The Developmental Toxicity of 2-Ethyihexanol Applied Dermally to Pregnant Fischer 344 Rats

Undiluted 2-ethylhexanol (2-EH) was administered by occludeddermal application for 6 hr per day on Gestation Days 6 through15 to pregnant Fischer 344 rats, in range-finding (R) and main(M) studies. The dermal route is considered to be the most relevantfor 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, and2520 mg/kg/day) and (M) 0.0, 0.3, 1.0, and 3.0 ml/kg/day (equivalentto 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-positivecontrol 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 referencecompound in a similar regimen. An oral reference compound, valproicacid, was administered by gavage in the range-finding studyon Gestation Days 6 through 15 at 400 mg/kg/day. The range-findingstudy employed an untreated (naive) control group. Numbers ofplug-positive females per group were (R) 8 and (M) 25. Maternalweight gain was reduced for 2-EH at 1680 (R) and 2520 (R andM studies) mg/kg/day. Exfoliation and encrustation were seenat the application site in both studies at 840, 1680, and 2520mg/kg. Maternal liver, kidney, thymus, spleen, adrenal, anduterine weights, and gestational and fetal parameters were unaffectedby treatment with 2-EH. There were no treatment-related increasesin the incidence of individual or pooled external, visceral,and skeletal malformations or variations following the applicationof 2-EH. The NOAELs for the maternal toxicity of 2-EH were 252mg/kg/day based on skin irritation and 840 mg/kg/day based onsystemic toxicity. The developmental toxicity NOAEL was at least2520 mg/kg/day, with no teratogenicity. Administration of 2-MEat 840 mg/kg/day resulted in reduced maternal weight gain andfood consumption, increased postimplantation loss, reduced numbersof live fetuses per litter, and reduced fetal body weights perlitter. The incidence of fetal malformations and variationswas increased. Oral administration of VPA produced maternaltoxicity, developmental toxicity, and teratogenicity. The Fischer344 rat is thus susceptible to known rodent teratogens by boththe dermal and oral routes. It is concluded that 2-EH is notdevelopmentally toxic by the dermal route in the Fischer 344rat at and below treatment levels which produce maternal toxicity.