Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via dermal route
Dose descriptor:
NOAEL
1 030 mg/kg bw/day
Additional information

The Combined Repeat Dose Toxicity Study with a Reproductive/Developmental screening Test comprises of two components, a repeat dose toxicity study with neurobehavioral evaluations and a reproduction/developmental toxicity screening (refer also to section 7.5.2 Repeated dose toxicity: dermal of IUCLID file).

The purpose of the reproduction/developmental toxicity screening component was to provide information on possible effects on male and female reproductive performance, such as gonadal function, mating behavior, conception, development of the conceptus, and parturition. Both the repeat dose and the reproductive/developmental component were comprised of three treatment groups and a saline-treated control group. Each reproductive group contained 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, while females in the reproductive component were treated for two weeks before pairing, during pairing, and from Gestation Days (GD) 0 to 20. 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. After two weeks of treatment, the animals were cohabited nightly with males from the repeat dose component, one male to one female, from the same treatment group, for up to 14 days. Females were evaluated daily for evidence of mating (sperm in the vaginal rinse or vaginal plug). Once mating was confirmed (GD 0), females were separated from the male for the remainder of gestation, and allowed to deliver and nurse litters until Postnatal Day (PND) 4. Litter size and pup evaluations (body weight, sexing, and external examination) were recorded at birth and PND 4. Pups were euthanized and externally examined on PND 4 and the carcasses were discarded without further examination. Complete necropsies were performed on all parent animals (repeat dose and reproductive components) and organs and tissues were collected, weighed, and preserved.

No effect of treatment was evident from mortality, clinical evaluations, dermal evaluations, body weights, food consumption, organ weights, macroscopic or microscopic evaluations, reproductive performance, gestation and lactation body weights or food consumption, gestation length, litter size, pup body weight, pup sex ratios, or pup external examinations to PND 4. Thus, in this rat dermal repeat 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 was1030 mg/kg/day, the highest dose level evaluated. The No-Observable-Effect Level (NOEL) of reproductive performance was1030 mg/kg/day, the highest dose level evaluated.

A teratology study ( Bio-Research Laboratories Ltd, 1985) provides also sufficient information on effects of diallyl diglycol carbonate on reproductive performance and fertility. In this study, New Zealand white rabbits were exposed dermally to extremly high doses (114, 572 and 1143 mg/kg bw /day) that resulted in severe skin lesions (described as blackened thickened skin) in the dams of all exposure groups. Marked body weight losses and abortion were observed for the mid and high dose groups and 7/18 dams in the high dose goup died. An increased incidence of resorptions and ocular lesions and a decrease in incidence of single thirteenth ribs was noted for the mid dose group. However, due to the excessive maternal toxicity noted at these dose levels, the reproductive and developmental effects noted in this study are not considered to be relevant.


Short description of key information:
1. MPI Research Inc., 2005. "Combined Repeat Dose Rat Dermal Toxicity Study with a Reproductive/Developmental Toxicity Screening Test (OECD 422)", GLP study.
2. Bio-Research Laboratories Ltd, 1985. "Teratology Study of CR-39R Monomer by Dermal Application in the Rabbit", comparable to the OECD guideline 414.

Effects on developmental toxicity

Description of key information
Bio-Research Laboratories Ltd, 1985. "Teratology Study of CR-39R Monomer by Dermal Application in the Rabbit", comparable to the OECD guideline 414.
Effect on developmental toxicity: via dermal route
Dose descriptor:
NOAEL
114 mg/kg bw/day
Additional information

CR-39®monomer, a (Methylene glycol carbonate ester), was administered by dermal application to groups of gravid rabbits throughout major organogenesis to assess its teratogenic potential (Bio-Research Laboratories, 1985).

Groups of 18 inseminated rabbits were treated, by dermal application, with CR-39®monomer at dosages of 0.1, 0.5 or 1.0 mL/kg/day (114, 572 and 1143 mg/kg bw/day), for 6 hours per day, from day 6 to day 18 of gestation, inclusive. A control group was treated in an identical manner except that it was dosed with sterile isotonic saline at a volume of 1.0 mL/kg/day. Six rabbits died and 1 was killed in a moribund condition in the 1.0 mL/kg/day treated group. No other animals died or were sacrificed in a moribund condition. There were skin lesions at the dosage sites for some rabbits in all CR-39®monomer-treated groups which were typified by dark red/black thickened areas which subsequently turned yellow and showed scab formation. The area affected was related to dosage. The incidence of rabbits not eating and/or having decreased fecal volume (quantitatively assessed) was increased in the 0.5 and 1.0 mL/kg/day group. The 1.0 mL/kg/day group had significant weight losses during all intervals in the treatment period (day 6 to day 18 of gestation) and between days 18 and 24 of gestation. In consequence the body weights were significantly less than those of the control group on days 12, 15, 18 and 24 of gestation. There was a marked weight loss between days 6 and 18 of gestation in the 0.5 mL/kg/day group. The growth of the 0.1 mL/kg/day group was similar to that of the controls. Pale foci, firmness and/or an irregular surface were common findings for the liver of animals in the 1.0 mL/kg/day group. Other findings seen at necropsy for this group (1.0 mL/kg/day) included pale foci or pale area(s) on the heart, kidneys and/or mesentery of some rabbits. In the 0.5 mL/kg/day group 1 rabbit had firmness and an irregular surface to the liver and a second rabbit had pale foci on the mesentery. One, 0, 3 and 6 does in the control, 0.1, 0.5 and 1.0 mL/kg/day treated groups, respectively, aborted. The pregnancy rate in all groups was at least 88.9%. The ovarian and uterine parameters (number of corpora lutea, implantation sites, live fetuses, dead fetuses, resorptions, fetal weights and pre- and post- implantation losses) of the 0.1 and 0.5 mL/kg/day treated does were unaffected. For the 1.0 mL/kg/day group there was a high level of resorptions observed for animal s dying, aborting, Uttering early or sacrificed preterminally, but the uterine parameters of the 3 females in this group alive on day 29 of gestation were similar to control values.

In the 0.5 and 1.0 mL/kg/day groups significant (P <0.01 and P <0.001, respectively) numbers of fetuses had small lens(es), In the 0.5 mL/kg/day group 6 -fetuses from 3 litters were affected and in the 1.0 mL/kg/day group 5 fetuses from 1 litter were affected. All the affected fetuses in the 1.0 mL/kg/day group and some in the 0.5 mL/kg/day group also had ocular opacities. Also among these fetuses there were other ocular findings. The overall incidence of minor visceral anomalies was not significantly different from control values. The incidences of major malformations and minor skeletal anomalies among term fetuses were not significantly different from control values. Findings of eventration of the liver and intestines among abortuses from 3 litters in the 1.0 mL/kg/day group were possibly related to trauma in the abortion process. The incidence of major malformations in the treated groups, among 1itters from females examined at cesarean section, was not significantly different from control values. In the 0.5 mL/kg/day group there was a significant (P <0.05) decrease in the incidence of single thirteenth ribs and an accompanying increase in the incidence of paired thirteenth ribs and a significant increase in the incidence of 27 presacral vertebrae. The incidence of sternebral variants in the treated groups was not significantly different from control values.

CR-39®monomer was found to produce maternal toxicity in terms of skin lesions at the treatment site at levels of 0.1, 0.5 and 1.0 mL/kg/day. Systemic toxicity occurred at the 0.5 and 1.0 mL/kg/day group, with the majority of rabbits in the 1.0 mL/kg/day group either dying or aborting. Maternal toxicity at the 0.5 and 1.0 mL/kg bw evidenced by body weight loss. Embryotoxicity was evidenced by significantly increased ocular anomalies in the 0.5 and 1.0 mL/kg/day groups. These findings when accompanying significant adverse effects upon maternal weight loss, are not considered to be of teratological significance. There was some indication of embyrolethality among those rabbits in the 1.0 mL/kg/day group which died or aborted. Neither embryolethality nor embroyotoxicity occurred at the 0.1 mL/kg/day dose level.

Justification for classification or non-classification

Due to the fact that neither adverse effects on gonads nor changes in reproductive performance and fertilty were found in the Combined Repeat Dose Toxicity Study with a Reproductive /Developmental Screening Test (MPI Research, 2005) and signs of embryolethality and embryotoxicity as well as adverse effects on fertility in the teratology study (Bio-Research Laboratories, 1985) are the consequences of severe systemic toxicity, 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.

Additional information