coconut oil, reaction products with glycerol esters of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Dose descriptor:

NOAEL

14 mg/kg bw/day

Additional information

In a one-generation reproduction toxicity study (Notox 487736, 2008) the test substance (dissolved in polyethylene glycol) was daily administered by gavage to 24 female/12 male Wistar rats per group at dose levels of 14, 56, and 222 mg/kg bw. The male animals were taken from the repeated dose toxicity study (see Notox 487736).

Parental toxicity

No treatment-related clinical signs were observed during this study. Body weights, body weight gain and food consumption were reduced for females treated at 56 and 222 mg/kg bw

Treatment resulted in a dose-dependent absolute and relative reduced food consumption of dams in all treated groups during the first week of the study. For later time-points, only dams of the high dose group were affected, specifically until post-coitum day 14 and then again during lactation.

The reduced food consumption reflected on statistically lower body weights and body weight gain of dams, beginning prior to implantation, on post-coitum day 4 for the mid and high dose groups.

Increased absolute and relative liver and thyroids weights were noted for females treated at 222 mg/kg bw. At histopathology, treatment related changes were present in the liver (periacinar hepatocytic hypertrophy) and thyroid (follicular epithelial hypertrophy) in the 56 and 222 mg/kg bw dose groups. The male animals also exhibited liver effects at 56 and 222 mg/kg bw. At histopathology, treatment related changes in the liver became obvious. They consisted of accentuated lobular pattern, enlarged livers and red-brown discoloration. Follicular epithelial hypertrophy in the thyroid was noted in males treated at 56 and 222 mg/kg bw. Additionally, thyroid follicular adenoma was noted for one male of the 222 mg/kg bw dose group.

The rat-specific mode of action for the thyroid induction is discussed in detail in the endpoint summary for repeated-dose toxicity.

Concerning reproductive organs, no treatment-related effects were observed in the female animals. For the males decreased sperm motility and progressive motility was noted at all dose levels. The concurrent control consisted of three studies and is therefore of limited value. The values of the treated groups were at the lower end of the historical control range. In this study, fertility indeces for all groups were unusually low, the value of 70% for the control group being lower than the historical control range of 79.2 - 100%. No histopathology findings and no effect on the number of corpus lutea were observed and so overall, no significant adverse effects on sperm motility and progressive motility occurred.

The number of testicular and epididymidal sperm cells and the percentage of normal sperm cells was similar for the 222 mg/kg bw dose group and control group. In the testes sections, no variation was present in the staging of spermatogenesis between the 222 mg/kg bw treated and the control group.

Due to the observed effects, a NOEL of 14 mg/kg bw was defined for parental systemic toxicity.

Reproductive performance

At doses of 56 and 222 mg/kg bw, the number of implantation sites were statistically reduced compared to controls. The number of corpus lutea was not affected. Relative pre-and postimplantation loss showed a high variability at these dose groups. A reduction in the number of pups born was only observed for the high dose group (significant at 1% level). Pup development was not affected until scheduled sacrifice on day 21.

Effects on embryo implantation were observed at doses for which maternal toxicity was indicated by a reduced food consumption and body weight gain as well as hyperplasia of liver and thyroid. As described in the section of repeated-dose toxicity, the substance belongs to the group of BHT-related antioxidants that induce rat liver metabolism and by that affect in a rat-specific way the turnover of thyroid hormones. It is therefore considered that the reduction in the number of implantations and the reduced number of pups occurred secondary to maternal toxicity and that it is not relevant for classification and labelling.

Short description of key information:
In a one-generation study was performed according to OECD guideline 415 in 2008. A slight reduction in implantation sites was observed at doses affecting maternal thyroid hormone status wth a NOEL of 14 mg/kg bw. Effects are considered secondary to the rat-specific induction of the liver/thyroid axis. Male fertility and pup development were not affected.

Effects on developmental toxicity

Description of key information

No adverse effects regarding developmental toxicity/teratogenicity were observed in a one-generation study. However, this type of study does only give limited information.

Additional information

In a one-generation reproduction toxicity study (Notox 487736, 2008) the test substance (dissolved in polyethylene glycol) was daily administerd by gavage to 24 female/12 male Wistar rats per dose group at dose levels of 14, 56, and 222 mg/kg bw.

As far as can be determined from the parameters investigated in a one-generation study, there were no adverse effects on pup development.

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available one-generation study is considered reliable and suitable for classification purposes under 67/548/EEC. The reduction in the number of implantation sites and pups is considered to have occurred secondary to maternal toxicity. As a result the substance is not considered to be classified for fertility under Directive 67/548/EEC, as amended for the 28th time in Directive 2001/59/EC.

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available one-generation study is reliable and suitable for classification purposes under Regulation 1272/2008.

The reduction in the number of implantation sites and pups is considered to have occurred secondary to maternal toxicity.

As a result the substance is not considered to be classified for fertility under Regulation (EC) No. 1272/2008, as amended for the second time in Directive (EC 286/2011).

From the limited data available on pup development, no need for classification and labelling is derived for developmental toxicity or effects via lactation.