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Inhalation juvenile rat studies can be performed as early as at day 4 post partum

: Lewin, G.; Fuhst, R.; Berger-Preiß, E.; Pohlmann, G.; Buschmann, J.

The Toxicologist 102 (2008), Nr.1, S.366
ISSN: 0731-9193
Fraunhofer ITEM ()
nose-only inhalation; Verapamil hydrochloride; reproductive toxicology; inhalation toxicology; rat - research

In order to test the feasibility of nose-only inhalation exposure in neonatal rodents, an inhalation study with Verapamil hydrochloride (CAS No. 152-11-4) as a model compound was conducted in neonatal rats aged day 4-21 post partum (pp). End points for the evaluation were adverse clinical signs, the body weight gain during development, substance serum concentrations for kinetic analysis and possible cross-contamination between dams and littermates. Standardized litters were assigned to the following groups: cage control, vehicle control, Verapamil treatment, Verapamil kinetic analysis and Verapamil cross-contamination analysis. For the cross-contamination kinetic approach, 3 litters were divided between vehicle control and substance exposure during treatment but raised together. Treatment was carried out for 2 hours daily from day 4 until day 21 pp. The exposure concentration was set at 50 mg/m3 Verapamil with a substance mass median aerodynamic diameter of 0.5 ?m. The results gave no indication of adverse clinical signs in neonates due to maternal deprivation for 2 hours. No increased mortality was observed. The cumulative body weight gain in the treatment groups vs. cage control was comparable. An efficient serum recovery of Verapamil as early as day 4 pp was achieved with consistent serum levels of 214, 274 and 276 ng/ml at day 4, 10 and 21 pp respectively. Cross contamination analysis gave no evidence of a carry-over via lactation and maternal behaviour or between littermates. Neonatal rats aged 4-21 days depict human pulmonal development stages between preterm newborns and children of about 6-8 years of age. The practicability of inhalation treatment in juvenile rats as young as day 4 pp permits new insights into human neonatal risk assessment and therefore this animal model is suitable for regulatory studies.