Evaluation of the potential developmental toxicity of cyclododecatriene (CDDT).

The potential maternal and developmental toxicity of cyclododecatriene (CDDT) was assessed in rats. Groups of 22 time-mated female Crl:CD (SD) BR rats were exposed by inhalation (whole-body, 6 h/day) to either 0 (control), 10, 25, or 67 ppm CDDT over days 6-20 of gestation (days 6-20 G); the day of copulation plug detection was designated day 0 G. The dams were euthanized on day 21 G, and their abdominal and thoracic viscera were examined grossly. The fetuses were weighed, sexed, and examined for external, visceral, and skeletal alterations. Evidence of maternal toxicity was seen at 25 and 67 ppm. There were compound-related reductions in maternal body weight and food consumption parameters as well as increased occurrences of wet and stained fur at these exposure levels. Developmental toxicity evident as reduced mean fetal weight and delayed skeletal ossification was seen only at 67 ppm. There was no evidence of either maternal or developmental toxicity at 10 ppm. Thus, the no-observed-effect level (NOEL) for maternal toxicity was 10 ppm, and the NOEL for developmental toxicity was 25 ppm. Because developmental toxicity was observed only after exposures that also produced signs of maternal toxicity, CDDT was not considered to be a selective developmental toxicant in the rat.

Reproductive and repeated dose toxicity of cyclododecatriene (CDDT) in rats following oral (gavage) treatment.

Cyclododecatriene (CDDT, CAS No. 4904-61-4) was administered daily by oral gavage to groups of Crl:CD (SD)IGS BR rats at dose levels of 0 (control), 30, 100, or 300 mg/kg/day. Female rats were dosed for four weeks premating, through mating, gestation, and lactation (a total of 55 to 63 days of treatment). Male rats were treated for 55 days (four weeks premating and through mating). Premating, body weights, food consumption, and clinical signs were recorded. Hematology, clinical chemistry, and urine analyses were conducted at the end of the premating period. A neurobehavioral test battery was conducted prior to and after four weeks of treatment. After the premating period, females were paired with males from the same groups for 1-2 weeks. Litters were delivered, pups were evaluated for structural integrity, and pup body weights were recorded on days 0 and 4 postpartum. Lactating females and their offspring were sacrificed on postpartum day 4. Selected organs were weighed and the tissues were examined microscopically from the lactating females. Offspring were examined for clinical abnormalities. A test substance-related reduction in body weight gain occurred in male rats administered 300 mg/kg/day. Decreased body weight gain in the 300 mg/kg/day males was accompanied by increased food consumption and decreased food efficiency. Females administered 100 or 300 mg/kg/day had test substance-related, significantly decreased body weight and body weight gain during gestation, that was accompanied by a significant increase in food consumption (300 mg/kg/day group only), and significantly decreased food efficiency. There were no test-substance related effects on clinical observations in males or females during the premating phase, or in females during gestation or lactation. Neurobehavioral parameters and motor activity were unaffected by CDDT-treatment. During this study, statistically significant treatment-related changes were observed in several clinical pathology parameters. The decreases in red cell mass (RBC, HGB, HCT) were minimal and, due to the magnitude, were not expected to result in biological effects. Similarly, minimally increased potassium and mildly decreased triglycerides were not of a magnitude to be biologically significant. Finally, changes in serum enzymes (AST, ALT, ALP), urea nitrogen, and serum protein occurred in directions that are not associated with toxicity. The changes in urine volume, urine concentration, and urea nitrogen may be the result of elevated glomerular filtration rate and altered tubular fluid flow, in the absence of any histopathological change. No effects on reproduction in parental males or females were produced by CDDT. Body weights of pups in the 300 mg/kg group were significantly decreased on postpartum days 0 and 4. There were no test-substance related effects on clinical observations, number of pups born, and the number of pups born alive, or the number of pups surviving through lactation day 4. The no-observed-adverse-effect level (NOAEL) for CDDT was 30 mg/kg/day based on decreased body weight and body weight gain, increased food consumption, and decreased food efficiency in females administered 100 or 300 mg/kg/day. The NOEL in pups was 100 mg/kg/day, based on decreased body weights of pups in the 300 mg/kg/day group during lactation.

Inhalation toxicity of cyclododecatriene in rats.

Cyclododecatriene (CDDT, CAS No. 4904-61-4) was tested for its inhalation toxicity in rats following repeated exposures. Male rats were exposed nose-only to CDDT for 6 hr/day, 5 days/wk for a total of 9 exposures over 2 weeks. Particular attention was paid to neurotoxicologic endpoints. Concentrations of 0 (control), 5, 50, and 260 ppm were studied. The 260 ppm chamber contained both vapor and aerosol while the 5 and 50 ppm chambers were vapor only. Four groups of 10 rats each were used to measure standard clinical signs and growth, clinical pathology (including hematology, biochemistries, and urine analysis), and tissue pathology. Another 4 groups of similar size were used for neurotoxicity testing. In the standard toxicity groups, 1/2 of the rats were sacrificed 1 day following the 9th exposure; the other half underwent a 2-week recovery period prior to being sacrificed (recovery group). During the exposures rats inhaling 260 ppm had a diminished or absent response to an alerting stimulus. Irregular respiration and lethargy were observed in these rats immediately following exposure. These signs were rapidly reversible and were not seen prior to the subsequent exposure. Body weights in rats exposed to either 50 or 260 ppm were significantly lower than the corresponding controls. No compound-related clinical pathology changes were seen in any of the test groups and tissue pathology effects only occurred in the nasal tissue. In rats exposed to 260 ppm, minimal degeneration/necrosis of nasal olfactory epithelium was observed in rats examined immediately following the exposure period. This change was not seen in the recovery rats. Functional observational battery (FOB) assessments and motor activity (MA) evaluations conducted after the 4th and 9th exposures on rats from all test groups, and specific neuropathologic evaluation on perfused brain, spinal cord, and skeletal muscle from rats exposed to 260 ppm failed to demonstrate any specific neurotoxicity. Outward signs of sedation were seen at the top level tested. Under the conditions of this test, the no-observed-adverse-effect level (NOAEL) was determined to be 5 ppm based upon a reduced rate of body weight gain in the 50 ppm group. No specific neurotoxicity was detected and the histopathologic response was limited to reversible changes in the nasal epithelia in rats exposed to 260 ppm.