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Description of key information

 OECD 422 (rat, dermal): the No-Observable-Adverse-Effect Level (NOAEL) of the test article diallyl diglycol carbonate, for parental toxicity was 1030 mg/kg/day, the highest dose level evaluated. 

Key value for chemical safety assessment

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
1 030 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

The study "Diallyl Diglycol Carbonate: combined repeated dose rat dermal toxicity study with a reproduction/developmental toxicity screening test (OECD 422)" is taken for risk characterization of repeated dermal exposures of the test material. This study was comprised of two components, a repeated dose toxicity study with neurobehavioral evaluations and a reproduction/developmental toxicity screening study. The purpose of the repeated dose toxicity component was to provide information on possible target organ effects and the potential for neurobehavioral effects arising from repeated exposures. Each repeat dose group contained ten male and ten female Sprague-Dawley rats [Crl: CD® (SD)IGS BR]. The ten male animals of each repeat dose group were also utilized for the reproductive/developmental component of the study. Animals were administered dermally once daily via occlusion for 6 hours at dose levels 150, 454, and 1030 mg/kg/day for at least 42 consecutive days. The control animals received 0.9% Sodium Chloride, USP, at a volume of 0.9 mL/kg for the same duration as the treated animals. Observations of the animals included clinical signs, neurobehavioral observations (repeated dose component only), dermal evaluation, body weights, and food consumption. Evaluations for motor activity, emotionality, and other behavioral observations, including auditory response, grip strength, pupil reflex, and corneal reflex, were conducted for all repeated dose animals, pretest and prior to scheduled terminal euthanasia (after seven weeks of treatment). Blood collections for clinical pathology evaluations were conducted at study termination. Complete necropsies were performed on all animals (repeated dose and reproductive components) and organs and tissues were collected, weighed, and preserved. Organs and tissues from control and high-dose animals in the repeated dose component were examined microscopically. Nervous system tissues (cervical, thoracic, and lumbar spinal cord and sciatic nerve) from female animals from the mid and high dose groups (454 and 1030 mg/kg bw/day) as well as the controls were evaluated for neuropathology.

No effect of treatment was evident from mortality, clinical evaluations, neurobehavioral evaluations, dermal evaluations, body weights, food consumption, hematological evaluations, serum clinical chemistry, organ weights, macroscopic, or microscopic evaluations. Decreased hindlimb grip strength as well as axonal degenerations in spinal cord and sciatic nerve were noted at termination for female animals in the 454 and 1030 mg/kg/day dose groups. These findings appear to be spurious and not toxicologically significant.

Thus, in this rat dermal repeated dose toxicity study with a reproduction/developmental toxicity component, the No-Observable-Adverse-Effect Level (NOAEL) of the test article diallyl diglycol carbonate, for parental toxicity was 1030 mg/kg/day, the highest dose level evaluated.

In a previous supporting range-finding 14-day dermal study in rats (MPI, 2005), animals were administered dermally with diallyl diglycol carbonate at 150, 300 and 600 mg/kg/day. No mortality was observed during the study. No effect of treatment at all dose levels was evident from clinical examinations, dermal irritation evaluations, food consumption, macroscopic evaluations, or organ weights. A slight reduction in body weight and body weight gain for males in the highest dose group was observed. Therefore, No-Observed-Effect-Level (NOEL) for males was 300 mg/kg/day and for females was 600 mg/kg/day, the highest dose level evaluated.

In an older "Fourteen-Day Range Finding Study in Rats with Diallyl Diglycol Carbonate" (Will Research Laboratories, 1980a, dated 1980 -01 -21), no signs of toxicity were observed in any of tested animals in the lower dose groups (91.4 and 457.2 mg/kg bw). There were problems with the dosing of the high dose 2286 mg/kg bw. There was unabsorbed test material on the application area. In the next "Fourteen-Day Range Finding Study in Rats with Diallyl Diglycol Carbonate" (Will Research Laboratories, 1980b, dated 1980 -08 -0) the only one dose level of 2000 µL/kg bw was tested in order to confirm findings observed at this dose level in the previous range finding study. In this study, all animals had a collar placed on the neck to prevent oral ingestion for the entire study. The excess compound was removed from the hair coat by the daily wiping of the hair and excess compound was also wiped from the cage surfaces. The findings were the same as in a previous study.The main toxic effect observed was a significant decrease in body weight in male rats only. This was supported by some decreases in food consumption.

The outcomes of the supporting studies confirm the accuracy of the established NOAEL in the Combined Repeated Dose rat Dermal Toxicity Study with a Reproduction/Developmental Screening Test.

Justification for read-across from supporting substance RAV 7AT (diallyl 2,2'-oxydiethyl dicarbonate; CAS 142-22-3; EC 205-528-7): About 53 % of RAV 7MC (EC 700-742-1) consists of components that can be found in RAV 7NG (EC 700-483-4). About 60 % of RAV 7NG (EC 700-483-4) in turn consists of components that can be found in the commercial ADC grades known as RAV 7AT, Nouryset 200 and CR39. Merely from comparing the similar production processes of these substances it is apparent that RAV 7AT, RAV 7NG and RAV 7MC are closely related to each other. Finally, it can be assumed that the physical-chemical, toxicological and ecotoxicological properties of RAV 7MC and RAV 7AT will be very similar and as a result, read across is justified.

Justification for classification or non-classification

The classification is not warranted according to the criteria of EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulations No 1272/2008.