The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings may not have been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. For more information, see the Explanation of Levels of Evidence for Developmental Toxicity. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.
Artificially-inseminated New Zealand White rabbits were administered ethylene glycol by gavage on gestational days 6 through 19 at doses of 0, 100, 500, 1000 or 2000 mg/kg/day , with 23-24 inseminated animals per group. Clinical signs were recorded daily during treatment and on gd 25 and 30 (animals were observed at least once daily throughout the study); maternal body weights were recorded on gd 0, 6-19, 25 and 30 and maternal water consumption was measured daily. At necropsy (gd 30), maternal body weight, liver weight, kidney weight and gravid uterine weight were recorded. Kidneys, from 10 animals/dose and all females who died, were examined histologically. Ovarian corpora lutea were counted; uterine implantation sites (total sites, resorptions, dead fetuses and live fetuses) were recorded. All live fetuses were weighed, sexed and examined for external, visceral, craniofacial and skeletal alterations.
EG administered by gavage to pregnant NZW rabbits during major organogenesis resulted in profound maternal toxicity (42% mortality; three early deliveries and one spontaneous abortion) at 2000 mg/kg/day associated with renal pathology and unaccompanied by any other indicators of maternal toxicity such as effects on periodic maternal body weights or weight change or on water consumption. At necropsy, there were no significant effects on gravid uterine weight, liver or kidney weights. The kidney lesion at 2000 mg/kg/day was limited to the cortical renal tubules and included intraluminal oxalate crystals, epithelial necrosis and tubular dilatation and renal tubular degeneration.
There was no dose-related maternal toxicity at 100-1000 mg/kg/day . There was no indication of developmental toxicity including no effects on pre- or postimplantation loss, the number of fetuses per litter, fetal body weight per litter or sex ratio (% male fetuses per litter), and no evidence of teratogenicity based on evaluation of external, visceral including craniofacial, skeletal or total malformations or variations at any dose tested. These dose levels include a dose which resulted in severe maternal toxicity (2000 mg/kg/day ) and doses which produced no observable maternal toxicity (100-1000 mg/kg/day ). The no observable adverse effect level for maternal toxicity was therefore 1000 mg/kg/day and the NOAEL for developmental toxicity was at least 2000 mg/kg/day under the conditions of this study. The sensitivity of NZW rabbits relative to CD rats and CD-I mice previously evaluated for maternal and developmental toxicity from gavage administration of EG during organogenesis can be determined for maternal toxicity: rabbits more sensitive than mice, mice more more sensitive than rats, and for developmental toxicity: mice more more sensitive than rats, and rats more more sensitive than rabbits.