Cyclododeca-1,5,9-triene

Endpoint summary

Description of key information

By oral route, a reliable OECD 422 study is available in rats with 1,5,9-cyclododecatriene. No target organ was identified but a decreased of bodyweight gain was observed in males and females. Therefore the NOAEL for systemic effect was 30 mg/kg bw/d.
By inhalation route, two subacute studies (10 and 14-day administration) are available. No target organ was identified but based on the decreased of bobyweight gain, the NOAEC was 33.4 mg/m3 for male rats after 14 -day inhalation exposure.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

30 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEC

33.4 mg/m³

Study duration:

subacute

Species:

rat

Additional information

Repeated dose toxicity: oral

In the OECD 422 study, male and female rats were administered an oral daily dose of 0, 30, 100, or 300 mg/kg/day 1,5,9-cyclododecatriene by gavage. Females were dosed during a premating period of approximately 4 weeks, a mating period of approximately 1 to 2 weeks, a gestation period of approximately 3 weeks, and a lactation period of approximately 4 days. Females that were not gestating were

dosed through the day prior to sacrifice. Males were dosed through test day 55.

A test-substance related, biologically significant decrease in body weight gains 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

only) and significantly decreased food efficiency in 100 and 300 mg/kg/day females.

There were no test substance-related effects on clinical observations in males and females during the premating phase or in females during gestation or lactation. There were no test substance-related effects on reproductive parameters. There were no test substance-related changes in neurobehavioral parameters or motor activity. There were no toxicologically significant changes in

hematology, coagulation, clinical chemistry, or urinalysis parameters in males or females. There were no test substance-related, biologically adverse changes in organ weights or tissue morphology in males or females.

Based on the decreased of bobyweight gain, the NOAEL was 30 mg/kg bw/d for female rat, and 100 mg/kg bw/d for male rats, after oral administration of 1,5,9-cyclododecatriene.

Repeated toxicity: Inhalation

In the first study, a total of 8 groups of male rats (2 groups per exposure concentration; approximately 7 weeks old on the day of arrival) were exposed nose-only to vapor or a vapor/aerosol mixture of 1,5,9-cyclododecatriene.

Four groups of 10 rats per concentration were used for standard toxicological evaluations, and 4 groups of 10 rats per concentration were used for neurotoxicity testing. Individual body weights and clinical signs were recorded. During the exposure, group clinical signs were recorded. In additio n, rats were checked for a startle response to an auditory stimulus during exposure. The neurotoxicity groups were given functional observational battery (FOB) assessments and motor activity (MA) evaluations immediately after the 4th and 9th exposures. Hematologic parameters and clinical chemistry parameters were measured or calculated.

Five rats in each group designated for standard toxicology evaluations were sacrificed and necropsied on test day 12 (day following the last exposure) and test day 26. The liver, kidneys, lungs, testes, and brain were weighed. Each rat was given a complete gross examination, and representative samp were saved for histopathologic examination.

There were no mortalities during the study. Body weights for rats exposed to 5 ppm 1,5,9-cyclododecatriene were similar to those of the control during the entire experiment. Rats exposed to 50 or 260 ppm 1,5,9-cyclododecatriene had significantly lower mean body weights and mean body weight gains when compared to controls. The effects on body weight were reversible. Diminished or absent startle response to an auditory stimulus was observed in rats exposed to 260 ppm 1,5,9-cyclododecatriene when compared to controls. The response was first observed generally 2 hours into the exposure. Neither onset nor intensity changed over the 9 exposure days, and the rats were responsive prior to the next day of exposure. These effects were not observed in the other exposure groups. Test substance-related clinical signs of toxicity observed immediately after exposure included irregular respiration (260 ppm) and lethargy (260 ppm). Clinical signs of toxicity noted during and after exposure were reversible and were not present in rats prior to the next exposure.

Body weights measured as part of the functional observational battery assessment were significantly lower for rats in the 260 ppm group when compared to controls. No additional toxicologically relevant findings were observed during the functional observational battery assessments or motor activity evaluation. There were no test substance-related effects in rats noted during clinical pathology evaluations, and no abnormalities were seen during gross pathology and gross neuropathology examinations. There were no compound-related organ weight effects. Histologic effects attributable to the test substance were found in the nasal tissue of rats in the 260 ppm group. There was a minimal degeneration/necrosis of nasal olfactory epithelium observed immediately after the exposure period. These effects were reversed after the 2-week recovery period. No other test-substance related effects were observed microscopically. There were no test substance-related effects in rats noted during the microscopic neuropathologic evaluation. Based on the decreased of bobyweight gain, the NOAEC was 33.4 mg/m3 for male rats after 14 -day inhalation exposure.

In the second study, rats were exposed to aerosol concentrations of 1,5,9-cyclododecatriene. The exposures were conducted under dynamic conditions in a 500 L stainless steel exposure chamber. An aerosol of 1,5,9-cyclododecatriene was generated by delivering a known volume of the liquid at a constant rate, employing a precision liquid metering pump, into a pressurized atomizing spray nozzle. The resulting aerosol mist was then directed into the main airstream entering the exposure chamber. The mean nominal concentration of aerosol in the chamber was calculated from the rate of liquid delivery and the rate of airflow through the chamber.

No deaths occurred throughout the study. In general, no major toxic signs were observed for the rats during exposure. For the most part, a lack of activity was recorded throughout each 6- hour exposure period. Peripheral vasodilatation was apparent throughout the entire study. A slight twitching was noted at the beginning of the exposure period on the 3rd day. The twitching was noted at the beginning of each exposure period for the remaining 7 days, but was noticeably absent as each exposure period progressed.

Mean and individual body weight gains appeared normal. No gross tissue alteration of any of the major organs was

noted at terminal necropsy. Inhalation of 1,5,9-cyclododecatriene did not produce any distinctive histologic alteration in the brain, lung, liver, or bone marrow of male albino rats. The only possible significant alteration was increased intracytoplasmic granularity of the renal

proximal tubule epithelium. Partly because of the nonspecific and somewhat variable appearance of the tubule alteration, the difference was a rather inconsistent degree of the granularity, which was difficult to attribute to the test substance.

Based on the results of this study, no NOAEL was identified because clincal signs and an alteratino of the lidneyx were observed on rats treated with 1.64 mg/L of 1,5,9-cyclododecatriene.

Justification for classification or non-classification

Proposed self-classification

- Regulation (EC) No 1272/2008

Not classified

- Directive 67/548/EEC

Not classified