Rabbits reproductive/developmental toxicity testing

Munro et al. (1996) explored the relationship between chemical structure and toxicities through the compilation of a large reference database consisting of 613 chemical substances tested for a variety of noncarcinogenic toxicological endpoints in rodents and rabbits in oral toxicity tests, including subchronic, chronic, reproductive, and developmental toxicity. For many of the substances, more... 

Historical control data can also be obtained from other laboratories such as CROs, some of which have a long history of reproductive and developmental toxicity testing and have large multispecies historical control databases that can span decades, and are therefore very useful for observing long term trends. This type of data can be especially informative when looking for occurrences of rare malformations in controls. Charles River Laboratories (www.criver.com) is one CRO that has made its historical data for reproductive and developmental toxicity publicly available. Historical control data for the CD rat and the New Zealand White rabbit is also available in the literature (8, 9, 13-15). Other laboratories may provide data upon request. 

By the time Phase III testing is completed, some additional preclinical safety tests must also generally be in hand. These include the three separate reproductive and developmental toxicity studies (Segments I and III in the rat, and Segment II in the rat and rabbit) and carcinogenicity studies in both rats and mice (unless the period of therapeutic usage is intended to be very short). Some assessment of genetic toxicity will also be expected. 

As part of the assessment of reproductive toxicity testing there is a regulatory requirement that fetuses from treated dams are examined for developmental and structural abnormalities by soft tissue examination. Current guidelines (1, 2) stipulate that this is performed in two laboratory species, one rodent (rat or mouse) and one non-rodent (routinely rabbit), in order to assess the safety of a test compound before, or in case, humans are exposed. 

Repeated inhalation or oral exposures to moderate to high doses of -butyl acetate and -butanol are well tolerated. These aforementioned molecules are readily and rapidly metabolized to -butyric acid. The no-observed-effect level (NOEL) for repeated dose oral exposure to -butanol was 125 mg kg day. In a 90 day inhalation study in rats with -butyl acetate a NOEL of 500 ppm was reported for systemic effects, and a NOEL of 3000 ppm (highest dose tested) was reported for postexposure neurotoxicity based on functional observational battery endpoints, quantitative motor activity, neuropathy, and sched-uled-controlled operant behavior endpoints. Results of inhalation studies conducted on -butanol and -butyl acetate were negative for inducing reproductive and developmental toxicity. The NOEL for female reproductive toxicity was 6000 ppm with -butanol and 1500 ppm for -butyl acetate. In a 90 day repeated-dose inhalation toxicity study with butyl acetate the NOEL for male reproductive toxicity was 3000 ppm. For developmental toxicity, a NOEL of 3500 ppm was observed with -butanol and a NOEL of 1500 ppm (the highest exposure tested) was seen in both rats and rabbits following exposure to -butyl acetate. 

---