Reproduction Study of Dimethylacetamide following Inhalation in the Rat

Reproduction Study of Dimethylacetamide following Inhalationin the Rat. Ferenz, R. L., and Kennedy, G. L., Jr. (1986). Fundam.Appl Toxicol. 7, 132-137. Groups of 10 male and 20 female Crl:CD(SD)BRrats were exposed to vapors of dimethylacetamide (DMAC) at concentrationsof 0 (control), 30, 100, or 300 ppm. Exposures were conductedfor 6 hr/day, 5 days/week for 10 weeks (prebreeding), then 7days/week for 7 to 8 weeks (through breeding, gestation, andlactation). The exposure period was interrupted for female ratsbetween gestation Day 21 and postpartum Day 4. No compound-relatedeffects on body weight, survival, or clinical signs were detectedin parental rats. Liver weight to body weight ratios were increasedin groups where both males and females were exposed to 300 ppmbut not in groups where only males or only females were exposedto 300 ppm. No significant differences were observed betweencontrol and test rats with respect to mating performance, fertility,length of gestation, progeny numbers, structure, and viability.At 21 days postpartum, pups derived from matings involving exposureof both sexes to 300 ppm or exposure of parental females to300 ppm had lower body weights than did the controls. Grosspathologic examination of representative pups and evaluationof liver and gonad weight data did not reveal any DMAC-relatedchanges. It is concluded that reproduction in rats was not alteredby repeated inhalation exposure to up to 300 ppm DMAC.     

Developmental toxicity of dimethylformamide in the rat following inhalation exposure.

Dimethylformamide (DMF) is a widely used industrial solvent. DMF has been reported to be a developmental toxin when given to rodents by injection or following dermal administration. In this study, groups of pregnant rats were exposed by inhalation to either 0 (control), 30, or 300 ppm DMF from gestation day 6 through 15. In the 300 ppm rats, both maternal weight gain during gestation and fetal weights were lower than those of the controls. Fetal resorptions were not increased in this group. No significant differences among either maternal or fetal rats were seen in the 30 ppm group compared to controls. Both fetal and maternal toxicity were noted at 300 ppm and the no observed effect level under these experimental conditions was 30 ppm for both the dams and the conceptuses. DMF did not produce malformations in the rat fetus even at a level that was toxic to the dam.     

Inhalation Teratology Studies of n-Butyl Mercaptan in Rats and Mice

Inhalation Teratology Studies of n-Butyl Mercaptan in Rats andMice. THOMAS, W. C., SECKAR, J. A., JOHNSON, J. T., ULRICH,C. E., KLONNE, D. R., SCHARDEIN, J. L., AND KIRWIN, C. J. (1987).Fundam. Appl. Toxicol. 8, 170–178. n-Butyl mercaptan (n-BM)is used as a solvent and a chemical intermediate. Pregnant CharlesRiver CD-1 mice and COBS CD rats were randomly assigned to acontrol group and to three n-BM-exposed groups of 25 rats and25 mice each. The animals were exposed by whole-body inhalationto mean n-BM concentrations of 10, 68, or 15 2 ppm on a 6-hrdaily exposure schedule. Rats were exposed on Gestation Days6–19 and mice on Gestation Days 6–16. The controlgroup was exposed to filtered air only on a comparable regimen.Cesarean sections were performed on all surviving mice on GestationDay 17 and on all rats on Gestation Day 20. Seventeen of then-BM-treated mice died: 8 at the 68-ppm level and 9 at the 152-ppmlevel; none of the n-BM-treated rats died. An increased postimplantationloss and increased early resorption occurred in mice exposedat 68 and 152 ppm, indicating embryotoxicity. An increased incidenceof cleft palate was observed in mice exposed to 10 or 68 ppmwhich was not statistically significant. Total fetal abnormalitieswere statistically significantly different from controls at68 ppm where maternal lethality was observed when based on thefetal unit although not when based on the litter unit. Ratsexposed to 152 ppm or less demonstrated no terata.     

Developmental Toxicity Evaluation of Inhaled Methyl Isobutyl Ketone in Fischer 344 Rats and CD-1 Mice

Developmental Toxicity Evaluation of Inhaled Methyl IsobutylKetone in Fischer 344 Rats and CD-1 Mice. Tyl, R. W., FRANCE,K. A., FISHER, L. C., PRITTS, I. M., TYLER, T. R., PHILLIPS,R. D., and MORAN, E. J. (1987). Fundam. Appl. Toxicol. 8, 310–327.Pregnant Fischer 344 rats and CD-1 mice were exposed to methylisobutyl ketone vapor (CAS No. 108-10-1) by inhalation on GestationalDays 6 through 15 at concentrations of 0, 300, 1000, or 3000ppm (mean analytical values of 0, 305, 1012, and 2997 ppm, respectively).The animals were sacrificed on Gestational Day 21 (rats) or18 (mice), and live fetuses were examined for external, visceral,and skeletal alterations. In rats, exposure to 3000 ppm resultedin maternal toxicity expressed as clinical signs, decreasedbody weight and body weight gain, increased relative kidneyweight, and decreased food consumption, and in fetotoxicityexpressed as reduced fetal body weight per litter and reductionsin skeletal ossification. In mice, exposure to 3000 ppm resultedin maternal toxicity expressed as exposure-related increasesin deaths (12.0%, 3/25 dams), clinical signs, and increasedabsolute and relative liver weight, and in fetotoxicity expressedas increased incidence of dead fetuses, reduced fetal body weightper litter, and reductions in skeletal ossification. No treatment-relatedincreases in embryotoxicity or fetal malformations were seenin either species at any exposure concentration tested. Therewas no evidence of treatment-related maternal, embryo, or fetaltoxicity (including malformations) at 1000 or 300 ppm in eitherSpecies.     

Inhalation teratology study on monochlorobenzene in rats and rabbits

The embryotoxic and teratogenic potential of inhaled monochlorobenzene (MCB) was evaluated in rats and rabbits. Bred Fischer 344 rats and inseminated New Zealand White rabbits were exposed to 0, 75, 210, or 590 ppm of MCB via inhalation for 6 hr/day during the period of major organogenesis. Exposure to 590 ppm caused elevated liver weights in both species and decreased body weight gain and feed consumption in rats. Inhalation of MCB vapors during gestation was not embryotoxic or teratogenic in rats. In rabbits, a few MCB-exposed fetuses exhibited visceral malformations which were not observed among concurrent controls, though no dose-related increase in malformations occurred. To further evaluate the effects of MCB in rabbits, additional groups were exposed to 0, 10, 30, 75, or 590 ppm. This subsequent study did not result in any increase in malformations in the MCB-exposed groups. Fetal effects were limited to a slight delay in skeletal development which occurred only in rats exposed to 590 ppm, a maternally toxic concentration.     

Developmental Toxicity Evaluation of Inhaled Nitrobenzene in CD Rats

Developmental Toxicity Evaluation of Inhaled Nitrobenzene inCD Rats. TYL, R. W., FRANCE, K. A., FISHER, L. C., DODD, D.E., PRITTS, I. M, LYON, J. P., O'NEAL, F. O., and KIMMERLE,G. (1987). Fundam. Appl. Toxicol. 8, 482–492. PregnantCD (Sprague–Dawley) rats were exposed to nitrobenzenevapor (CAS Registry No. 98-95-3) at 0, 1, 10, and 40 ppm (meananalytical 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 sacrificeon gd 21, fetuses were evaluated for external, visceral, andskeletal malformations and variations. Maternal toxicity wasobserved: weight gain was reduced during exposure (gd 6–9and 6–15) to 40 ppm, with full recovery by gd 21, andabsolute and relative spleen weights were increased at 10 and40 ppm. There was no effect of treatment on maternal liver,kidney, or gravid uterine weights, on pre- or postimplantationloss including resorptions or dead fetuses, on sex ratio oflive fetuses, or on fetal body weights (male, female, or total)per litter. There were also no treatment-related effects onthe incidence of fetal malformations or variations. In summary,during organogenesis in CD rats, there was no developmentaltoxicity (including teratogenicity) associated with exposureto nitrobenzene concentrations that produced some maternal toxicity(10 and 40 ppm) or that produced no observable maternal toxicity(1 ppm).     

Evaluation of the Teratogenic Effects of Tri-ortho-cresyl Phosphate in the Long-Evans Hooded Rat

Evaluation of the Teratogenic Effects of Tn-ortho-ciesyl Phosphatein the Long–Evans Hooded Rat. TOCCO, D. R., RANDALL, J.L., YORK, R. G., and SMITH, M. K. (1987). Fundam. Appl. Toxicol.8, 291–297. The developmental toxicity of tri-ortho-cresylphosphate (TOCP) was evaluated in Long–Evans rats. Pregnantrats were treated with 87.5, 175, and 350 mg/kg/day TOCP throughoutorganogenesis from gestation Days 6 through 18 (Day of sperm= Day 0). The highest dose tested (350 mg/kg) was lethal in28% of the dams; no maternal deaths or toxicity were observedin the 87.5 or 175 mg/kg dose groups. There were no significantdifferences noted among the experimental and control groupsfor preimplantation loss or resorption. Fetal weights for bothsexes in the TOCP groups were significantly greater than inthe control group; however, no difference among the TOCP groupswas observed. Malformation rates were too low to warrant statisticalanalysis. Numerous soft tissue and skeletal variations wereobserved in both control and TOCP-treated groups; there wereno significant differences in the frequency of variations amongthe dose groups. The results of this study indicate that TOCPis not teratogenic in the Long–Evans rat.     

Evaluation of the Effects of Inhalation Exposure to 1,3-Dichloropropene on Fetal Development in Rats and Rabbits

Evaluation of the Effects of Inhalation Exposure to 1,3-Dichloropropeneon Fetal Development in Rats and Rabbits. HANLEY, T. R., Jr.,JOHN-GREENE, J. A., YOUNG, J. T., CALHOUN, L. L., AND RAO, K.S. (1987). Fundam. Appl. Toxicol. 8, 562–570. 1,3-Dichloropropene(DCP), which has found widespread use as a soil fumigant, wasevaluated for its potential effects on embryonal and fetal developmentin rats and rabbits. Pregnant Fischer 344 rats and New ZealandWhite rabbits were exposed to 0, 20, 60, or 120 ppm of 1,3-dichloropropenefor 6 hr/day during gestation Days 6–15 (rats) or 6–18(rabbits). Exposure-related decreases in maternal weight gainand feed consumption were observed in rats at all treatmentlevels. Decreased weight gain was also observed among rabbitsat 60 and 120 ppm. A slight, but statistically significant,increase in the incidence of delayed ossification of the vertebralcentra in rats exposed in ulero to 120 ppm of DCP was consideredof little toxicologic significance in light of the maternaltoxicity observed at this exposure concentration. No evidenceof a teratogenic or embryotoxic response was observed in eitherspecies at any exposure level tested. Thus, it was concludedthat DCP was not teratogenic at exposure levels up to 120 ppmin either rats or rabbits.     

The Effects of Love Canal Soil Extracts on Maternal Health and Fetal Development in Rats

The Effects of Love Canal Soil Extracts on Maternal Health andFetal Development in Rats. SILKWORTH, J.B., TUMASONIS, C, BRIGGS,R.G., NARANG, A.S., NARANG, R.S., REJ, R., STEIN, V., MCMARTIN,D.N., AND KAMINSKY, L.S. (1986). Fundam. Appl. Toxicol. 7,471-485.The effects of a solvent extract of the surface soil of theLove Canal chemical dump site, Niagara Falls, New York, andof a natural extract, or leachate, which is drained from thecanal for treatment, on the maternal health and fetal developmentwere determined in rats. The solvent extract, which was contaminatedwith 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) at 170ppb and numerous other chlorinated organic compounds with theprimary identified components being the isomers of benzenehexachloride(BHC), was dissolved in corn oil and administered by gavageto pregnant rats at 0,25,75, or 150 mg crude extract/kg/dayon Days 6-15 of gestation. A 67% mortality was observed at thehighest dose. The rats were sacrificed on Day 20. Dose-relatedincreases in relative liver weight accompanied by hepatocytehypertrophy were observed at all dose levels. Fetal birthweightwas decreased at 75 and 150 mg extract/kg/day. No major treatment-relatedsoft tissue or skeletal malformations, except for delayed ossification,were observed. Based on literature values for BHC, all of theobserved toxicity could be accounted for by the BHC contaminantsof the extract. The crude organic phase of the leachate wasadministered to pregnant rats at 0, 10, 100, or 250 mg/kg/dayas described above. Maternal weight gain decreased at 100 and250 mg/kg/day, accompanied by 5 and 14% maternal mortality,and 1 and 3 dead fetuses, respectively. Early resorptions andthe percentage of dead implants increased whereas fetal birthweightswere decreased at 250 mg/kg/day. No major treatment-relatedsoft tissue or skeletal malformations, except for delayed ossification,were observed. The primary components of the complex leachateby mass were tetrachloroethanes; however, 2,3,7,8-TCDD, whichwas present at 3 ppm, probably accounted for all the observedtoxicity.     

Developmental Toxicity of Oral and Inhaled Vinyl Acetate in the Rat

Vinyl acetate (VA) is used almost exclusively as an industrialchemical in polymerization, copolymerization, or as a chemicalintermediate. The present studies were undertaken as part ofa collaborative effort by the VA producers of Western Europe,Japan, and the United States to provide animal toxicology datafor risk assessment. To assess the potential of VA causing developmentaltoxicity in rodents, groups of 23 or 24 Crl:CD(SD)BR rats weregiven 0, 200, 1000, or 5000 ppm VA in drinking water or exposed6 hr/day to 0, 50, 200, or 1000 ppm VA vapors on Days 6–15of gestation (both routes approximating 0, 25, 100, or 500 mg/kg/day).Administration of VA in the drinking water produced no evidenceof maternal or developmental toxicity. A significantly loweredwater intake was observed in dams from the 5000 ppm VA groupand probably reflected unpalatability of the VA water solutionat the highest dose level. In the inhalation study, maternaltoxicity was evident by a marked reduction in weight gain ofdams exposed to 1000 but not 200 or 50 ppm VA. Fetal toxicitywas evident by a statistically significant decrease in meanfetal weight and mean crown-rump length in fetuses from the1000-ppm VA group. In addition, there was a statistically significantincrease in the incidence of minor skeletal alterations in fetusesfrom dams exposed to 1000 ppm VA. Delayed ossification was themain skeletal alteration. In summary, pregnant rats were relativelyinsensitive to the effects of VA administered in the drinkingwater at a concentration level as high as 5000 ppm. However,VA did adversely affect both the dam and the conceptus at aninhaled concentration of 1000 ppm, but not at lower exposurelevels. These results indicate that VA is not uniquely toxicto the conceptus. The no-observed-effect level for the dam andconceptus under these experimental conditions was greater than5000 ppm for the drinking water study and was 200 ppm for theinhalation study.     

Teratology study in fischer 344 rats exposed to ethylene oxide by inhalation

Pregnant Fischer 344 rats were exposed 6 hr/day to either 100, 33, or 10 ppm of ethylene oxide vapor on Days 6 through 15 of the gestation period. Two separate control groups were maintained under the same conditions but were exposed to room air only. Two other groups of rats were given a known rodent teratogen, aspirin, by gavage; one group was given 500 mg/kg body weight on Day 9 of gestation, and the other was given 625 mg/kg body weight on Day 10 of gestation. No treatment-related effects of ethylene oxide were noted for the following evaluations; maternal survival, litter size, number of implantation and resorption sites, and number of preimplantation losses. Exposure to 100 ppm of ethylene oxide resulted in a significant depression of body weight in the fetuses, but did not result in any abnormal effects of embryonic or fetal lethality, or teratologic effects of the soft tissues or skeleton. Consequently, ethylene oxide was not considered a teratogen by inhalation in the Fischer 344 rat at an exposure concentration of 100 ppm.     

Inhalation studies to evaluate the teratogenic and embryotoxic potential of beta-chloroprene (2-chlorobutadiene-1,3)

Pregnant rats in two studies were exposed by inhalation to 0, 1, 10, and 25 ppm of β-chloroprene for 4 hr daily. Dams in one study (50 per group) were exposed on Days 1 through 12 and sacrificed on Day 17 to evaluate the embryotoxic potential of β-chloroprene. Dams in a teratology study (25 per group) were exposed on Days 3 through 20 and sacrificed on Day 21 of gestation. Male rats in a reproduction study were exposed to 25 ppm or β-chloroprene, 4 hr daily for 22 days and bred with untreated virgin females (three new females per male each week) for 8 consecutive weeks. No maternal, embryonal, or fetal toxicity was observed in the first two studies at levels of 1, 10, or 25 ppm β-chloroprene. Maternal exposure to β-chloroprene did not affect the development of rat fetuses as measured by weight and crownrump length and did not result in major external, skeletal, or soft tissue malformations. The reproductive capability of males exposed to 25 ppm of β-chloroprene 4 hr daily for 22 days was not impaired. The results of these studies indicate that 25 ppm of β-chloroprene, the present threshold limit value, is not embryotoxic or teratogenic and does not impair reproductive capability of male rats. These results are at variance with previous findings from the Soviet Union.     

Teratologic Evaluation of Inhaled Epichlorohydrin and Allyl Chloride in Rats and Rabbits

Teratologic Evaluation of Inhaled Epichlorohydrin and AllylChloride in Rats and Rabbits. John, J.A., Gushow, T.S., Ayres,J.A., Hanley, T.R., Jr., Quast, J.F. and Rao, K.S. (1983). Fundam.Appl Toxicol. 3:437–442. Pregnant Sprague-Dawley ratsand New Zealand white rabbits were exposed to vapors of epichlorohydrin(ECH) at concentrations of 0, 2.5 or 25 ppm or to allyl chloride(AC) at concentrations of 0, 30, or 300 ppm. Exposures werefor 7 hr/day on days 6 through 15 (rats) or 6 through 18 (rabbits)of gestation. Maternal effects including decreased body weightand food consumption were observed among rats inhaling 25 ppmof ECH. No evidence of an adverse effect to the embryo or fetuswas observed among rats or rabbits following exposure to ECH.In the AC study maternal toxicity occurred in both rats andrabbits treated at 300 ppm. These consisted of depressed weightgain during gestation and increases in liver weight (both species)and kidney weights (rats only). Fetuses from rats exposed to300 ppm of AC had a slight delay in skeletal development butthere were no other signs of embryotoxicity. Thus, ECH and ACwere not teratogenic or embryolethal in rats or rabbits followinginhalation exposure to concentrations which induced effectsin the maternal animals.     

Teratogenic Potential of Inhaled Dichlorobenzenes in Rats and Rabbits

Teratogenic Potential of Inhaled Dichlorobenzenes in Rats andRabbits. HAYES, W. C., HANLEY, T. R., JR., GUSHOW, T. S., JOHNSON,K. A., AND JOHN, J. A. (1985). Fundam. Appl. Toxicol. 5, 190–202.Orthodichlorobenzene (ODCB) and paradichlorobenzene (PDCB) wereevaluated for teratogenic potential in rats (ODCB only) andrabbits. Groups of bred rats and inseminated rabbits were exposedto 0, 100, 200, or 400 ppm of ODCB; groups of inseminated rabbitswere exposed to 0, 100, 300, or 800 ppm of PDCB. Animals wereexposed for 6 hr/ day on Days 6 through 15 (rats) or 6 through18 (rabbits) of gestation. Maternal toxicity, as evidenced bya significant decrease in body weight gain, was observed inall groups of ODCB-exposed rats and liver weight was significantlyincreased in the 400-ppm ODCB-exposed group. Slight maternaltoxicity was observed in groups of rabbits exposed to 400 ppmODCB or 800 ppm PDCB as indicated by significantly decreasedbody weight gain during the first 3 days of exposure. Inhalationof up to 400 ppm of ODCB was not teratogenic or fetotoxic inrats, and neither ODCB nor PDCB was teratogenic or fetotoxicin rabbits at exposure levels up to 400 or 800 ppm, respectively.     

Prenatal Toxicity of 2-Methoxypropylacetate-1 in Rats and Rabbits

Prenatal Toxicity of 2-Methoxypropylacetate-l in Rats and Rabbits.MERKLE, J., KLIMISCH, H.-J., and JÄCKH, R. (1987). Fundam.Appl. Toxicol. 8, 71–79. 2-Methoxypropylacetate-1 wasinvestigated in Wistar rats and Himalayan rabbits for embryotoxicpotential. Rats after inhalation exposure to 0, 0.6, 3.0, or14.9 mg/liter (approximately 0, 110, 550, or 2700 ppm, respectively)for 6 hr per day from gestation Days 6 through 15 exhibitedsome degree of maternal toxicity at 2700 and 550 ppm. At 2700ppm an increase of skeletal anomalies of the thoracic vertebraeamong the fetuses was observed and interpreted as an exposure-relatedslight teratogenic effect. In Himalayan rabbits exposed viainhalation to 0,0.2,0.8, or 3.0 mg/liter (approximately 0, 36,145, or 550 ppm, respectively) for 6 hr per day from gestationDays 6 through 18 teratogenicity was much more pronounced: at550 ppm, in the absence of clear maternal toxicity, the fetusesof all litters showed severe malformations. No maternal or fetaleffects were observed at 145 and 36 ppm. Dermal applicationof 1000 and 2000 mg/kg to Himalayan rabbits from gestation Days6 through 18 failed to produce maternal or fetal toxicity.     

Ethylene Glycol Monomethyl Ether II. Reproductive and Dominant Lethal Studies in Rats

Ethylene Glycol Monomethyl Ether II. Reproductive and DominantLethal Studies in Rats. Rao, K.S., Cobel-Geard, S.R., Young,J.T., Hanley, T.R. Jr., Hayes, W.C., John, J.A. and Miller,R.R. (1983). Fundam. Appl Toxicol. 3:80-85. Groups of male andfemale Sprague-Dawley (CD) rats were exposed to 0, 30, 100,or 300 ppm ethylene glycol monomethyl ether (EGME) vapor 6 hours/day,5 days/week for 13 weeks. The 0 and 30 ppm groups each contained30 rats/sex and the 100 and 300 ppm groups each had 20 rats/sex.Following the exposure period, males were bred to unexposedfemales to evaluate reproductive capability and dominant lethality.Additional matings of control and 300 ppm exposed males wereperformed during the post-exposure period in order to evaluatethe recovery of fertility. Exposed females were bred with unexposedmales to assess reproductive parameters. Results of the presentstudy indicate a potential for inhaled EGME to completely suppressfertility in male rats at the 300 ppm level. Fertility of theserats was partially restored at 13 weeks post-exposure. Bodyweights of animals in the 300 ppm group were reduced as a resultof the exposures. No dominant lethal effect or impaired fertilitywas observed in male rats exposed to 30 or 100 ppm EGME. Treatment-relatedpathologic alterations were observed only in male rats at the300 ppm level and included decreased testicular size and atrophicseminiferous tubules. Female rats tolerated up to 300 ppm EGMEwithout any adverse reproductive effects. Based on these results,it was concluded that the no-adverse effect level of EGME forfertility and reproduction was 100 ppm in rats.     

DEVELOPMENTAL TOXICITY STUDY OF TETRAMETHYLUREA (TMU) IN RATS

The developmental toxicity of tetramethylurea (TMU) was assessed in rats by inhalation exposure of the test material over days 6–20 of gestation. Groups of 25 mated female Crl:CD®BR rats were exposed whole-body for 6 hours/day to concentrations of either 0, 2, 20 or 100 ppm TMU. The dams were euthanized on day 21 and the offspring were weighed, sexed, and examined for external, visceral, and skeletal alterations. Maternal toxicity was demonstrated at both 20 and 100 ppm. Maternal body weights, weight changes, and food consumption were statistically significantly reduced at these concentrations; effects were more pronounced at 100 ppm. There was evidence of developmental toxicity only at 100 ppm. The only finding was a decrease in mean fetal weight. No fetal malformations or variations occurred in fetuses derived from rats exposed to all 3 test concentrations (up to 100 ppm). The maternal no-observed-effect-level (NOEL) was 2 ppm, the fetal NOEL was 20 ppm. Thus, TMU was not considered to be uniquely toxic to the rat conceptus.     

Developmental toxicity study of tetramethylurea (TMU) in rats.

The developmental toxicity of tetramethylurea (TMU) was assessed in rats by inhalation exposure of the test material over days 6-20 of gestation. Groups of 25 mated female Crl:CD BR rats were exposed whole-body for 6 hours/day to concentrations of either 0, 2, 20 or 100 ppm TMU. The dams were euthanized on day 21 and the offspring were weighted, sexed, and examined for external, visceral, and skeletal alterations. Maternal toxicity was demonstrated at both 20 and 100 ppm. Maternal body weights, weight changes, and food consumption were statistically significantly reduced at these concentrations; effects were more pronounced at 100 ppm. There was evidence of developmental toxicity only at 100 ppm. The only finding was a decrease in mean fetal weight. No fetal malformations or variations occurred in fetuses derived from rats exposed to all 3 test concentrations (up to 100 ppm). The maternal no-observed-effect-level (NOEL) was 2 ppm, the fetal NOEL was 20 ppm. Thus, TMU was not considered to be uniquely toxic to the rat conceptus.     

Developmental Toxicity Evaluation of Inhaled 2-Ethoxyethanol Acetate in Ficher 344 Rats and New Zealand White Rabbits

Developmental Toxicity Evaluation of Inhaled 2–EthoxyethanolAcetate in Fischer 344 Rats and New Zealand White Rabbits. Tyl,R. W., Pritts, I. M, France, K. A., Fisher, L. C, and Tyler,T. R. (1988). Fundam. Appl. Toxicol. 10, 20–39. PregnantFischer 344 rats and New Zealand white rabbits were exposedto 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 Gesta–tionalDay 21 (rats) or 29 (rabbits) and fetuses were examined forexternal, visceral, and skeletal malformations and variations.In rabbits, exposure to 100–300 ppm resulted in maternaltoxic–ity: decreased weight gain at 100–300 ppm,clinical signs at 200–300 ppm, alterations in hema–tologyat 100–300 ppm, reduced gravid uterine weight at terminationat 200–300 ppm, and elevated absolute liver weight at300 ppm. Developmental toxicity was observed at 100–300ppm: an increased incidence of totally resorbed litters at 200–300ppm, an increase in nonviable fetuses at 300 ppm, and a decreasein viable implants (live fetuses) per litter at 200–300ppm. The incidence of fetal malformations (external, visceral,and skeletal) was increased at 200–300 ppm. The incidenceof total malformations was 100% at 300 ppm and significantlyincreased at 200 ppm. Reduced fetal ossification was observedat 100–300 ppm. In rats, exposure to 100–300 ppmalso resulted in maternal toxicity: reduced weight gain andreduced food consumption at 200–300 ppm and elevated relativeliver weight and alterations in hematology at 100–300ppm. Absolute maternal liver weight was increased at all EEAexposure concentrations; relative liver weight was increasedat 100–300 ppm. Developmental toxicity was observed at100–300 ppm: increased nonviable implantations/litter(300 ppm), reduced fetal body weight/litter (200–300 ppm),and increased incidence of external (300 ppm), visceral, andskeletal (100–300 ppm) variations indicative of toxicity.The incidence of visceral, skeletal, and total malformationswas increased at 200–300 ppm. In conclusion, in both species,inhalation exposure to EEA during organogenesis produced maternaltoxicity at 100–300 ppm and developmental toxicity at100–300 ppm, including teratogenicity at 200–300ppm. At 50 ppm in both species, there was no evidence of maternalor developmental toxicity, including teratogenicity.     

Reproductive toxicology of inhaled styrene oxide in rats and rabbits

Experiments were performed to evaluate reproductive and developmental toxicology in rats and rabbits exposed to styrene oxide by inhalation. Female rats were exposed to 100 or 300 ppm styrene oxide or to filtered air for 7 h/day, 5 days/week for 3 weeks. Extensive mortality occurred in rats that received prolonged exposure to 100 ppm styrene oxide while 300 ppm was rapidly lethal. As a result exposures were terminated in this latter group and the group was eliminated from further study. The rats of the 0 and 100 ppm groups were then mated and exposed to 0 or 100 ppm styrene oxide daily through 18 days of gestation (dg). Female rabbits were artificially inseminated and exposed for 7 h daily to 0, 15, or 50 ppm styrene oxide through 24 dg. Both of these lower concentrations used for exposure of the rabbits produced mortality of does. The rats were killed at 20 dg and the rabbits at 30 dg. Pregnant animals were examined for toxic changes including altered tissue weights and histopathologic effects. Litters were evaluated using several measures of embryotoxicity, and live fetuses were examined for external, visceral, and skeletal malformations. Exposure during gestation appeared to increase preimplantation loss in rats, and tended to increase the incidence of resorptions in rabbits. In both species, fetal weights and crown-rump lengths were reduced by gestational exposure. The incidences of ossification defects of the sternebrae aned occipital bones were increased by gestational exposure of rats to styrene oxide. These results indicate that inhalation exposures at these concentrations produce reproductive and development toxicity, as well as maternal toxicity.