Developmental Toxicity Evaluation of Triethylenetetramine by Occluded Cutaneous Application in New Zealand White Rabbits

Abstract

Naturally bred New Zealand White rabbits, 22 does/group, were treated with triethylenetetramine (TETA; CAS No. 112-24-3) in water by occluded cutaneous application on gestational days (gd) 6-18,6 h/day, at a volume of 2.0 ml/animal (approximately 0.5 ml/kg) at dosages of 0.0, 5.0, 50.0, or 125.0 mg/kg/day. Clinical observations were made daily and does were weighed on gd 0, 6, 12, 15, 18, and 29. Daily observations of the dosing site were recorded from initiation of treatment through study termination. At necropsy on gd 29, maternal body, uterus, liver, lung, and kidneys (two) were weighed; corpora lutea and implantation sites (resorptions, dead fetuses, live fetuses) were evaluated. Maternal blood and urine were analyzed for copper content. Live fetuses were weighed, sexed, and examined for structural alterations.

Two does (9.1%) died at the dosage of 125 mg/kg/day. Does treated at 125 mg/kg/day also exhibited significantly decreased weight gain during dosing. Severe skin irritation was observed at the 50 and 125 mg/kg/day dosage levels with some recovery postdosing. Slight transient skin irritation was observed at 5 mg/kg/ day, with essentially total recovery postdosing. There were no effects on maternal organ weights, gravid uterine weight, or on maternal serum or urinary copper concentrations. There was no effect of treatment on pre- or postimplantation loss, percentage of live fetuses, or on fetal body weights/litter. There were no significant treatment- or dose-related increases in the incidence of individual or pooled fetal external, visceral, skeletal or total malformations, or variations. Therefore, TETA by occluded cutaneous application in rabbits during organogenesis produced maternal toxicity other than at the dosing site only when administered at 125 mg/kg/day, with no developmental toxicity observed at any dosage level.