Developmental toxicity evaluation of inhaled toluene diisocyanate vapor in CD rats.

Mated female CD (Sprague-Dawley) rats, 25/group, were exposed to toluene diisocyanate (TDI) vapor, for six h/day on gestational days (gd) 6 through 15, at 0.00, 0.02, 0.10, or 0.50 p.p.m.. Maternal clinical signs, body weights, and feed and water consumption were recorded throughout gestation. At termination (gd 21), maternal body, gravid uterine, and liver weights were recorded. Corpora lutea were counted, and implantation sites were identified: resorptions and dead and live fetuses. All live fetuses were examined for external alterations. One-half of the live fetuses/litter were examined for visceral (including craniofacial) alterations. The remaining intact fetuses/litter were stained with alizarin red S and examined for ossified skeletal alterations. Maternal toxicity at 0.50 ppm consisted of reduced body weights, body weight gains, feed consumption, and clinical signs of toxicity. Water consumption was unaffected. Gestational parameters exhibited no significant treatment-related changes, including pre- and postimplantation loss, sex ratio/litter, or fetal body weights/litter. Incidences of individual malformations, malformations by category (external, visceral, and skeletal), total malformations, individual external and visceral variations, variations by category, and total variations were unaffected. Of 111 skeletal variants observed, only 1, incidence of poorly ossified cervical centrum 5, was increased at 0.50 ppm, indicating possible minimal fetotoxicity, although it occurred in the absence of any other indications of developmental toxicity. Therefore, exposure to TDI vapor by inhalation, during major organogenesis in CD rats, resulted in maternal toxicity and minimal fetotoxicity at 0.50 ppm no observed adverse effect level (NOAEL) for maternal and developmental toxicity was 0.10 ppm. No treatment-related embryotoxicity or teratogenicity was observed.

Two-generation reproductive toxicity study of inhaled toluene diisocyanate vapor in CD rats.

Twenty-eight 42-day-old pups/sex/group (F0) were exposed to toluene diisocyanate vapor (TDI; 80% 2,4-TDI, 20% 2,6-TDI) by inhalation at 0.0, 0.02, 0.08, or 0.3 ppm, 6 h/day, 5 days/week, for 10 weeks, then mated within groups for 3 weeks, with exposure 7 days/week during mating, gestation, and lactation. F0 maternal animals were not exposed from gestational day (gd) 20 through postnatal day (pnd) 4; maternal exposures resumed on pnd 5. Twenty-eight weanlings/sex/group continued exposure for 12 weeks (starting on pnd 28) and were bred as described above. F0 and F1 parents and ten F1 and F2 weanlings/sex/group were necropsied, and adult reproductive organs, pituitary, liver, kidneys, and upper respiratory tract (target organs) were evaluated histologically in ten/sex/group. Adult toxicity was observed in both sexes and generations at 0.08 and 0.3 ppm, including occasional reductions in body weights and weight gain, clinical signs of toxicity at 0.08 and 0.3 ppm, and histologic changes in the nasal cavities at 0.02, 0.08, and 0.3 ppm (including rhinitis, a nonspecific response to an irritating vapor, at all concentrations). There was no reproductive toxicity, reproductive organ pathology, or effect on gestation or lactation at any exposure concentration. Postnatal toxicity and reduced body weights and weight gains during lactation occurred only in F2 litters at 0.08 and 0.3 ppm. Therefore, under the conditions of this study, a no observed adverse effect level (NOAEL) was not determined for adult toxicity; the NOAEL for reproductive toxicity was at least 0.3 ppm, and the NOAEL for postnatal toxicity was 0.02 ppm.

Developmental toxicity study of inhaled acrylic acid in New Zealand White rabbits.

In range-finding and definitive developmental toxicity studies, timed pregnant New Zealand White rabbits were exposed to acrylic acid (CAS No. 79-10-7) vapour for 13 consecutive days during pregnancy. In the range-finding study, eight pregnant does/group were exposed to 30, 60, 125 or 250 ppm acrylic acid vapour on gestation days (gd) 10-22 of pregnancy. Monitors of toxicity included body weight measurements, daily food consumption measurements and clinical observations. Three of the eight does/group were killed on the day following the last exposure (gd 23), and the remaining does were killed and autopsied on gd 29. At autopsy, special attention was given to gross observation of maternal nasal turbinates, and nasal turbinates from all does were evaluated histologically. No evaluation of foetuses was performed in the range-finding study. In the definitive study, 16 does/group were exposed to concentrations of 25, 75 or 225 ppm acrylic acid vapour from gd 6 to 18, the major period of organogenesis. Monitors of maternal toxicity included clinical observations and measurements of body weight and daily food consumption measurements. Does were killed and autopsied on gd 29. Maternal liver and kidney weights were measured and external, visceral and skeletal evaluations of foetuses were conducted. Maternal nasal turbinates were not evaluated histologically in the definitive study. Effects in does from both studies included consistent concentration-related reductions in food consumption and body weight gains throughout the exposure period at concentrations of acrylic acid vapour above 60 ppm. Characteristic clinical signs of sensory irritation, including perinasal and perioral wetness and severe nasal congestion, were noted in does from both studies at or above vapour concentrations of 75 ppm. Gross observation of nasal turbinates immediately following exposures in the range-finding study indicated colour changes in the nasal turbinates of does in the 60 and 250 ppm groups. Colour changes in the nasal turbinates were noted in one doe from the 250 ppm exposure group killed on gd 29. Pertinent autopsy findings in the does from the definitive study included ulceration of the nasal turbinates of a single doe in the 225 ppm group. Histological evaluation of turbinates from does killed the day following exposures in the range-finding study revealed lesions in the nasal epithelium in all acrylic acid-exposed groups. The severity of the lesions was concentration related. Microscopic evaluation of turbinates from does killed on gd 29 showed the presence of nasal lesions in the 60, 125 and 250 ppm groups. However, the nasal tissues had recovered considerably during the post-exposure interval. Despite the severe effects on the nasal mucosa of does in both studies, there was no evidence of developmental toxicity including teratogenicity at any exposure concentration used in the definitive study.

Neurotoxicological evaluation of methyl tertiary-butyl ether in rats.

Methyl tertiary-butyl ether (MTBE) is an oxygenate that is added to gasoline to boost octane and enhance combustion, thereby reducing carbon monoxide and hydrocarbon tailpipe emissions. The acute and subchronic neurotoxicity of MTBE were evaluated in rats using a functional observation battery (FOB), measures of motor activity (MA) and a neuropathological evaluation. In the acute study, rats were exposed once to 0, 800, 4000 or 8000 ppm MTBE by inhalation for 6 h and then evaluated three times over a 24-h period. In the FOB evaluations, treatment-related effects were seen at the 1-h session immediately following exposure and were indicative of transient central nervous system (CNS) depression. Effects were most apparent in the high-dose group (8000 ppm) but were also evident to a lesser extent in the mid-dose (4000 ppm) group. Labored respiration, ataxia, duck-walk gait and decreases in muscle tone, hind-limb grip strength and treadmill performance were the most frequently noted findings. No significant effects were observed in the FOB when testing was conducted at 6 h and 24 h post-exposure. The pattern of motor activity measured in the different dose groups following exposure was also in keeping with a reversible CNS-depressant effect of MTBE. In the subchronic study, rats were exposed to 0, 800, 4000 or 8000 ppm MTBE for 6 h a day, 5 days per week, for 13 weeks. No persistent or cumulative effects on neurobehavioral function were found. Body weights and absolute brain weights were reduced in the 8000 ppm group, however there were no differences among groups when brain weight was expressed relative to body weight. No histopathological changes were noted in the brains or peripheral nervous tissues of MTBE-exposed animals. In summary, MTBE produced signs of acute reversible CNS depression following exposure to 8000 ppm and, to a lesser extent, to 4000 ppm vapor. The no-observed-adverse-effect level for these effects was 800 ppm in the present study. No persistent or cumulative neurotoxic effects were observed following exposure to MTBE at concentrations up to 8000 ppm for 13 weeks.

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)

Evaluation of exposure to water aerosol or air by nose-only or whole-body inhalation procedures for CD-1 mice in developmental toxicity studies.

This study was performed to evaluate the effects of nose-only restraint versus whole-body exposure procedures in the absence of test chemical, and to determine the appropriate control environment (water aerosol or air) for subsequent developmental toxicity studies of test materials administered as aerosols. Timed-pregnant CD-1 mice, 30/group, were exposed to high concentrations of water aerosol or to air by whole-body or nose-only inhalation procedures on Gestational Days (GD) 6 through 15 for 6 hr per day. The group exposed to air by whole-body procedures was designated as the control group. Clinical observations and maternal body weights were recorded throughout gestation. At scheduled necropsy on GD 18, maternal animals were evaluated for body weight, gravid uterine weight, liver weight, number of ovarian corpora lutea, and status of uterine implantation sites. Fetuses were counted, weighed, and sexed and were examined for external, visceral (including craniofacial), and skeletal alterations. Indices of maternal toxicity were affected in both nose-only groups. Maternal body weights were reduced during and after the exposure period; maternal weight gain was reduced during the exposure period. Clinical signs observed, from animals struggling during restraint, were resolved by GD 18. At sacrifice on GD 18, maternal body weights and maternal gestational weight gains (both corrected for gravid uterine weights) and absolute liver weights were reduced in both nose-only groups. Four females died (13.3%, all pregnant) in the air nose-only group, and maternal liver weight (relative to body weight) was reduced in the aerosol nose-only group. Gestational parameters were unaffected by any of the treatments. There were no statistically significant differences in the incidences of any individual malformations or malformations by category (external, visceral, or skeletal) or of total malformations. However, exencephaly, low set ears, cleft palate and ventricular septal defect were observed only in both aerosol-exposed groups (whole-body and nose-only exposed). The incidences of individual external or visceral variations or of variations by category or of total variations were unaffected. The incidence of one skeletal variation, poorly ossified supraoccipital skull bone, was significantly increased in the aerosol nose-only group relative to the air whole-body controls. There were also increased incidences (not statistically significant) of extra (14th) ribs in both aerosol groups. Therefore, maternal restraint (in both nose-only groups) during organogenesis produced indications of maternal toxicity, but restraint did not appear to affect normal embryo/fetal morphologic development.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of ethylene on micronucleus formation in the bone marrow of rats and mice following four weeks of inhalation exposure.

Male Fischer 344 rats and male B6C3F1 mice (10/species/group) were exposed to ethylene 6 h/day, 5 days/week, for 4 weeks. The ethylene target concentrations were 0, 40, 1000, and 3000 ppm. An ethylene oxide (EO) control group for each species was exposed under the same conditions at a target concentration of 200 ppm. Bone marrow was collected approximately 24 h after the final exposure. Polychromatic erythrocyte (PCE) to normochromatic erythrocyte (NCE) ratios were determined and 2000 PCE/animal were scored for the presence of micronuclei. Ethylene did not produce statistically significant, exposure-related increases in the frequency of micronucleated PCE (MNPCE) in the bone marrow of either rats or mice when compared to air-exposed control animals. As expected, EO exposure resulted in significant increases in the frequencies of MNPCE in both species.

An evaluation of the developmental toxicity of 2,4-pentanedione in the Fischer 344 rat by vapour exposure.

The developmental toxicity of 2,4-Pentanedione (2,4-PD; CAS No. 123-54-6), a widely used industrial chemical, was investigated by vapour exposure, because of its widespread use, and potential for human exposure. Timed-pregnant Fischer 344 rats were exposed on gestational days (gd) 6 to 15 inclusive to analytically measured concentrations (as mean +/- SD) of 53 +/- 1.6, 202 +/- 4.7 and 398 +/- 5.7 ppm 2,4-PD vapour. At sacrifice (gd 21) foetuses were examined for external, visceral and skeletal variations and malformations. There was no maternal mortality, and body weight was reduced only at 398 ppm. Histological examination of maternal brains from the 398 ppm group showed no abnormalities. No treatment-related effects were seen on number of corpora lutea; total, nonviable or viable implants per litter; pre-or post-implantation losses; or foetal sex ratio. Reduced foetal body weight per litter was seen at 398 ppm (males and females and all foetuses) and 202 ppm (males and all foetuses). There was no concentration-related, or statistically significant, increase in the incidence of individual malformations, malformations by category (external, visceral or skeletal), or total malformations. Partial foetal atelectasis was increased at 398 ppm, and the increased incidence of 17 skeletal variants (out of 79 observed) indicated a consistent pattern of foetotoxicity at 398 ppm. In summary, at 398 ppm there was maternal toxicity (reduced body weight) and foetotoxicity (reduced body weight and ossification) and at 202 ppm there was foetotoxicity (reduced body weight). Embryotoxicity or teratogenicity were not seen at any concentration. The no-observable-effects concentration was 53 ppm for both maternal and developmental toxicity.

Acute vapour inhalation toxicity of acrolein and its influence as a trace contaminant in 2-methoxy-3,4-dihydro-2H-pyran.

1. The LC50 values for acrolein (AC) vapour to Sprague-Dawley rats (combined sexes) were determined to be 26 ppm (1 h) and 8.3 ppm (4 h). Signs of severe irritancy were present, and death was due to lung injury. 2. Exposure of rats to a 2-methoxy-3,4-dihydro-2H-pyran (MDP) saturated vapour atmosphere statistically generated from liquid MDP containing 0.037% AC, caused severe irritancy and death from accumulation of AC vapour. Sparging the impure material with nitrogen gas before atmosphere generation significantly reduced or abolished lethal toxicity. 3. Dynamically generated MDP vapour atmosphere produced transient respiratory and ocular irritancy, but no mortalities. The intrinsic acute vapour inhalation toxicity of MDP is low. 4. The presence of highly volatile toxic impurities in a material may confer a significant acute inhalation toxicity and hazard under conditions of low air movement. Assessment of potential inhalation hazards from liquid mixtures may require investigation by static and dynamic methods for vapour generation.

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.

The acute toxicity of tris(dimethylamino)silane.

The acute handling hazards of tris(dimethylamino)silane [TDMAS] were investigated. The acute male rat peroral LD50 (with 95% confidence limits) was 0.71 (0.51-0.97) ml/kg, and the acute male rabbit percutaneous LD50 was 0.57 (0.35-0.92) ml/kg. The liquid was severely irritating to the rabbit eye and skin, and the vapor severely irritating to the rat eye. The dynamically generated saturated vapor Lt50 in female rats was 12 (9.7-15) min. The effect of varying the atmospheric concentration of vapor from TDMAS on acute inhalation toxicity was investigated by passing ordinary moist air countercurrent to liquid TDMAS metered into a slightly heated glass tube. Based on nominal concentrations, the 4 hr-LC50 for vapor from TDMAS was 734 (603-893) ppm in female rats by this procedure. Stoichiometrically, this accords with toxicity due to liberation of dimethylamine (DMA) from TDMAS. In a subsequent study designed to assess the influence of relative humidity on vapor toxicity, nitrogen was passed over heated liquid TDMAS and the resultant atmosphere was introduced into the air intake duct of the inhalation exposure chamber. Gas chromatographically measured TDMAS concentrations (+/- SD) were 395 +/- 111, 127 +/- 25, 62 +/- 8 and 23 +/- 21 ppm; the corresponding DMA vapor concentrations were 112 +/- 171, 31 +/- 43, 10 +/- 6 and 26 +/- 44 ppm. The 4-hr LC50 (males and females) was 38 (34-43) ppm TDMAS vapor. Thus, TDMAS is of moderate acute peroral and percutaneous toxicity, a severe primary skin and eye irritant, an aspiration hazard, and of high intrinsic acute inhalation toxicity, but in moist air conditions lethal toxicity may be reduced and in such circumstances DMA may be a significant factor in toxicity.

Developmental toxicity evaluation of inhaled 2-ethoxyethanol acetate in Fischer 344 rats and New Zealand white rabbits.

Pregnant Fischer 344 rats and New Zealand white rabbits were exposed to 2-ethoxyethanol acetate (EEA; CAS No. 111-15-9) vapor by inhalation on Gestational Days 6 through 15 (rats) or 6 through 18 (rabbits) at concentrations of 0, 50, 100, 200, or 300 ppm, 6 hr/day. The animals were terminated on Gestational Day 21 (rats) or 29 (rabbits) and fetuses were examined for external, visceral, and skeletal malformations and variations. In rabbits, exposure to 100-300 ppm resulted in maternal toxicity: decreased weight gain at 100-300 ppm, clinical signs at 200-300 ppm, alterations in hematology at 100-300 ppm, reduced gravid uterine weight at termination at 200-300 ppm, and elevated absolute liver weight at 300 ppm. Developmental toxicity was observed at 100-300 ppm: an increased incidence of totally resorbed litters at 200-300 ppm, an increase in nonviable fetuses at 300 ppm, and a decrease in viable implants (live fetuses) per litter at 200-300 ppm. The incidence of fetal malformations (external, visceral, and skeletal) was increased at 200-300 ppm. The incidence of total malformations was 100% at 300 ppm and significantly increased at 200 ppm. Reduced fetal ossification was observed at 100-300 ppm. In rats, exposure to 100-300 ppm also resulted in maternal toxicity: reduced weight gain and reduced food consumption at 200-300 ppm and elevated relative liver weight and alterations in hematology at 100-300 ppm. Absolute maternal liver weight was increased at all EEA exposure concentrations; relative liver weight was increased at 100-300 ppm. Developmental toxicity was observed at 100-300 ppm: increased nonviable implantations/litter (300 ppm), reduced fetal body weight/litter (200-300 ppm), and increased incidence of external (300 ppm), visceral, and skeletal (100-300 ppm) variations indicative of toxicity. The incidence of visceral, skeletal, and total malformations was increased at 200-300 ppm. In conclusion, in both species, inhalation exposure to EEA during organogenesis produced maternal toxicity at 100-300 ppm and developmental toxicity at 100-300 ppm, including teratogenicity at 200-300 ppm. At 50 ppm in both species, there was no evidence of maternal or developmental toxicity, including teratogenicity.

Hyalin droplet nephrosis in male Fischer-344 rats following inhalation of diisobutyl ketone.

Four groups, each consisting of 10 male and 10 female Fischer-344 rats, were exposed 6 h/day, 5 days/week, for 9 days to diisobutyl ketone (DIBK) vapor at concentrations of 905, 300, 98, or 0 (control) ppm. An additional 10 rats/sex were assigned to the 905 and 0 ppm groups and allowed two weeks recovery prior to sacrifice. Rats exposed to 905 ppm had mild ocular irritation (lacrimation) and evidence of kidney toxicity, manifested as: 1) an increase in absolute and relative (as a percentage of body weight) kidney weights, 2) an increase in urine volume (and water intake) with a concomitant decrease in urine osmolality (males only), and 3) an increase in severity of hyalin droplet nephrosis in the proximal tubules (males only). Absolute and relative liver weights were also increased in both male and female rats of the 905 and 300 ppm groups. These effects either disappeared or lessened in severity following the 2-week recovery period. Male rats exposed to 300 ppm had similar renal alterations to the males of the 905 ppm group, although the alterations were fewer in number and smaller in magnitude. Kidney weights and renal histology of the males of the 98 ppm group were similar to the control male rats, although an increase in urine volume with a decrease in urine osmolality was observed. The kidney findings in this study were not surprising because of the chemical relationship of DIBK with other aliphatic ketones (e.g., methyl isobutyl ketone, methyl isoamyl ketone) which, after repeated inhalation exposure, cause hyalin droplet nephropathy in male rats. The significance of this male rat nephrosis with regard to human exposure is unknown.

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.

Methyl isocyanate eight-day vapor inhalation study with Fischer 344 rats.

Groups of ten male and ten female Fischer 344 rats were exposed by inhalation 3.1, 0.6, 0.15, or 0.0 (control) ppm of methyl isocyanate (MIC) vapor 6 hr per day for 8 days (two 4-day sessions separated by a 2-day rest). Evaluation of toxic effects included body weight, food consumption, organ weights, and selected hematologic, ophthalmic, neurologic, gross anatomic, and histologic examinations. There were no deaths during the study. Rats of the 3.1 ppm exposure group had decreased body weights, food consumption, and blood oxygen saturation (males only). An increase in hemoglobin concentration (males only) and in lung weights (absolute and as a percentage of body weight) were also observed in the 3.1 ppm rats. Ophthalmic or neurofunctional behavior evaluations were negative for all MIC exposure groups. Only 3.1 ppm of MIC vapor resulted in lesions in the respiratory tract, 0.6 or 0.15 ppm did not. The types of lesions observed were inflammation and squamous metaplasia in the nasal cavity, trachea, and bronchi; inflammation of the bronchioles and alveoli; and submucosal fibroplasia of the bronchioles. No significant lesions were observed in tissues other than those of the respiratory tract in all MIC exposure groups. The results of this study indicate the current 0.02 ppm threshold limit value for MIC is not too high regarding toxicity.

Reproduction and fertility evaluations in CD rats following nitrobenzene inhalation.

A two-generation reproduction study was performed by exposure of Sprague-Dawley CD rats to concentrations of 40, 10, 1, or 0 (control) ppm of nitrobenzene (NB) vapor. No NB-related effects on reproduction were observed at 10 or 1 ppm. At 40 ppm, a decrease in the fertility index of the F0 and F1 generations occurred, which was associated with alterations in the male reproductive organs. Specifically, weights of testes and epididymides were reduced and seminiferous tubule atrophy, spermatocyte degeneration, and the presence of giant syncytial spermatocytes were observed. The only significant finding in the litters derived from rats exposed to 40 ppm was an approximate 12% decrease in the mean body weight of F1 pups on Postnatal Day 21. Survival indices were unaltered. To examine the reversibility of this selective effect on male gonads, the F1 males from the 40-ppm group were allowed a 9-week nonexposure period and mated to naive females. An almost fivefold increase in the fertility index was observed, indicating at least partial functional reversibility upon removal from NB exposure. Also, the numbers of giant syncytial spermatocytes and degenerated spermatocytes were greatly reduced. The results of this study support the selection of 10 ppm of NB as the no-observable-effect level for reproduction and fertility effects in rats.

Development toxicity evaluation of inhaled nitrobenzene in CD rats.

Pregnant CD (Sprague-Dawley) rats were exposed to nitrobenzene vapor (CAS Registry No. 98-95-3) at 0, 1, 10, and 40 ppm (mean analytical values of 0.0, 1.06, 9.8, and 39.4 ppm, respectively) on gestational days (gd) 6 through 15 for 6 hr/day. At sacrifice on gd 21, fetuses were evaluated for external, visceral, and skeletal malformations and variations. Maternal toxicity was observed: weight gain was reduced during exposure (gd 6-9 and 6-15) to 40 ppm, with full recovery by gd 21, and absolute and relative spleen weights were increased at 10 and 40 ppm. There was no effect of treatment on maternal liver, kidney, or gravid uterine weights, on pre- or postimplantation loss including resorptions or dead fetuses, on sex ratio of live fetuses, or on fetal body weights (male, female, or total) per litter. There were also no treatment-related effects on the incidence of fetal malformations or variations. In summary, during organogenesis in CD rats, there was no developmental toxicity (including teratogenicity) associated with exposure to nitrobenzene concentrations that produced some maternal toxicity (10 and 40 ppm) or that produced no observable maternal toxicity (1 ppm).

Developmental toxicity evaluation of inhaled methyl isobutyl ketone in Fischer 344 rats and CD-1 mice.

Pregnant Fischer 344 rats and CD-1 mice were exposed to methyl isobutyl ketone vapor (CAS No. 108-10-1) by inhalation on Gestational Days 6 through 15 at concentrations of 0, 300, 1000, or 3000 ppm (mean analytical values of 0, 305, 1012, and 2997 ppm, respectively). The animals were sacrificed on Gestational Day 21 (rats) or 18 (mice), and live fetuses were examined for external, visceral, and skeletal alterations. In rats, exposure to 3000 ppm resulted in maternal toxicity expressed as clinical signs, decreased body weight and body weight gain, increased relative kidney weight, and decreased food consumption, and in fetotoxicity expressed as reduced fetal body weight per litter and reductions in skeletal ossification. In mice, exposure to 3000 ppm resulted in maternal toxicity expressed as exposure-related increases in deaths (12.0%, 3/25 dams), clinical signs, and increased absolute and relative liver weight, and in fetotoxicity expressed as increased incidence of dead fetuses, reduced fetal body weight per litter, and reductions in skeletal ossification. No treatment-related increases in embryotoxicity or fetal malformations were seen in either species at any exposure concentration tested. There was no evidence of treatment-related maternal, embryo, or fetal toxicity (including malformations) at 1000 or 300 ppm in either species.