percutaneous absorption. Therefore, CD-1 mice were exposed to EG aerosol (MMAD 2.6 +/- 1.7 microns) on Gestational Days (GD) 6 through 15, 6 hr/day, by nose-only (NO) (0, 500, 1000, or 2500 mg/m3) or WB exposures (0 or 2100 mg/m3, as positive control), 30/group. Five additional "satellite" females each at 2500 mg/m3 NO and 2100 mg/m3 WB were exposed on GD 6 for measurement of EG on fur. Control environments were water aerosol (4200 mg/m3 for NO; 2700 mg/m3 for WB). Females were weighed and evaluated for clinical signs and water consumption throughout gestation. On GD 18, maternal uterus, liver, and kidneys (2) were weighed, with kidneys examined microscopically. Corpora lutea and implantation sites were recorded. Live fetuses were weighed, sexed, and examined for structural alterations. For NO dams, kidney weights were increased at 1000 and 2500 mg/m3; no renal lesions and no other treatment-related maternal toxicity were observed. There were no effects on pre- or postimplantation loss; fetal body weights/litter were reduced at 2500 mg/m3. At 2500 mg/m3, incidences of fused ribs and skeletal variations were increased. The 2500 mg/m3 NO satellite animals had approximately 330 mg/kg extractable EG. The WB group exhibited maternal and developmental toxicity including increased fetal skeletal malformations and variations, confirming previous results, with 1390 mg/kg extractable EG on fur. Therefore, exposure of CD-1 mice to a respirable EG aerosol during organogenesis by NO inhalation resulted in minimal maternal toxicity at 1000 and 2500 mg/m3 and developmental toxicity at 2500 mg/m3. The NOAEL was 500 mg/m3 NO for maternal and 1000 mg/m3 NO for developmental toxicity. This study supports the interpretation of the initial EG WB results as due to systemic exposure from noninhalation routes since limiting noninhalation routes prevented almost all of the effects (including teratogenicity) observed in mice after WB exposure.

Evaluation of the developmental toxicity of ethylene glycol aerosol in the CD rat and CD-1 mouse by whole-body exposure.

Ethylene glycol (EG) is a major industrial chemical, shown to be teratogenic at high doses by gavage in rodents. Since one route of industrial exposure is to the aerosol at high concentrations, timed-pregnant CD rats and CD-1 mice were exposed, whole-body, to a respirable aerosol of EG (mass median aerodynamic diameter, 2.3 microns) on Gestational Days (GD) 6 through 15 for 6 hr per day at target exposure concentrations of 0, 150, 1000, or 2500 mg/m3 (analytical concentrations of 0, 119 +/- 13, 888 +/- 149, and 2090 +/- 244 mg/m3, respectively), with 25 plug-positive animals per species per group. Clinical observations and maternal body weights were documented throughout gestation for both species. Maternal food and water consumption was measured in rats only throughout gestation. At scheduled necropsy (GD 21 for rats, GD 18 for mice), maternal animals were evaluated for body weight, liver weight, kidney weight, gravid uterine weight, number of ovarian corpora lutea, and status of implantation sites, i.e., resorptions, dead fetuses, live fetuses. Fetuses were dissected from the uterus, counted, weighed, sexed, and examined for external, visceral, and skeletal malformations and variations. All rat dams survived to scheduled termination. Minimal maternal toxicity was indicated by a significant increase in absolute and relative liver weight at 2500 mg/m3. Food and water consumption, maternal body weights and weight gain, and maternal organ weights (other than liver) were unaffected by exposure. Gestational parameters were unaffected by exposure, including pre- and post-implantation loss, live fetuses/litter, sex ratio, and fetal body weight/litter. There was no treatment-related increase in the incidence of any individual malformation, in the incidence of pooled external, visceral, or skeletal malformations, or in the incidence of total malformations by fetus or by litter. There were no increases in the incidence of external or visceral variations. Evidence of fetotoxicity, expressed as reduced ossification in the humerus, the zygomatic arch, and the metatarsals and proximal phalanges of the hind-limb, was observed at 1000 and 2500 mg/m3. All mouse dams survived to scheduled termination. One dam at 2500 mg/m3 was carrying a totally resorbed litter at termination. Maternal toxicity was observed at 1000 and 2500 mg/m3, expressed as reduced body weight and weight gain during and after the exposure period, and reduced gravid uterine weight. (Maternal effects may have been due, in part or whole, to effects on the conceptuses; see below.)(ABSTRACT TRUNCATED AT 400 WORDS)

Two-week aerosol inhalation study on polyethylene glycol (PEG) 3350 in F-344 rats.

PEGs in the 3000 to 4000 MW range are used in many pharmaceutical and cosmetic applications; they produce little ocular or dermal irritation and have extremely low acute and subchronic toxicity by oral and dermal routes of administration. However, little information exists on the potential of aerosols of these materials to produce adverse health effects. F-344 rats were exposed to aerosols of PEG 3350 (20% w:w in water) at 0, 109, 567, or 1008 (highest attainable) mg/m3 for 6 hr/d, 5 d/wk for 2 wk. No exposure-related toxicity was found with regard to clinical signs, ophthalmology, serum chemistry, urinalysis, or gross pathology. Exposure-related effects included: a 50% increase in the neutrophil count (males only) at 1008 mg/m3; decreased body weight gain (16%) for both the 567 and 1008 mg/m3 groups (males only); absolute lung weights of both sexes were increased 10 and 18% for the 567 and 1008 mg/m3 groups, respectively. A slight increase in the number of macrophages in the alveoli was the only change observed histologically in all PEG 3350-exposed groups. Therefore, inhalation of aerosols of PEG 3350 at concentrations up to 1008 mg/m3 produced relatively little toxicity in rats, the lung was the target organ, and the no-observable-effect-level was between 109 to 567 mg/m3.

Evaluation of the developmental toxicity of ethylene glycol monohexyl ether vapor in Fischer 344 rats and New Zealand white rabbits.

Timed pregnant Fischer 344 rats and New Zealand White rabbits were exposed to vapor from ethylene glycol monohexyl ether (EGHE, CAS No. 112-25-4) for 6 hr/day on gestational days (gd) 6 through gd 15 (rats) or gd 6 through gd 18 (rabbits) at analytically measured concentrations (as means +/- SD) of 20.8 +/- 0.90, 41.1 +/- 1.77, or 79.2 +/- 10.8 ppm; control animals were exposed to air alone. Monitors for maternal toxicity were body weight, food and water consumption, clinical signs, and hematology. At sacrifice (gd 21 rats, gd 29 rabbits) maternal weight, liver weight, and gravid uterine weight were measured. Gestational parameters monitored were numbers of corpora lutea, preimplantation losses, viable implants, early and late resorptions, and dead fetuses. Live fetuses were sexed, weighed, and examined for external, visceral, and skeletal malformations and variations. Rabbit maternal toxicity occurred at 79.2 ppm as transient weight gain reduction during the exposure period. For maternal rats at 79.2 ppm, there were transient decrease in body weight and body weight gain during exposure, reduced food consumption, increased water consumption, and excess lacrimation. At 41.1 ppm, maternal body weight gain was reduced during the exposure period only. There were no treatment-related effects with respect to hematology, necropsy, or gestational parameters and no significant change in the incidence of malformations or variations (expressed as total, individual, external, visceral, or skeletal). Thus, exposure of rats and rabbits to EGHE vapor during the period of organogenesis produced maternal toxicity at near-saturation vapor concentrations (79.2 ppm), but no evidence for developmental toxicity or teratogenicity. The no-effect vapor concentrations for maternal toxicity were 41.1 ppm for rabbits and 20.8 ppm for rats.

Enzyme activity and sulfhydryl status in rat renal cortex following mercuric chloride and dithiothreitol administration.

Previous experiments indicated that the partial reversal of mercuric chloride-induced renal dysfunction in rats by subsequent dithiothreitol (DTT) administration was not related to increased mercury excretion, decreased renal mercury concentration, a change in renal cortical subcellular mercury distribution, or the formation of a Hg-DTT complex. The present studies investigated whether DTT, a sulfhydryl reducing agent, protected renal cortical sulfhydryl status in general, or the activity of various renal enzymes (Mg- and Na,K-ATPases, alkaline phosphatase, and glutathione peroxidase) in particular. Additionally, the occurrence of conjugated dienes was used to assess the degree of lipid peroxidation. HgCl2 produced significant decreases in renal cortical protein-bound sulfhydryl concentration, alkaline phosphatase activity, and ATPase activity within 2.5 h of administration, with no effect observed on glutathione peroxidase activity or the levels of conjugated dienes in rat renal cortex. Administration of DTT 60 min after mercury neither provided protection from inhibition nor promoted restoration of the affected enzymes or sulfhydryl status. It is concluded that the partial protection of renal function offered by DTT in the early stages of mercury toxicity does not result from maintaining the integrity of renal cortical sulfhydryl status or the activity of the enzymes investigated. Furthermore, the early stages of mercury toxicity did not appear to be related to lipid peroxidation.

Pulmonary fibrosis produced in F-344 rats by subchronic inhalation of aerosols of a 4000 molecular weight ethylene oxide/propylene oxide polymer.

Inhalation of aerosols of the ethylene oxide/propylene oxide polymer (U-5100) evaluated in this study has previously been shown in acute and 2-week studies to produce toxicologic effects on the lungs, with increased lung weights and microscopic findings of congestion and hemorrhage of pulmonary alveolar capillaries and necrosis of alveolar epithelial cells (D. R. Klonne, D.J. Nachreiner, D. E. Dodd, P. E. Losco, and T.R. Tyler, 1987, Fundam. Appl. Toxicol. 9, 773-784). In the present studies, F-344 rats were exposed 6 hr/day, 5 day/week for 2 weeks to aerosols at mean concentrations of 0, 0.9, or 5.0 mg/m3 or for 13 weeks to mean concentrations of 0, 0.3, 1.1, or 5.2 mg/m3. Following the 2-week study, minimal multifocal hemorrhage and eosinophilic proteinaceous debris in alveoli were observed in the 0.9 mg/m3 group; similar lesions plus alveolar cell necrosis were found in the 5 mg/m3 group. In the 13-week study, the 5.2 mg/m3 group had a slight decrease in body weight gain, while increases in absolute and/or relative lung weights occurred for both the 1.1 and 5.2 mg/m3 groups at the end of the exposure regimen and at the end of a 5-week recovery period. Histologic lesions of the lungs occurred in all U-5100-exposed groups and consisted of hemorrhage, alveolar histocytosis, interstitial pneumonia, and multifocal fibrosis. The incidence and severity of the pulmonary lesions were concentration related.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute toxicity and primary irritation of para-tertiary butylphenol.

Para-tertiary butylphenol [(PTBP); the Union Carbide Corporation trademark for this chemical is UCAR Butylphenol 4-T Flake] has applications as a raw material in the manufacture of resins and also as an industrial intermediate. Acute peroral LD50 values (95% confidence limits) of 5.4 (3.6-7.9) g/kg and 3.6 (3.0-4.4) g/kg were obtained for male and female albino rats, respectively. Occluded cutaneous applications of moistened PTBP at 16 g/kg for 24 hr produced no mortalities in male or female rabbits, but signs of local toxicity and irritation were apparent at the site of application. A 6 hr exposure to a substantially saturated vapor under static conditions produced no mortality, while a 4 hr exposure to a dynamically generated respirable dust aerosol at a concentration of 5.6 mg/L produced 20% mortality. Occluded dermal contact (4 hr) with 0.5 g moistened PTBP produced a range of effects from no reaction to necrosis. PTBP placed in the conjunctival sac of rabbits produced severe ocular injury which generally persisted for 21 days after exposure. The major hazard associated with acute exposure to PTBP appears to be the irritation produced by dermal or ocular contact.

Acute and 2-week inhalation toxicity studies on aerosols of selected ethylene oxide/propylene oxide polymers in rats.

The ethylene oxide/propylene oxide (EO/PO) polymers evaluated in this study have previously been shown to have a low order of toxicity and/or irritancy by ocular, dermal, or oral routes of administration. These studies evaluated the acute inhalation toxicity of respirable aerosols of three EO/PO compounds (U-660, U-2000, and U-5100) that differ in chain length, molecular weight, and viscosity. The respective 4-hr LC50 values (95% confidence limits) for U-660, U-2000, and U-5100 in Wistar albino rats were 4670 (4090-5320), 330 (227-480), and 106 (45-245) mg/m3. Occasionally, slight increases in respiration rate and slight hyperactivity were observed during the postexposure period. All deaths were delayed for 2-5 days postexposure. Body weight gains were transiently depressed in rats exposed to U-2000 and U-5100. Discolored lungs and livers occurred in animals which died during the 14-day postexposure period. Subsequently, a repeated-exposure study was conducted on U-5100 in F-344 rats exposed for 6 hr/day, 5 days/week, for 9 exposures at mean concentrations of 0, 5, 26, and 50 mg/m3. Portions of the control and 50 mg/m3 groups were maintained for an additional 2-week recovery period. Exposure-related effects included transient urogenital wetness in 50 mg/m3 group females; decreased body weight gain (7-29%) in all U-5100 groups except the 5 mg/m3 group females; increases in absolute (17-52%) and relative lung weights in all U-5100 groups; macroscopic red foci in the lungs; and microscopic findings of congestion and hemorrhage of pulmonary alveolar capillaries and necrosis of alveolar epithelial cells. Lung weights remained elevated after the 2-week recovery period, but the severity of the microscopic lesions was noticeably less, indicating partial reversibility of the lesions. In conclusion, EO/PO polymers have a higher order of toxicity by inhalation in comparison to other routes of administration, vary considerably in their acute lethal toxicity as a function of chain length/molecular weight, and induce pulmonary hemorrhage, and possibly edema, following repeated aerosol exposures at concentrations as low as 5 mg/m3.

Dimethylethanolamine: acute, 2-week, and 13-week inhalation toxicity studies in rats.

Dimethylethanolamine (DMEA) is a volatile, water-soluble amine that has applications in the chemical and pharmaceutical industries. These studies evaluated the acute and subchronic inhalation toxicity of DMEA. Acute (4-hr) exposures of Wistar rats to DMEA vapor resulted in an LC50 value (95% confidence limits) of 1641 (862-3125) ppm. Clinical signs of nasal and ocular irritation, respiratory distress, and body weight loss were observed in rats exposed to 1668 ppm DMEA and higher. In the 2-week study, F-344 rats exposed to 98, 288, or 586 ppm DMEA for 9 days (6 hr/day) during an 11-day period also exhibited signs of respiratory and ocular irritation (except the 98 ppm group). All animals of the 586 ppm group and 4 of 15 male rats of the 288 ppm group died. Body weight values for the 288 ppm group were reduced to about 75% of preexposure values, while the 98 ppm group gained 35% less weight than controls. Statistically significant differences in clinical pathology parameters (288 ppm group) and in organ weight values (288 and 98 ppm groups) probably resulted from the decreased food consumption and not from specific target organ toxicity. In the groups evaluated histologically (the 98 and 288 ppm groups) the eye and nasal mucosa were the primary target organs. In the 13-week subchronic study, F-344 rats were exposed to 0, 8, 24, or 76 ppm DMEA for 6 hr/day, 5 days/week for 13 weeks. The principal exposure-related changes were transient corneal opacity in the 24 and 76 ppm groups; decreased body weight gain for the 76 ppm group; and histopathologic lesions of the respiratory and olfactory epithelium of the anterior nasal cavity of the 76 ppm group and of the eye of several 76 ppm group females. Rats maintained for a 5-week recovery period only exhibited histological lesions of the nasal tissue, with the lesions being decreased in incidence and severity. DMEA acts primarily as an ocular and upper respiratory tract irritant and toxicant at vapor concentrations of 76 ppm, while 24 ppm or less produced no biologically significant toxicity in rats. Thus, 24 ppm was considered to be the no-observable-effect level.

One-year inhalation toxicity study of chlorine in rhesus monkeys (Macaca mulatta).

Chlorine (Cl2) gas is a potentially lung-damaging irritant which is used in the chemical, plastics, and paper industries. There are no data published using experimental animals on the chronic inhalation toxicity of chlorine. The purpose of this study was to investigate the chronic effects of Cl2 inhalation in Rhesus monkeys (Macaca mulatta). Rhesus monkeys were exposed to concentrations of 0, 0.1, 0.5, or 2.3 ppm Cl2 for 6 hr per day. 5 days per week for 1 year. Pulmonary physiology (pulmonary diffusing capacity and distribution of ventilation), body weights, urinalysis, electrocardiographs, hematology, and clinical chemistry were evaluated monthly during the study. Blood gas evaluations were performed at 3-month intervals during the study. Histopathologic, ophthalmologic, and neurologic parameters were evaluated after the 1-year exposure period. Monkeys exposed to 2.3 ppm Cl2 exhibited signs of ocular irritation during the daily exposures and a superficial conjunctival irritation was present in the 2.3 ppm group after the 1-year exposure regimen. Treatment-induced lesions revealed by histopathology were confined to the respiratory tract. Lesions associated with the nasal parasite Anatrichosoma spp. were present in the region of squamous epithelium of the nasal vestibule and did not interfere with interpretation of Cl2-induced effects. Treatment-induced histopathologic changes were found in the respiratory epithelium of the nasal passages and trachea and were limited to focal, concentration-related epithelial hyperplasia with loss of cilia and decreased numbers of goblet cells in affected areas. These changes in the nose and trachea were focal and mild in monkeys exposed to 2.3 ppm and were not found in all animals in these exposure groups. Tracheal lesions were confined to the 2.3 ppm group. The lesions observed at 2.3 ppm were not present in all animals. At the lower Cl2 concentrations, similar though less prominent respiratory epithelial lesions were observed. The latter changes were very minimal and were confined to the nasal passages of some treated monkeys and one male control animal. The results of this study indicate that 2.3 ppm chlorine acts as an upper respiratory irritant in monkeys, while 0.5 and 0.1 ppm induce changes of questionable clinical significance. Furthermore, the monkey appears to be less sensitive than the rat to chlorine toxicity.

Inhalation teratology studies of n-butyl mercaptan in rats and mice.

n-Butyl mercaptan (n-BM) is used as a solvent and a chemical intermediate. Pregnant Charles River CD-1 mice and COBS CD rats were randomly assigned to a control group and to three n-BM-exposed groups of 25 rats and 25 mice each. The animals were exposed by whole-body inhalation to mean n-BM concentrations of 10, 68, or 152 ppm on a 6-hr daily exposure schedule. Rats were exposed on Gestation Days 6-19 and mice on Gestation Days 6-16. The control group was exposed to filtered air only on a comparable regimen. Cesarean sections were performed on all surviving mice on Gestation Day 17 and on all rats on Gestation Day 20. Seventeen of the n-BM-treated mice died: 8 at the 68-ppm level and 9 at the 152-ppm level; none of the n-BM-treated rats died. An increased postimplantation loss and increased early resorption occurred in mice exposed at 68 and 152 ppm, indicating embryotoxicity. An increased incidence of cleft palate was observed in mice exposed to 10 or 68 ppm which was not statistically significant. Total fetal abnormalities were statistically significantly different from controls at 68 ppm where maternal lethality was observed when based on the fetal unit although not when based on the litter unit. Rats exposed to 152 ppm or less demonstrated no terata.

Acute, 9-day, and 13-week vapor inhalation studies on ethylene glycol monohexyl ether.

At ambient conditions, the low vapor pressure of ethylene glycol monohexyl ether (EGHE) allows for a maximum vapor concentration of approximately 85 ppm. In an acute inhalation study on Wistar albino rats, a 4-hr exposure to 83 ppm EGHE produced no clinical signs, body weight effects, mortality, or macroscopic lesions in thoracic or abdominal organs. Fischer 344 rats exposed for 9 days (6 hr/day) over an 11-day period, to 0 (control), 19, 41, or 84 ppm EGHE had decreased body weight gains and increased liver to body weight values at 84 ppm EGHE. No alterations of the hematology parameters or the morphology of the testes or liver were observed. In a subsequent study, rats were exposed to mean EGHE concentrations of 0 (control), 20, 41, or 71 ppm for 6 hr/day, 5 days/week, for 13 weeks. Urogenital wetness was observed in all EGHE-exposed groups of females and in males of the 71-ppm group. Decreased body weight gains were observed in both sexes of the 71-ppm group, and a slight decrease was also observed in females of the 41-ppm group. Increased absolute and/or relative liver weights were observed in both sexes of the 71-ppm group and to a lesser extent in the 41-ppm group. Possibly related to these findings in the liver were decreases in serum transaminases (aspartate and alanine aminotransferase) and sorbitol dehydrogenase, with an increase in alkaline phosphatase observed in the 71-ppm group of female rats. However, there were no gross or histopathologic lesions found to indicate impairment of the liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute inhalation toxicity of aliphatic (C1-C5) nitrites in rats.

The 4-hr inhalation LC50 was determined for methyl-, ethyl-, n-propyl-, n-butyl-, isobutyl-, and isopentyl nitrite in Sprague-Dawley rats. LC50 values were 176, 160, 300, 420, 777, and 716 ppm, respectively. The dose-mortality curves were characterized by extremely steep slopes. Toxic signs observed during exposure included cyanosis, prostration, and rarely, convulsions. There were no effects of exposure on body weight gain during a 14-day postexposure observation period. Signs of pulmonary hemorrhage were apparent in rats which died during exposure but were much less prominent in rats sacrificed at study termination. No animals died after cessation of exposure, and rapid recovery was apparent after exposure. Concentration X Time (CT) relationships suggested that the actual concentration was more important than the "dose" in determining the lethal effects of inhalation exposure to nitrites. Because of the extremely steep dose-mortality curves, the aliphatic nitrites are more hazardous than the LC50 values would indicate.

Two-year inhalation toxicity study of petroleum coke in rats and monkeys.

Sprague-Dawley rats and Cynomolgus monkeys were exposed to dust aerosol concentrations (0, 10.2, and 30.7 mg/m3) of micronized delayed process petroleum coke for 6 hr/day, 5 days/week over 2 years. With the exception of pulmonary effects, particularly in the rats, no significant adverse treatment-related effects were observed. Both dust-exposed groups of both species exhibited a gray to black discoloration of the lung, an observation consistent with pulmonary deposition of the coke dust, as well as increased absolute and/or relative lung weight values. The pulmonary histopathology in the monkeys was limited to the deposition and phagocytosis of the test material by pulmonary macrophages. The rats also exhibited these responses, but with concomitant signs of chronic inflammation and focal areas of fibrosis, bronchiolization, sclerosis, squamous alveolar metaplasia, and keratin cyst formation. No difference in the mortality rate was observed between the control and exposed groups of rats. Lastly, no significant increases in chromosomal aberrations were observed in rodents of the 10.2 or 30.7 mg/m3 exposure groups when examined after 5 days, 12 months, and 22 months of exposure.

The acute toxicity and primary irritancy of 2-ethyl-1,3-hexanediol.

2-Ethyl-1,3-hexanediol (EHD), an insect repellant, was found to have acute peroral LD50 values in the rat of 9.85 ml/kg (males) and 4.92 ml/kg (females). Acute percutaneous LD50 values in the rabbit were 10.8 ml/kg (males) and 9.51 ml/kg (females). There were neither deaths nor signs of toxicity during or following a 6 hr exposure to a statically or dynamically generated substantially saturated vapor atmosphere. A 4 hr exposure to a high concentration (3.8 mg/liter) of a respirable aerosol of EHD (mass median aerodynamic diameter of 2.0 um) produced only minor signs of irritation during exposure, but no signs of toxicity. Occluded dermal contact with EHD on rabbits (4 and 24 hr) produced mild local erythema and, in several animals, edema. Contamination of the eye with EHD (0.005 to 0.1 ml) produced marked to severe conjunctivitis, with moderate iritis and diffuse corneal injury; healing occurred in most animals within 3 to 7 days. The major acute hazards with EHD are by swallowing and, to a greater extent, by contamination of the eye.

Renal cortical mercury distribution following dithiothreitol administration.

Previous studies from this laboratory have indicated that dithiothreitol (DTT) administration (31 mg DTT/kg, i.p.) 1 h after mercuric chloride injection (3 mg/kg, i.v.) results in partial reversal of Hg-induced renal toxicity without altering total renal mercury deposition. Studies were performed, therefore, to determine if DTT administration altered the renal delivery, excretion, and/or, in particular, subcellular distribution of mercury in a way that may explain the observed phenomenon. Analysis of mercury partitioning between red cells and plasma revealed no difference in relative distribution when Hg- or Hg + DTT-treated groups were compared. However, absolute mercury concentration in both whole blood and plasma of Hg + DTT-treated rats was significantly higher than in the Hg-treated group. Total urinary excretion of mercury was significantly less in Hg + DTT-treated rats than in rats treated with mercury alone. The subcellular distribution of mercury in the particulate and supernatant fractions of renal cortical homogenates from Hg-treated and Hg + DTT-treated rats was similar. Fractionation of the supernatant on G-75 Sephadex gel revealed no difference in the protein profiles between the Hg- and Hg + DTT-treated groups. It is concluded that DTT administration ameliorates the nephrotoxic effect of prior mercury injection by a more subtle mechanism than redistribution of renal cortical mercury.

Amelioration of mercuric chloride-induced acute renal failure by dithiothreitol.

Experiments were conducted to determine if administration of the sulfhydryl reducing agent and metal chelator dithiothreitol (31 mg/kg body wt) alters the development of renal dysfunction in the first 3 hr after injection of mercuric chloride (3 mg/kg). Mercuric chloride alone resulted in elevation of urine flow rate and fractional excretion of solutes within 30 min of injection. In animals injected with dithiothreitol 60 min after mercuric chloride, urine flow rate and fractional excretion of solutes were reduced within 30 min to values intermediate between control and mercuric chloride-treated rats. Neither the injection of mercuric chloride alone nor when followed by dithiothreitol resulted in changes in mean arterial blood pressure or glomerular filtration rate. In addition, dithiothreitol did not reduce urine flow rate or fractional excretion of solutes when these parameters were elevated during extracellular fluid volume expansion. Measurement of mercury in organs of those rats injected with mercuric chloride alone or prior to dithiothreitol revealed no alteration in organ distribution. The renal cortex contained the highest concentrations of mercury, and these concentrations were comparable in both groups of rats. These studies demonstrate that dithiothreitol can ameliorate the renal toxicity of mercury and suggest that this effect is mediated through an intrarenal site of action.