Methyl (R)-2-(4-hydroxyphenoxy)propionate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Toxicity to Reproduction (Oral route): Under the conditions of this study, the No Adverse Effect Level for paternal and maternal toxicity is higher than 1000 mg/kg/day. The No Effect Level for pre-natal and early post-natal development was lower than 15 mg/kg/day. The No Effect Level for teratogenic effects is higher than 1000 mg/kg/day.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

15 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The key study was a guideline study conducted under GLP conditions. It was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997) and the quality of the database is therefore considered to be good.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Toxicity to Reproduction (Oral route)

The potential for the test material to cause reproductive toxicity was investigated in accordance with 87/302/EEC, 18th November 1987 (or Annex V, 92/69/EEC) under GLP conditions.

The study evaluated the potential of toxic effects of the test material on gonadal function, mating behaviour, conception, developmental of the conceptus during gestation, parturition development and development of the pups during lactation.

Three groups of 12 male and 24 female Sprague-Dawley rats received the test material by oral gavage, once a day, at 15, 150 or 1000 mg/kg/day throughout the premating period (10 weeks), mating period and until final sacrifice in the males and throughout the premating period (2 weeks), mating period, pregnancy and lactation until final sacrifice (day 21 post-partum) in the females. A group of 12 males and 24 females was given the vehicle alone (aqueous methylcellulose at 1 %) and acted as a negative control group.

Mortality and clinical signs were checked daily. Body weight and food consumption were recorded at designated intervals. A mating trial was carried out in all animals: males and females were paired for 3-week maximum period, until mating was obtained. Oestrous cycle stage was recorded daily during this period. The females were allowed to deliver and to rear their progeny until weaning (day 21 postpartum). During the lactation period, the pups were examined daily for survival, external abnormalities and clinical signs. The body weight and sex were recorded.

At final sacrifice of the parent males and females, a macroscopic examination was carried out and the genital organs, accessory sex organs and pituitary gland were sampled. A microscopic examination was performed in the animals suspected to be infertile. At final sacrifice of the pups, both external and internal examinations were performed to search for gross abnormalities.

No deaths or clinical signs of toxicity were noted in the treated groups. There was only a moderate to high incidence of ptyalism at 150 mg/kg/day (males) and 1000 mg/kg/day (males and females); this sign was not considered to represent an adverse effect. The body weight gain and food consumption of the treated animals did not present differences from the control values which were considered to be of toxicological significance.

The mating, gestation and fertility indexes were similar in the control and the treated groups. The pre-coital interval and the duration of gestation were not notably different in the control and the treated groups. The oestrous cycle stages were similar in the control and treated groups.

The difference between the number of uterine implantation sites and the number of delivered pups showed, in all the treated groups, a slight to moderate increase of the post-implantation loss: 17.0, 16.2 and 20.4 % in the 15, 150 and 1000 mg/kg/day groups, respectively, vs. 5.0 % in the control group. This effect was considered to be related to treatment with the test material. Nevertheless, ovulation and implantation were not affected at any dose-level. No external abnormalities were observed in the pups at birth. The survival of the pups during the lactation period was similar in the control and 15 mg/kg/day group and was slightly lower in the 150 and l 000 mg/kg/day groups, principally during the first week after delivery. This effect was considered to be related to treatment with the test material. There were no clinical signs in the pups of any group during the lactation period. The body weight gain of the pups of the treated groups was slightly lower than that of the control pups during the first week of the lactation period. This finding was considered to be related to treatment with the test material. The sex ratio was similar in all the groups.

There were no macroscopic changes at examination of the parent males or females or the pups which were attributable to treatment with the test material. There were no treatment-related microscopic findings in the organs of the animals suspected of being infertile.

The test material was clinically well tolerated. Mating, fertility and gestation endpoints were not affected in any sex. Nevertheless, there was a slight to moderate increase of the post-implantation loss at all dose-levels, a slight reduction of the survival of the pups at 150 and 1000 mg/kg/day and a slight reduction of growth at 15, 150 and 1000 mg/kg/day. No evidence of teratogenic effects was observed at any dose-level.

Under the conditions of this study, the No Adverse Effect Level for paternal and maternal toxicity is higher than 1000 mg/kg/day. The No Effect Level for pre-natal and early post-natal development was lower than 15 mg/kg/day. The No Effect Level for teratogenic effects is higher than 1000 mg/kg/day.

As no explanation was provided for the post implantation loss and the effects are considered to be non-specific (not dose related), in the absence of further information classification is proposed as a precautionary measure.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance requires classification with respect to reproductive toxicity as Category 2 (H361: Suspected of damaging fertility or the unborn child).