3,7,11,15-tetramethylhexadecane-1,2,3-triol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Combined 28 -day repeated dose toxicity study with reproduction/development toxicity screening test (oral route, OECD 422):

The test item, formulated in propylene glycol, was administered daily by oral gavage to SPFbred Wistar Han rats in a combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test.

One control group and three treated groups were tested (50, 150, 500 mg/kg bw/day), each consisting of 10 males and 10 females. Males were treated for 30 days, i.e. 2 weeks prior to mating, during mating, and up to termination. Females were treated for 50-55 days, i.e. during 2 weeks prior to mating, during mating, during post-coitum, and during 13-15 days of lactation. Females which failed to deliver healthy offspring were treated for 41-54 days.

The following observations and examinations were evaluated: mortality / viability, clinical signs (daily), functional observations and locomotor activity (end of treatment), body weight and food consumption (at least at weekly intervals), estrous cycle determination (14 days prior to treatment, 14 days of treatment and during mating until evidence of mating, and the day of necropsy), clinical pathology (end of treatment), measurement of thyroid hormone T4 (F0-males at the end of treatment, PND 13-15 pups), macroscopy at termination, organ weights and histopathology on a selection of tissues. In addition, the following reproduction/developmental parameters were determined: mating, fertility, precoital time, number of implantation sites, gestation index and duration, parturition, maternal care, sex ratio and early postnatal pup development (mortality, clinical signs, body weights, sex, anogenital distance, areola/nipple retention and macroscopy). Blood was sampled for exposure control evaluation (from first 5 F0-males and all F0-females/sex/group at day 14 of treatment and from PND 13-15 pups from litters of the selected 5 F0-females). Accuracy and homogeneity of formulations were demonstrated by analyses.

Parental results:

Refer to repoeat dose toxicity section.

Reproductive results:

Incidental occurrences of non-mated and non-pregnant females and females with implantation sites only and/or a female with total litter loss were noted among the test groups treated with Phytantriol, but none in the vehicle control group. The incidence of each finding was within normal limits for rats of this strain and age and the distribution of each of these findings over the test groups did not indicate an immediate relation to treatment. Moreover, the overall distribution of the females with litters comprising a normal number of pups was 10, 8, 6 and 8 for the control, 50, 150 and 500 mg/kg bw/day treated groups respectively. These results also did not indicate a dose effect relationship.

A reduction was observed in the mean number of implantation sites at 150 and 500 mg/kg bw/day reaching statistical significance only at the high dose. Whereas the mean number of implantation sites were below the lower limit of the historical background data in females treated at 150 mg/kg bw/day (minimally lower) and 500 mg/kg bw/day, the mean number of living pups per litter was not affected at 150 mg/kg bw/day and only slightly decreased at 500 mg/kg bw/day. The mean number of living pups per litter remained within the historical range in all dose groups. No corroborating effects (of toxicity) were observed in either the parental females or the offspring in the 150 mg/kg bw/day dose group.

Developmental results:

After treatment at 500 mg/kg bw/day, a lower number of pups per litter were observed, which was directly correlated to the lower number of implantation sites in the corresponding dam. Since the post-implantation survival index was normal, the lower number of pups per litter was considered not a developmental effect. After birth, the body weights of pups were similar in all groups. During lactation, retardation of growth of the pups from litters at 500 mg/kg bw/day was observed resulting in lower body weights of these pups on PND 13 of approximately 11% in comparison with the other groups. No further treatment-related changes were noted in the other developmental parameters investigated in this study (i.e. gestation index and duration, parturition, maternal care and early postnatal pup development consisting of mortality, clinical signs, macroscopy, anogenital distance, nipple retention and thyroid hormone assessment).

In conclusion, treatment with Phytantriol by oral gavage in male and female Wistar Han rats at dose levels of 50, 150 and 500 mg/kg bw/day revealed parental toxicity at 500 mg/kg bw/day, expressed as reduced body weight gain and food consumption. Furthermore, non-adverse increases in enzyme levels of ALAT and ASAT and liver weights (both sexes), hepatocellular hypertrophy (females only) and mild local reaction in the stomach to the test item in males (squamous cell hyperplasia and edema) were observed.

Treatment-related effects in reproduction were observed as reduced number of implantation sites at 150 and 500 mg/kg bw/day, being statistically significant only at 500 mg/kg bw/day. A corresponding reduction of mean number of living pups per litter was observed at 500 mg/kg bw/day only. Retardation of growth of pups during lactation was observed at 500 mg/kg bw/day.

Based on these results, the following No Observed Adverse Effect Levels (NOAEL) were derived:

Parental NOAEL: 150 mg/kg bw/day

Reproduction NOAEL: 150 mg/kg bw/day

Developmental NOAEL: 150 mg/kg bw/day

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

Refer to effects on fertility section.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

subacute

Species:

rat

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

Phytantriol is not classified for reproductive toxicity based on the results of a combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422).