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.
Tyl
R W
RW
Bushy Run Research Center, Export, Pennsylvania, USA.
Ballantyne
B
B
Fisher
L C
LC
Fait
D L
DL
Dodd
D E
DE
Klonne
D R
DR
Pritts
I M
IM
Losco
P E
PE
D000014:Abnormalities, Drug-Induced; D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D019855:Ethylene Glycol; D005026:Ethylene Glycols / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D008297:Male; D051379:Mice; D019055:No-Observed-Adverse-Effect Level; D011247:Pregnancy
D000336:Aerosols; D005026:Ethylene Glycols; D019855:Ethylene Glycol