REPEATED EXPOSURE INHALATION STUDY OF PENTANE IN RATS

Pentane (CAS No. 109-66-0) is a chemical being used as a co-solvent in a polymer production facility with potential for inhalation exposure in humans. To assess the toxicity of pentane, groups of 10 male rats each were exposed by inhalation, 6 hr/day, 5 days/week for 2 weeks to either 0 (control), 1,000, 3,000 or 10,000 ppm. Five rats per group were killed following the 10th exposure; the remaining 5/group were killed after a 14-day post-exposure recovery period. Parameters investigated were clinical signs of toxicity, functional behavior, body weights, clinical pathology, and gross and microscopic pathology including organ weights. No unusual clinical observations were seen in the pentane-treated rats, and body weights were not altered. Test rats generally exhibited normal behavioral responses in the functional observational battery. Increases in serum calcium and phosphorus concentrations were seen in rats exposed to either 3,000 or 10,000 ppm. These were reversible during the 2-week recovery period. No other clinical pathology changes were observed and no pentane-related tissue pathology was seen in any of the groups. The no-observed-adverse-effect level was 1,000 ppm with reversible clinical pathology changes produced at 3,000 and 10,000 ppm.     

Inhalation toxicity of cyclododecatriene in rats.

Cyclododecatriene (CDDT, CAS No. 4904-61-4) was tested for its inhalation toxicity in rats following repeated exposures. Male rats were exposed nose-only to CDDT for 6 hr/day, 5 days/wk for a total of 9 exposures over 2 weeks. Particular attention was paid to neurotoxicologic endpoints. Concentrations of 0 (control), 5, 50, and 260 ppm were studied. The 260 ppm chamber contained both vapor and aerosol while the 5 and 50 ppm chambers were vapor only. Four groups of 10 rats each were used to measure standard clinical signs and growth, clinical pathology (including hematology, biochemistries, and urine analysis), and tissue pathology. Another 4 groups of similar size were used for neurotoxicity testing. In the standard toxicity groups, 1/2 of the rats were sacrificed 1 day following the 9th exposure; the other half underwent a 2-week recovery period prior to being sacrificed (recovery group). During the exposures rats inhaling 260 ppm had a diminished or absent response to an alerting stimulus. Irregular respiration and lethargy were observed in these rats immediately following exposure. These signs were rapidly reversible and were not seen prior to the subsequent exposure. Body weights in rats exposed to either 50 or 260 ppm were significantly lower than the corresponding controls. No compound-related clinical pathology changes were seen in any of the test groups and tissue pathology effects only occurred in the nasal tissue. In rats exposed to 260 ppm, minimal degeneration/necrosis of nasal olfactory epithelium was observed in rats examined immediately following the exposure period. This change was not seen in the recovery rats. Functional observational battery (FOB) assessments and motor activity (MA) evaluations conducted after the 4th and 9th exposures on rats from all test groups, and specific neuropathologic evaluation on perfused brain, spinal cord, and skeletal muscle from rats exposed to 260 ppm failed to demonstrate any specific neurotoxicity. Outward signs of sedation were seen at the top level tested. Under the conditions of this test, the no-observed-adverse-effect level (NOAEL) was determined to be 5 ppm based upon a reduced rate of body weight gain in the 50 ppm group. No specific neurotoxicity was detected and the histopathologic response was limited to reversible changes in the nasal epithelia in rats exposed to 260 ppm.     

Inhalation Toxicity of Cyclododecatriene in Rats

ABSTRACT

Cyclododecatriene (CDDT, CAS No. 4904-61-4) was tested for its inhalation toxicity in rats following repeated exposures. Male rats were exposed nose-only to CDDT for 6 hr/day, 5 days/wk for a total of 9 exposures over 2 weeks. Particular attention was paid to neurotoxicologic endpoints. Concentrations of 0 (control), 5, 50, and 260 ppm were studied. The 260 ppm chamber contained both vapor and aerosol while the 5 and 50 ppm chambers were vapor only. Four groups of 10 rats each were used to measure standard clinical signs and growth, clinical pathology (including hematology, biochemistries, and urine analysis), and tissue pathology. Another 4 groups of similar size were used for neurotoxicity testing. In the standard toxicity groups, 1/2 of the rats were sacrificed 1 day following the 9th exposure; the other half underwent a 2-week recovery period prior to being sacrificed (recovery group). During the exposures rats inhaling 260 ppm had a diminished or absent response to an alerting stimulus. Irregular respiration and lethargy were observed in these rats immediately following exposure. These signs were rapidly reversible and were not seen prior to the subsequent exposure. Body weights in rats exposed to either 50 or 260 ppm were significantly lower than the corresponding controls. No compound-related clinical pathology changes were seen in any of the test groups and tissue pathology effects only occurred in the nasal tissue. In rats exposed to 260 ppm, minimal degeneration/necrosis of nasal olfactory epithelium was observed in rats examined immediately following the exposure period. This change was not seen in the recovery rats. Functional observational battery (FOB) assessments and motor activity (MA) evaluations conducted after the 4th and 9th exposures on rats from all test groups, and specific neuropathologic evaluation on perfused brain, spinal cord, and skeletal muscle from rats exposed to 260 ppm failed to demonstrate any specific neurotoxicity. Outward signs of sedation were seen at the top level tested. Under the conditions of this test, the no-observed-adverse-effect level (NOAEL) was determined to be 5 ppm based upon a reduced rate of body weight gain in the 50 ppm group. No specific neurotoxicity was detected and the histopathologic response was limited to reversible changes in the nasal epithelia in rats exposed to 260 ppm.     

Inhalation toxicity of tetramethylurea in rats

Tetramethylurea (TMU, CAS No. 632-22-4) was tested for its inhalation toxicity in rats following repeated exposures. Male rats were exposed whole-body to TMU for 6 hours/day, 5 days/week for a total of 9 exposures over 2 weeks. Concentrations of 0 (control), 2, 20, and 100 ppm were studied. Four groups of 10 rats each were used to measure clinical signs and growth, clinical pathology (including hematology, biochemistries, and urine analysis), and tissue pathology. One-half of the rats were sacrificed 1 day following the 9th exposure; the other half underwent an 18-day recovery period prior to being sacrificed (recovery group). Body weight gains in rats exposed to 100 ppm were reduced as compared to the controls; no body weight effects were seen in either 2 or 20 ppm rats and no clinical signs of toxicity were observed in rats at any of the levels throughout the study. No compound-related clinical pathology changes were seen in any of the test groups and tissue pathology effects only occurred in the nasal tissue. In rats exposed to 100 ppm, microscopic observations of degeneration, necrosis, and ulceration of olfactory mucosa was seen. These lesions were still present but seen as recovering and healing after the 18-day recovery. Under the conditions of this test, the no-observed-adverse-effect level (NOAEL) was determined to be 20 ppm based upon both body weight changes and upper respiratory tract pathologic changes in 100 ppm rats.     

Inhalation Toxicology of Trimethylamine

Abstract

Trimethylamine (TMA) is a pungent gas that occurs in nature and has many industrial applications, including use as an intermediate in the manufacture of many chemicals. The lowest lethal concentration following a single 4-h inhalation exposure was determined to be 3500 ppm. Croups of 70 male rats each were then exposed by nose-only inhalation 6 h/d, 5 d/wk for 2 wk to either 0 (control), 75, 250, or 750 ppm TMA. Rats were sacrificed either immediately following exposure or following a 14-d recovery period. Parameters investigated included in-life observations and body weights, clinical pathology, and histopathology with organ weights. Exposure to 750 ppm produced a decreased rate of weight gain in rats. Evidence of mild, reversible, polycytnemia was also seen in these rats. Effects of TMA were present in the nose, trachea, and lungs. Degenerative changes in the nose were reversible at 75 ppm, but not at 250 or 750 ppm. Mild emphysematous alveoli were seen in lungs of rats exposed to 750 ppm immediately following the exposures, but not after a recovery period. A no-observed-effect level for TMA under these test conditions was not determined, although the nasal effects seen at 75 ppm were minimal.     

Two-week (ten-day) inhalation toxicity and two-week recovery study of phenol vapor in the rat

The toxicity of phenol vapor was evaluated in male and female Fischer 344 rats (20/sex/group) via flow-past nose-only inhalation exposure. The test animals were exposed to target concentrations of 0 (air control), 0.5, 5.0, or 25 parts per million (ppm) of phenol in air for 6 hours/day, 5 days/week, for 2 weeks. High pressure liquid chromatography (HPLC) measurement of phenol test atmospheres determined mean (+/- standard deviation) analytical concentrations of 0.0 +/- 0.0, 0.52 +/- 0.078, 4.9 +/- 0.57, and 25 +/- 2.2 ppm, respectively. After 2 weeks of exposure, 10 test animals/sex/group were sampled for clinical chemistry and hematology parameters, and then sacrificed. Histopathological examination included the nasopharyngeal tissues, larynx, trachea, lungs with mainstem bronchi, kidney, liver, and spleen. The remaining 10 animals/sex/group were retained for a 2-week recovery period. Recovery groups of animals were evaluated as described previously and then sacrificed. No signs of toxicity in clinical observations (including overt neurological signs), body weights, food consumption, clinical pathology, organ weights, macroscopic pathology or microscopic pathology were seen during the exposures or at either sacrifice interval. In conclusion, 2-week inhalation exposures to phenol vapor at concentrations up to and including 25 ppm did not produce any adverse effects.     

Subchronic inhalation study of 1-hexene in Fischer 344 rats.

The objective of this study was to evaluate the toxicity of 1-hexene following repeated inhalation exposures in male and female Fischer 344 rats. Groups of 40 male and 40 female rats were exposed for 6 hours per day, 5 days per week, over a 13-week period. Treatment groups consisted of air-exposed control (0 ppm) and three test groups of 300, 1000, and 3000 ppm 1-hexene. During the treatment period, the rats were observed daily for clinical signs of toxicity; body weights and neuromuscular coordination [females only] were measured at 7-day intervals. After 7 weeks of exposure and at the end of the treatment period, the rats were subject to macroscopic and microscopic pathology, clinical chemistry, hematology, urinalysis, and sperm counts. No mortalities were observed during the course of the study. No clinical signs of toxicity attributable to 1-hexene exposure were observed. Female rats exposed to 3000 ppm had significantly lower body weights compared to control rats from exposure day 5 persisting throughout the treatment period. Male rats exposed to 3000 ppm had slightly but not statistically significant lower body weights in comparison to controls. Male rats exhibited slightly increased absolute and relative testicular weights, and female rats had slightly decreased absolute [but not relative] liver and kidney weights, at 3000 ppm. There were no gross or microscopic morphological findings attributed to treatment. Exposure to 1-hexene did not affect neuromuscular coordination in females as determined using the Rotarod, nor sperm counts in male rats. Several statistically significant effects in hematology, clinical chemistry, and urinalysis evaluations were observed, but were either of small magnitude or did not correlate with histopathological findings, and thus did not appear to be of biological significance. In summary, the no-adverse-effect-level for this study was determined to be 1000 ppm, based on decreased weight gain in female rats, and on slight organ weight changes in both sexes at 3000 ppm.     

Inhalation Toxicity Study of Formamide in Rats

Formamide is a widely used solvent for the manufacture and processingof plastics, and the possibility for inhalation exposure existsfor workers. To assess the toxicity of repeated inhalation ofsublethal concentrations of formamide, three groups of 10 maleCrl:CD BR rats each were exposed nose-only for 6 hr/day, 5 days/weekfor 2 weeks to design concentrations of 100, 500, or 1500 ppmof formamide vapor in air. A control group of 10 male rats wasexposed simultaneously to air only. At the end of the exposureperiod, blood and urine samples were collected for clinicalanalyses, and 5 rats per group were killed for pathologic examination.The remaining 5 rats per group were retained for a 14-day postexposureobservation (recovery) period and then subjected to the sameclinical and pathologic examinations. Male rats exposed to 1500ppm had significantly depressed body weights and body weightgains during the exposure and recovery periods compared to controls.Clinical pathologic examinations revealed that decreased plateletand/or lymphocyte counts were observed in rats exposed to 500or 1500 ppm of formamide. Pathologic examinations revealed compound-relatedmicroscopic changes in the kidneys of rats exposed to 1500 ppmformamide. Minimal to severe necrosis and regeneration of renaltubular epithelial cells were observed principally in the outerstripe of the outer medulla and in cortical medullary rays.Based upon the hematologic and clinical chemical parametersmeasured, the no-observed-effect exposure concentration forrepeated inhalation of formamide was considered to be 100 ppm,under the conditions of this study. The findings of treatment-relatedmicroscopic lesions in the kidneys as well as increases in meanabsolute kidney weights and kidney-to-body weight ratios reflectthe target organ toxicity.     

A limited developmental toxicity study of pentane by inhalation in the rat.

Pentane (CAS No. 109-66-0) is a widely-used chemical that finds many industrial applications. As part of a program looking at the inhalation toxicity of pentane, we studied the potential effects of the chemical on the developing embryo. This communication reports the findings of a limited study which was used to determine whether a full-scale developmental toxicity study was necessary. Groups of 7 to 8 pregnant rats were exposed by inhalation to pentane, 6 hr/day from gestation days 6 through 15 at concentrations of 0 (control), 1000, 3000 and 10,000 ppm, Maternal body weights, clinical signs and food consumption were measured; foetuses were weighed and examined for gross external development. Skeletal and internal organ evaluations were not performed. There were no effects in either the maternal or fetal rats (at concentrations up to and including 10,000 ppm) that could be associated with pentane exposure. Based on those findings, we did not conduct a full-spectrum developmental toxicity study in rats, but concluded that it is unlikely that the foetus would be adversely affected by pentane exposure.     

Subchronic inhalation toxicity of diglyme.

Diglyme [1,1'-oxybis(2-methoxyethane)] is an organic solvent belonging to the glycol ether class of compounds. To assess the inhalation toxicity of diglyme, groups of 20 male and 10 female rats were exposed by nose-only inhalation 6 hours/day, 5 days/week for 2 weeks to either 0 (control), 110, 370 or 1100 ppm diglyme. To compare potency, 2-methoxyethanol was also tested at 300 ppm. Rats were sacrificed either immediately following exposure, after a 14-day recovery period, or after 42 and 84 days of recovery (males only). Parameters investigated included in-life observations and body weights, clinical pathology, and histopathology with organ weights. Exposure to diglyme produced a variety of concentration-related haematological, clinical chemical and histopathological changes in both sexes. The most striking effect produced in all test groups was cellular injury involving the testes, seminal vesicles, epididymides and prostate. Although these effects were more severe at the higher concentrations tested, partial or complete recovery was seen by 84 days post-exposure. Changes in the haematopoietic system occurred in both sexes and involved the bone marrow, spleen, thymus, leucocytes and erythrocytes. The testicular effects of diglyme were somewhat less pronounced than those seen with 2-methoxyethanol. The no-observed-effect level (NOEL) for repeated inhalation exposure to diglyme in female rats is 370 ppm. For males, all concentrations tested produced effects to the reproductive system, hence a no-observed-effect level could not be demonstrated.     

Subchronic Inhalation Study of 1-Hexene in Fischer 344 Rats

ABSTRACT

The objective of this study was to evaluate the toxicity of 1-hexene following repeated inhalation exposures in male and female Fischer 344 rats. Groups of 40 male and 40 female rats were exposed for 6 hours per day, 5 days per week, over a 13-week period. Treatment groups consisted of air-exposed control (0 ppm) and three test groups of 300, 1000, and 3000 ppm 1-hexene. During the treatment period, the rats were observed daily for clinical signs of toxicity; body weights and neuromuscular coordination [females only] were measured at 7-day intervals. After 7 weeks of exposure and at the end of the treatment period, the rats were subject to macroscopic and microscopic pathology, clinical chemistry, hematology, urinalysis, and sperm counts. No mortalities were observed during the course of the study. No clinical signs of toxicity attributable to 1-hexene exposure were observed. Female rats exposed to 3000 ppm had significantly lower body weights compared to control rats from exposure day 5 persisting throughout the treatment period. Male rats exposed to 3000 ppm had slightly but not statistically significant lower body weights in comparison to controls. Male rats exhibited slightly increased absolute and relative testicular weights, and female rats had slightly decreased absolute [but not relative] liver and kidney weights, at 3000 ppm. There were no gross or microscopic morphological findings attributed to treatment. Exposure to 1-hexene did not affect neuromuscular coordination in females as determined using the Rotarod®, nor sperm counts in male rats. Several statistically significant effects in hematology, clinical chemistry, and urinalysis evaluations were observed, but were either of small magnitude or did not correlate with histopathological findings, and thus did not appear to be of biological significance. In summary, the no-adverse-effect-level for this study was determined to be 1000 ppm, based on decreased weight gain in female rats, and on slight organ weight changes in both sexes at 3000 ppm.     

Subchronic toxicity of cyclohexane in rats and mice by inhalation exposure

Inhalation studies were conducted to determine the potential toxicity and/or potential neurotoxicity of cyclohexane. Groups of rats and mice were exposed to 0, 500, 2000, or 7000 ppm concentrations of cyclohexane vapor 6 hr/day, 5 days/week for 14 weeks. Subgroups of rats and mice were further observed during a 1-month recovery period. Functional observational battery (FOB) and motor activity (MA) behavioral tests were conducted on rats. These tests were conducted prior to the exposure series and during weeks 4, 8, and 13 on non-exposure days. Clinical pathology evaluations were conducted after approximately 7, 13, and 18 weeks. Approximately 14 and 18 weeks after study initiation, tissues from rats and mice were histologically processed and evaluated by light microscopy. During exposure to 2000 or 7000 ppm, rats and mice had a diminished response or an absent response to delivery of a punctate auditory alerting stimulus. Immediately following removal of rats from the inhalation chambers, 7000 ppm males and females and 2000 ppm females displayed a compound-related increase in the incidence of wet and/or stained fur (which occurred in the areas of the mouth, chin, and/or perineum). These signs were transient, were not observed during exposure or prior to exposure the following day, and were not associated with any behavioral or morphological changes. During exposure sessions, mice exposed to 7000 ppm exhibited clinical signs of toxicity which included hyperactivity, circling, jumping/hopping, excessive grooming, kicking of rear legs, standing on front legs, and occasional flipping behavior. Clinical signs of toxicity observed in 7000 ppm mice immediately after exposure included hyperactivity, hyperreactivity, ruffled fur (females only), gait abnormalities, spasms in both rear legs, and excessive grooming (males only). The clinical signs observed in mice during and immediately after exposure were transient, and were not present prior to the subsequent exposure. A few mice exposed to 2000 ppm appeared hyperactive during exposure in the latter portion of the study. There were no compound-related changes in mean body weights, body weight gains, food consumption, food efficiency, or mortality; and there were no ophthalmological abnormalities in rats or mice. In addition, there were no compound-related effects on 37 different behavioral parameters assessed during the FOB or during motor activity tests in rats. Male and female mice exposed to 7000 ppm had slight increases in measures of circulating erythrocyte mass (red blood cells, hemoglobin, hematocrit) and plasma protein concentration (males only). Male rats and male and female mice exposed to 7000 ppm had significantly increased relative liver weights, and 7000 ppm male mice also had significantly increased absolute liver weights at the end of the exposure period. At the end of the 1-month recovery period, absolute and relative liver weights of male and female mice were similar to control. However, relative liver weights of 7000 ppm male rats continued to be significantly higher at the end of the recovery period. Male and female rats exposed to 7000 ppm had a significantly increased incidence of hepatic centrilobular hypertrophy at the end of the exposure period, which was not observed at the conclusion of the 1-month recovery period. No microscopic changes were observed in mice. In rats, the no-observed-effect level (NOEL) for acute, transient effects was 500 ppm based on a diminished/absent response to an auditory alerting stimulus at 2000 ppm and above. The NOEL for subchronic toxicity in rats was 7000 ppm based on the lack of adverse effects on body weight, clinical chemistry, tissue morphology, and neurobehavioral parameters. In mice, the NOEL for acute, transient effects was 500 ppm based on behavioral changes during exposure at 2000 ppm and above. The NOEL for subchronic toxicity in mice is 2000 ppm based on hematological changes at 7000 ppm.     

TOXICITY EVALUATION OF PETROLEUM BLENDING STREAMS: INHALATION SUBCHRONIC TOXICITY/NEUROTOXICITY STUDY OF A LIGHT CATALYTIC REFORMED NAPHTHA DISTILLATE IN RATS

A 13-wk whole-body inhalation study was conducted with Sprague-Dawley CD rats (16/sex/group) exposed to a light catalytic reformed naphtha distillate (LCRN-D, CAS number 64741-63-5) at target concentrations of 0, 750, 2500, and 7500 ppm for 6 h/d, 5 d/wk. Sixteen rats per sex in the control and high-dose groups were maintained after final exposure for a 4-wk recovery period. The highest exposure concentration was 75% of the lower explosive limit. Standard parameters of subchronic toxicity were measured throughout the study; at necropsy, organs were weighed and tissues processed for microscopic evaluation. Neurotoxicity evaluations consisted of motor activity (MA) and a functional operational battery (FOB) measured pretest, throughout exposure and after the recovery period. Neuropathology was evaluated at termination. No test-related mortality or effects on physical signs, body weight, food consumption, or clinical chemistry were observed. In males exposed to 7500-ppm LCRN-D, a statistically significant decrease in white blood cell counts and lymphocyte counts was observed at the termination of exposure that was not present in animals after the 4-wk recovery period. However, mean corpuscular volume was slightly decreased in high-dose males after the recovery period. Statistically significant increases in kidney weights relative to body weights in 7500-ppm male rats correlated with microscopically observed hyaline droplet formation and renal tubule dilation, indicative of light hydrocarbon nephropathy, a condition in male rats that is not toxicologically significant for humans. Statistically significant decrease in absolute and relative spleen weights in 7500-ppm male rats correlated with decreases in hematologic parameters but had no microscopic correlate and was not observed in animals after 4 wk of recovery. This mild, reversible effect in white blood cell populations may relate to the presence of aromatics in the distillate. The only effect of LCRN-D on neurobehavioral parameters was significantly higher motor activity counts among high-dose (7500 ppm) males after the 4-wk recovery period, suggesting a possible delayed effect of LCRN-D. However, there was no evidence of hyperactivity or abnormal behavior from the functional observational battery evaluations, and there were no microscopic changes in neural tissue to support this observation. The no-observed-adverse-effects level (NOAEL) for LCRN-D was 2500 ppm for both subchronic toxicity and neurotoxicity. The no-observed-effects level (NOEL) was 750 ppm.     

Toxicity evaluation of petroleum blending streams: inhalation subchronic toxicity/neurotoxicity study of a light catalytic reformed naphtha distillate in rats

A 13-wk whole-body inhalation study was conducted with Sprague-Dawley CD rats (16/sex/group) exposed to a light catalytic reformed naphtha distillate (LCRN-D, CAS number 64741-63-5) at target concentrations of 0, 750, 2500, and 7500 ppm for 6 h/d, 5 d/wk. Sixteen rats per sex in the control and high-dose groups were maintained after final exposure for a 4-wk recovery period. The highest exposure concentration was 75% of the lower explosive limit. Standard parameters of subchronic toxicity were measured throughout the study; at necropsy, organs were weighed and tissues processed for microscopic evaluation. Neurotoxicity evaluations consisted of motor activity (MA) and a functional operational battery (FOB) measured pretest, throughout exposure and after the recovery period. Neuropathology was evaluated at termination. No test-related mortality or effects on physical signs, body weight, food consumption, or clinical chemistry were observed. In males exposed to 7500-ppm LCRN-D, a statistically significant decrease in white blood cell counts and lymphocyte counts was observed at the termination of exposure that was not present in animals after the 4-wk recovery period. However, mean corpuscular volume was slightly decreased in high-dose males after the recovery period. Statistically significant increases in kidney weights relative to body weights in 7500-ppm male rats correlated with microscopically observed hyaline droplet formation and renal tubule dilation, indicative of light hydrocarbon nephropathy, a condition in male rats that is not toxicologically significant for humans. Statistically significant decrease in absolute and relative spleen weights in 7500-ppm male rats correlated with decreases in hematologic parameters but had no microscopic correlate and was not observed in animals after 4 wk of recovery. This mild, reversible effect in white blood cell populations may relate to the presence of aromatics in the distillate. The only effect of LCRN-D on neurobehavioral parameters was significantly higher motor activity counts among high-dose (7500 ppm) males after the 4-wk recovery period, suggesting a possible delayed effect of LCRN-D. However, there was no evidence of hyperactivity or abnormal behavior from the functional observational battery evaluations, and there were no microscopic changes in neural tissue to support this observation. The no-observed-adverse-effects level (NOAEL) for LCRN-D was 2500 ppm for both subchronic toxicity and neurotoxicity. The no-observed-effects level (NOEL) was 750 ppm.     

Inhalation Studies in Rats Exposed to Dimethylacetahide (DMAc) from 3 to 12 Hours Per Day

ABSTRACT

Male rats were exposed by inhalation from 10 to 300 ppm Dimethylacetamide (DMAc) for either 3, 6, or 12 hrs/day for a total of 10 exposures (5 exposures, 2 rest days, 5 exposures). Rats were observed daily for signs of DMAc-related effects, growth was monitored by body weights, clinical laboratory tests and microscopic examination of the liver, testes epididymides, and nasal passages were conducted. One half of the rats in each group was allowed a 14-day post-exposure period to evaluate the reversibility of DMAc-induced changes. No clinical signs of toxicity or DMAc-related gross changes at necropsy were seen in any of the rats although 1 rat exposed to 300 ppm for 12 hours per day died following the seventh exposure. Slight (< 5%) decreases in body weight gain were seen in rats exposed to 300 ppm for 6 or 12 hrs/day. Serum cholesterol levels were elevated in rats exposed to either 100 or 300 ppm (all exposure durations) and in rats exposed to 30 ppm for 12 hours. Total serum protein concentrations were increased in rats exposed for 12 hours/day to either 30, 100, or 300 ppm. Hepatocellular hypertrophy together with margination of hepatocellular cytoplasmic contents and lipid-like cytoplasmic vacuolation in hepatocytes were seen microscopically only in rats exposed for 12 hours/day to 300 ppm. Recovery from these liver changes was not complete after 14-day post-exposure period. No evidence of either testicular damage or irritation to the upper respiratory tract was seen.     

The effects of maternally inhaled formaldehyde on embryonal and foetal development in rats

Sprague-Dawley rats were exposed to 0, 5, 10, 20 or 40 ppm formaldehyde for 6 hr/day from day 6 to 20 of gestation. On day 21 of gestation the rats were killed for evaluation of maternal reproductive and foetal parameters. No effect on embryonic or foetal lethality, nor significant alterations in the external, visceral or skeletal appearance of the foetuses were noted in any of the exposed groups. Significant concentration-related reduction of foetal body weight occurred at 20 and 40 ppm, and at 40 ppm foetal body weights were 20% less than those of the controls. Maternal toxicity, indicated by significant reduction in body weight and absolute weight gain, was observed at 40 ppm. The results of this study show that formaldehyde is slightly foetotoxic at 20 ppm. Neither embryolethal nor teratogenic effects were observed following inhalation exposure at levels up to 40 ppm.     

2-Week Inhalation Study of N-Monomethylformamide in Rats

2-Week Inhalation Study of yV-Monomethylformamide in Rats. KENNEDY,G. L., JR., FERENZ, R. L., BURGESS, B. A., AND STULA, E. F.(1990). Fundam. Appl. Toxicol. 14, 810–816. N-Monomethylformamide(MMF) is a chemical intermediate with potential for inhalationexposure in humans. Human exposures to MMF have occurred incancer chemotherapy but have been limited due to liver damage.To assess the toxicity of MMF, groups of 15 male rats each wereexposed by nose-only inhalation, 6 hr/day, 5 days/week, for2 weeks to either 0 (control), 50, 130, or 400 ppm MMF. Fiverats per group were killed following the 10th exposure, fivewere killed after a 14-day postexposure recovery period, andfive rats were used to determine urinary MMF excretion. Parametersinvestigated were clinical observations and body weights, clinicalpathology, and gross and microscopic pathology including organweights. Liver damage occurred in rats exposed to either 130or 400 ppm. This was detected both by increases in serum enzymeactivity indicative of liver injury and by microscopic changesin the liver. The changes were more severe in the 400-ppm ratsand were partially reversible. Other organs were not adverselyaffected by inhalation of MMF. The amount of MMF excreted inthe urine was dependent on the exposure concentration and MMFwas present 14 days postexposure at the higher exposure levels.The no-observed-effect level under the conditions of this experimentwas 50 ppm.     

Toxicology and carcinogenesis studies of p,p'-dichlorodiphenyl sulfone in rats and mice.

p,p'-Dichlorodiphenyl sulfone (DDS) is used as a starting material in the production of polysulfones and polyethersufones, a family of thermoplastics. DDS was studied because of its high production volume and use. In toxicology studies, 10 Fischer 344 rats and 10 B6C3F1 mice/sex/group were fed diets containing 0, 30, 100, 300, 1,000 or 3,000 ppm DDS for 14 weeks. All animals survived until the end of the studies. Mean body weights of groups exposed to 300 ppm or greater were significantly decreased. Liver and kidney in rats and liver in mice were the major target organs of DDS toxicity. Dose-related increases in liver weights and incidences of centrilobular hepatocyte hypertrophy were observed in DDS-exposed groups. Nephropathy was seen in male and female rats only at and above 300 ppm. Neurotoxicity evaluations were negative in DDS-treated animals. Clinical chemistry and hematology parameters were minimally affected. In the 2-year toxicity and carcinogenicity studies, 50 rats and 50 mice/sex/group were fed diets containing 0, 10 (male rats), 30, 100, or 300 ppm DDS for 104 to 105 weeks. Survival of exposed groups was not affected. There were no clinical signs of toxicity related to DDS exposure. Final mean body weights were 2-17% lower in DDS-treated groups. Liver was the only target organ of DDS-induced toxicity. The incidence of centrilobular hepatocyte hypertrophy in mice and rats, and the incidence of bile duct hyperplasia and centrilobular degeneration in female rats was significantly greater than in controls. A no-observed-adverse-effect level (NOAEL) of 30 ppm DDS in the diet (1.5 mg/kg body weight) was established for rats. DDS was not carcinogenic in these studies.     

TOXICITY EVALUATION OF PETROLEUM BLENDING STREAMS: INHALATION SUBCHRONIC TOXICITY/NEUROTOXICITY STUDY OF A LIGHT ALKYLATE NAPHTHA DISTILLATE IN RATS

A 13-wk inhalation study was conducted with Sprague-Dawley CD rats ( 12/sex/ group) were exposed by inhalation for 13 weeks to a light alkylate naphtha distillate (LAND-2, C-C ; average molecular weight 89.2) at actual average concentrations of 0 (room 4 10 air), 668, 2220, or 6646 ppm, 6 h/d, 5 d/wk; 12 additional rats/sex in the control and high dose groups were held after final exposure for a 4-wk recovery period. The highest exposure concentration was 75% of the lower explosive limit. Standard parameters of subchronic toxicity were measured throughout the study; at necropsy, organs were weighed and tissues processed for microscopic evaluation. Neurotoxicity evaluations consisted of motor activity (MA) and a functional operational battery (FOB) measured pretest, during 5, 9, and 14 wk of the study, and after the 4-wk recovery period. Wholebody perfusion and microscopic examination of selected organs and nervous tissue from the control and high dose rats were conducted at the end of exposure. No testrelated mortality or effects on physical signs, body weight, or food consumption were observed. Statistically significant increases in absolute and relative kidney weights in high-exposure males correlated with microscopically observed hyaline droplet formation and renal nephropathy, effects in male rats that are not toxicologically significant for humans. Increased liver weights in both sexes at the highest dose had no microscopic correlate and appeared reversible after the 4-wk recovery period. Exposure to LAND-2 at any dose did not produce neurotoxicity measured by MA, FOB, or neuropathology. The no-observed-effects level (NOEL) for LAND-2 was 2220 ppm for subchronic toxicity and 6646 ppm for neurotoxicity.     

Inhalation carcinogenicity bioassay of vinyl bromide in rats

The carcinogenicity of vinyl bromide was evaluated during an inhalation study in which Sprague-Dawley rats were exposed for 6 hr daily, 5 days per week for 2 years, in 6-m³ stainless steel and glass inhalation chambers. The four exposure levels to vinyl bromide in air were 9.7, 52, 247, and 1235 ppm. The controls were exposed to filtered and conditioned outside air. Moribund rats and rats in groups scheduled for termination from the control and exposed levels following 6, 12, 18, and 24 months of exposure were necropsied and examined for histopathologic changes. Body weights, mortality, hematology, urinalysis, clinical chemistry, terminal organ weights, histopathology, and analytical observations were conducted. A decline in body weights was evident among all exposure levels. Microcytic anemia, elevated serum bromide levels, decreased BUN, elevated alkaline phosphatase, elevated LDH, and hematuria were observed. Angiosarcomas, primarily of the liver, were induced in both male and female rats in all four exposure groups. An increase in the number of Zymbal's gland neoplasms was found in both male and female rats at 52-, 247-, and 1235-ppm exposure levels. An increased incidence of primary hepatocellular neoplasms was seen in males exposed to 247 ppm and in females exposed to 9.7, 52, and 247 ppm. The increase in primary hepatocellular neoplasms was detected primarily in animals that survived the 24-month exposure or died following 18 months of exposure. No exposure-related pathology was observed in the brains of the rats.