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.

Assessment of the developmental toxicity of ethylene glycol applied cutaneously to CD-1 mice.

Ethylene glycol (EG; CAS No. 107-21-1) is teratogenic to mice by whole-body exposure to an aerosol at high concentrations, but results were confounded by possible exposure from ingestion after grooming and/or from percutaneous absorption. Therefore, CD-1 mice were exposed to EG on Gestational Days (GD) 6 through 15, 6 hr/day by occluded cutaneous application at 0, 12.5, 50, or 100% (undiluted) EG (0.1 ml/animal, equivalent to approximately 0, 404, 1677, or 3549 mg/kg/day [10 ml/kg, positive control gavage (PCGG)], 30 females/group. Dams were weighed and evaluated daily (including application site) for clinical signs and water consumption throughout gestation. On GD 18, maternal uterus, liver, and paired kidneys were weighed; kidneys of 0 and 100% and the PCGG were examined microscopically. Corpora lutea and implantation sites were recorded. Live fetuses were weighed, sexed, and examined for structural alterations. For cutaneously exposed dams, there was no treatment-related maternal, no differences in pre- or postimplantation loss in fetal body weights/litter, and no increased incidences of any fetal malformations. Two skeletal variations, increased at 100% may represent effects of restraint stress and/or findings due to chance. In the PCGG, 8 females (26.7%) died, water consumption was increased, fetal body weights/litter were reduced, and fetal malformations and variations were increased. PCGG kidneys exhibited tubular nephrosis and tubular cell degeneration, with no oxalate crystals, documenting renal toxicity at this oral dose in mice. Minimal-grade renal tubular lesions observed in 3 mice (of 30) at 100% EG may represent treatment-related or incidental findings. Therefore, exposure of pregnant CD-1 to 0, 12.5, 50 or 100% EG during organogenesis by occluded cutaneous application resulted in minimal or no observable maternal or developmental toxicity at 100% (approximately 3549 mg/kg/day), the NOEL.

Determination of a no-observed-effect level for developmental toxicity of ethylene glycol administered by gavage to CD rats and CD-1 mice.

Previous studies have indicated that ethylene glycol (EG) is a developmental toxicant in rats and mice primarily when ingested. This study was designed to establish no-observed-effect levels (NOELs) for developmental toxicity of EG administered by gavage in both rodent species. Dams were administered EG on Gestation Days 6-15; rats were given 0, 150, 500, 1000, or 2500 mg EG/kg/day; mice were dosed with 0, 50, 150, 500, or 1500 mg EG/kg/day. In rat dams given 2500 mg EG/kg/day, water consumption was increased during treatment and body weights were reduced throughout gestation; liver and kidney weights were increased at euthanization (Gestation Day 21). Relative liver weights were also increased at 1000 mg/kg/day. Effects observed in rat fetuses at 2500 mg/kg/day included the following: hydrocephaly; gastroschisis; umbilical hernia; fused, duplicated, or missing arches, centra, and ribs; poor ossification in thoracic and lumbar regions; and reduced body weights. Reduced body weights, duplicated or missing ribs, centra, and arches, and poor ossification were also observed in rat fetuses at 1000 mg/kg/day. In mice, there was no apparent treatment-related maternal toxicity. In mouse fetuses (Gestation Day 18), effects were observed at 1500 mg/kg/day and included reduced body weights, fused ribs and arches, poor ossification in thoracic and lumbar centra, and increased occurrence of an extra 14th rib. At 500 mg/kg/day, slight reductions in fetal body weight and increased incidences of extra ribs were observed. Under conditions of these studies, NOELs for developmental toxicity were 500 mg/kg/day for rats and 150 mg/kg/day for mice, indicating that mice were more susceptible than rats to the teratogenic effects of EG.

Assessment of the developmental toxicity of 2-ethylhexanoic acid in rats and rabbits.

This study was carried out to assess the developmental toxicity of orally administered 2-ethylhexanoic acid (2-EHA) throughout organogenesis in the rat and the rabbit. Treatment of Fischer 344 inbred rats with doses of 100 to 1000 mg 2-EHA/kg/day on (Gestation Days) (GD) 6-15 in a range-finding and a definitive study resulted in a high level of maternal death at 1000 mg/kg/day. Clinical signs of maternal toxicity, including increased liver weight, as well as increased resorptions, dead fetuses, and growth retardation, but no malformations, were observed at 500 mg/kg/day. Slight developmental toxicity, manifested as a reduction in skeletal ossification, occurred in fetuses exposed to 250 mg/kg/day. No adverse effects of treatment were associated with the lower 2-EHA doses (100 and 125 mg/kg/day). Maternal toxicity was also observed in range-finding and definitive studies in New Zealand white rabbits exposed to 25 to 1000 mg 2-EHA/kg/day on GD 6-18 with excessive mortality observed at the highest doses (500 and 1000 mg/kg/day). A low incidence of maternal death as well as abortion occurred following treatment with 125 and 250 mg 2-EHA/kg/day. Less severe clinical signs (reduced weight and food consumption and hypoactivity) were also observed in the 250 mg/kg/day group. There were no adverse effects on fetal viability, growth, or morphology at any dose level. Thus, exposure to 2-EHA during the entire period of organogenesis caused developmental toxicity only at maternally toxic doses in the rat or adverse maternal effects in the absence of developmental toxicity in the rabbit. No evidence of teratogenicity was associated with 2-EHA in this classical safety assessment regimen in either species. The no observed adverse effect levels (NOAELs) for maternal and developmental toxicities in rats are 250 and 100 mg/kg/day, respectively; the corresponding NOAELs for rabbits are 25 mg/kg/day (maternal) and > or = 250 mg/kg/day (developmental).

The developmental toxicity of 2-ethylhexanol applied dermally to pregnant Fischer 344 rats.

Undiluted 2-ethylhexanol (2-EH) was administered by occluded dermal application for 6 hr per day on Gestation Days 6 through 15 to pregnant Fischer 344 rats, in range-finding (R) and main (M) studies. The dermal route is considered to be the most relevant for human exposure. Treatment levels were (R) 0.0, 0.5, 1.0, 2.0, and 3.0 ml/kg/day (equivalent to 0, 420, 840, 1680, and 2520 mg/kg/day) and (M) 0.0, 0.3, 1.0, and 3.0 ml/kg/day (equivalent to 0, 252, 840, and 2520 mg/kg/day). Controls (0.0 ml/kg/day, sham controls) received deionized water at 3.0 ml/kg/day. Dermal-positive control groups received undiluted 2-methoxyethanol (2-ME) at (R) 0.5 and 1.5 ml/kg/day and (M) 1.0 ml/kg/day as a reference compound in a similar regimen. An oral reference compound, valproic acid, was administered by gavage in the range-finding study on Gestation Days 6 through 15 at 400 mg/kg/day. The range-finding study employed an untreated (naive) control group. Numbers of plug-positive females per group were (R) 8 and (M) 25. Maternal weight gain was reduced for 2-EH at 1680 (R) and 2520 (R and M studies) mg/kg/day. Exfoliation and encrustation were seen at the application site in both studies at 840, 1680, and 2520 mg/kg. Maternal liver, kidney, thymus, spleen, adrenal, and uterine weights, and gestational and fetal parameters were unaffected by treatment with 2-EH. There were no treatment-related increases in the incidence of individual or pooled external, visceral, and skeletal malformations or variations following the application of 2-EH. The NOAELs for the maternal toxicity of 2-EH were 252 mg/kg/day based on skin irritation and 840 mg/kg/day based on systemic toxicity. The developmental toxicity NOAEL was at least 2520 mg/kg/day, with no teratogenicity. Administration of 2-ME at 840 mg/kg/day resulted in reduced maternal weight gain and food consumption, increased postimplantation loss, reduced numbers of live fetuses per litter, and reduced fetal body weights per litter. The incidence of fetal malformations and variations was increased. Oral administration of VPA produced maternal toxicity, developmental toxicity, and teratogenicity. The Fischer 344 rat is thus susceptible to known rodent teratogens by both the dermal and oral routes. It is concluded that 2-EH is not developmentally toxic by the dermal route in the Fischer 344 rat at and below treatment levels which produce maternal toxicity.