Overview of the acute, subchronic, reproductive, developmental and genetictoxicology of beta-chloroprene

beta -Chloroprene (CD), the 2-chloro derivative of 1,3-butadiene, is used f or the manufacture of the synthetic rubber, polychloroprene. Acute inhalati on studies show that CD is lethal to Crl:CD(R) rats at >2300 p.p.m. (4 h), the primary target organ effects were pulmonary hemorrhage and edema, and h epatic necrosis. In 2- and 4-week inhalation studies in Fischer 344 (F344) and Wistar rats, early deaths occurred at 500 and greater than or equal to 161 p.p.m.. respectively. Organ system injury was found in the nose (degene ration/metaplasia of olfactory epithelium). liver (centrilobular necrosis), and blood (decreased red blood cell count in F344 rats only). In a 90-day inhalation study with F344 rats, degeneration/metaplasia of the olfactory e pithelium and reduced nonprotein sulfhydryl content of lungs and liver were found in animals exposed to 80 p.p.m., and anemia. hepatocellular necrosis , and forestomach inflammation were observed at 200 p.p.m. In a 90-day stud y with B6C3F1 mice, CD caused deaths at 200 p.p.m., the highest concentrati on tested, and epithelial hyperplasia of the forestomach at 80 p.p.m. Other than a slight (<10%) reduction in sperm motility in mate rats at 200 p.p.m ., all other reproductive parameters (sperm count or morphology in males, a nd estrous cyclicity or cycle length in females) were unaffected in these 9 0-day rat/mouse studies. There were no significant indications or neurologi cal toxicity. The study No-Observable Adverse Effect Level was 32 p.p.m. ba sed on nasal injury in rats. Despite some early reports of reproductive sys tem abnormalities at levels <1 p.p.m.. recent studies show no embryotoxic o r developmental toxicity in female Wistar or Crl:CD(R) rats, or in New Zeal and White rabbits at CD exposure concentrations up to 25 or 175 p.p.m., res pectively. In a one-generation reproduction study with Wistar rats, CD prod uced growth retardation in the F-0 generation exposed to 100 p.p.m.. and in the F-1 offspring at 33 and 100 p.p.m.; no effects on reproductive paramet ers or histopathology were found. CD is nonmutagenic in standard plate inco rporation bacterial reverse mutation assays (Ames assays) but positive usin g direct gas-phase incubation methods. Bacterial mutagenicity (primarily ba se pair substitution) was either negative or weakly positive when freshly p repared CD was tested. Mutagenicity increased markedly with time. presumabl y from CD dimer formation, and also by addition of liver S9 metabolic activ ation system. In vivo micronucleus. chromosome aberration and sister chroma tid exchange studies in mice showed no structural chromosomal damage. Overa ll, the pathological effects in the liver and nose dominate the subchronic toxicity of CD. The genotoxicity of CD is inconsistent and requires further study. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.