Phenol, 2,4-bis[(dodecylthio)methyl]-6-methyl-

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

The read-across substance differs in the length of the alkyl chain at the thio ether. Specifically, it is a C8 chain in comparison to a C12 chain in the target substance. Due to the shorter chain length, the molecule is smaller and predicted to be of slightly better solubility in water. Therefore, it is considered to be of better systemic availability which might result in a slightly higher toxicity compared to the target substance. Detailed information including a datamatrix are attached to the Chemical Safety report.

As both C8 and C12 chains are metabolized via beta oxidation, both substances are predicted to have the same metabolites. Overall read-across is justified.

In an one-generation reproduction toxicity study (Ciba Specialty Chemicals Inc, 2000) study conducted according to the OECD Guideline 415, the effects of the test substance on reproductive function and fertility were evaluated in male and female rats (24 animals per sex per group) following oral administration by gavage at dosages of 15, 50 and 200 mg/kg/day. Male parental (F0) rats were treated for 10 weeks prior to pairing until the day before sacrifice. Female parental (F0) rats were treated for 2 weeks prior to pairing, during gestation and lactation periods and up to the day before sacrifice, on or shortly after day 21 post-partum. A concurrent group received the vehicle (peanut oil) at the same dose volume and served as control.

 

1) F0 generation

- Fate and mortality of F0 generation: there were no mortalities in the treated groups. Two control males died (one was found dead and another was humanely sacrificed) during the course of the study. A total of 3 males failed to induce pregnancy; one each in the control, mid and high-dose groups and consequently the females in the same groups were not pregnant. One mid-dose female had total litter loss on post-partum day 0 and one low-dose female gave birth prematurely on gestation day 18.

- Post-dose observations and clinical signs: no treatment-related effects were observed.

- Body weights and body weight gain, food consumption: no changes of toxicological significance in body weight or body weight gain in males. The occasional differences observed in dams are not considered to be of toxicological significance. Food consumption was unaffected by treatment.

- Reproductive parameters: oestrus cycle, mating performance, and pregnancy rate were unaffected by treatment.

- Implantation and pre-birth loss: no effects on implantation, pre-birth loss data or gestation length were seen in F0 treated females.

- Litter data, sex ratios and lactation index: total and live litter size, litter and mean pup weights and pup loss were similar between groups. Sex ratios and lactation index were not affected by treatment.

- Macroscopic examination: no signs of toxicological significance were observed at necropsy of the F0 generation.

- Sperm analysis: there were no differences in sperm motility or sperm concentration between the control, the high-dose group or the mid-dose male which failed to induce pregnancy

 

1) F1 generation

- Pre-weaning clinical signs: no signs were observed during the post-partum period which could be considered related to maternal treatment.

- Pre-weaning development: pre-weaning development did not show any differences between the control and the treated groups.

- Necropsy findings Fl pups: there were no toxicologically relevant findings in Fl pups which died during the lactation period or in Fl pups which were culled on Day 4 post-partum. No changes were seen at the necropsy of Fl pups sacrificed on or shortly after Day 21 post-partum. No findings of toxicological significance were seen at necropsy of Fl selected pups.

 

In conclusion, oral administration of the test substance to parental F0 animals, prior to pairing and throughout gestation and lactation periods at dosages of 15, 50 and 200 mg/kg/day showed no signs of toxicological significance. Reproductive function, as assessed by oestrus cycles, mating performance, pregnancy rate and parturition was not affected by treatment. These results suggest that a dosage of 200 mg/kg/day can be considered the NOAEL. Moreover, since no signs of toxicity were observed, the study was stopped at the first generation after weaning and selection of the Fl generation.

Short description of key information:
Read-across to the structural analogon 4,6-bis(octylthiomethyl)-o-cresol is used. In a one-generation reproduction toxicity study (Ciba Specialty Chemicals Inc, 2000) according to the OECD Guideline 415, dosages of 15, 50 and 200 mg/kg/day showed no signs of toxicological significance. Reproductive function, as assessed by oestrus cycles, mating performance, pregnancy rate and parturition was not affected by treatment. The dosage of 200 mg/kg/day is the NOEL.

Effects on developmental toxicity

Description of key information

Read-across to the structural analogon 4,6-bis(octylthiomethyl)-o-cresol is applied. In a GLP-compliant prenatal developmental toxicity study (BASF, 874066) according to the OECD Guideline 414, administration of the test substance during organogenesis by oral gavage at a dose level up to 300 mg/kg elicited slight maternal toxicity (slightly reduced body weight gain and - possibly - slightly reduced food consumption) at the high dose level, but no embryotoxicity, and no teratogenicity.

Additional information

In a study conducted according to the OECD Guideline 414 (Prenatal Developmental Toxicity Study), groups of 25 sexually mature and mated female rats received the test substance by oral gavage at dosages of 50, 150, or 300 mg/kg daily for ten consecutive days from day 6 to day 15 post-coitum (inclusive)

(BASF SE, no. 874066).

A further group of 25 rats of the same strain which received the vehicle (arachis oil) over the same period served as the control group. The animals were sacrificed on day 20 post-coitum and the results of the study can be summarized as follows:

1) There were no clinical observations and no necropsy findings which might be considered to be related to the treatment with the test substance.

2) At a dose level of 300 mg/kg, maternal body weight gain during gestation was slightly reduced. This is considered to be a slight maternally toxic effect of the compound, although the mean daily food consumption was also slightly lower in this group (300 mg/kg) than in the control group.

3) There was no effect of treatment on pregnancy incidence, implantations, or post-implantation loss

4) The mean number of foetuses per dam was slightly reduced in group 4 (300 mg/kg). This finding is considered to be related with the slightly reduced mean number of implantations per female and not to be a compound-related effect.

5) Sex distribution was not affected by the treatment, but mean foetal weight of group 4 (300 mg/kg) was slightly increased. This finding is considered to be related with the slightly reduced mean number of foetuses per female in this group and not to indicate any effect of treatment.

6) Nature and incidence of malformations and variations did not reveal any compound-related effect.

In conclusion, administration of the test substance during organogenesis by oral gavage at a dose level of 300 mg/kg elicited slight maternal toxicity (slightly reduced body weight gain and - possibly - slightly reduced food consumption), but no embryotoxicity, and no teratogenicity. Administration of 50 and 150 mg/kg did not elicit any maternal toxicity, embryotoxicity, or teratogenicity.

Justification for classification or non-classification

Neither embryotoxicity nor teratogenicity was observed in a prenatal developmental toxicity study conducted according to the OECD Guideline 414. Additionally, the reproductive function, as assessed by oestrus cycles, mating performance, pregnancy rate and parturition, as well as postnatal development (during lactation) were not affected by treatment in one-generation reproduction toxicity study (Ciba Specialty Chemicals Inc, 2000) study conducted according to the OECD Guideline 415. Therefore, there is no need to classify the test substance for reproduction toxicity according to the EU Dangerous Substance Directive 67/548/EEC and to the CLP Regulation (EU) 1272/2008 as amended for the second time in Directive EC 286/2011.