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

Endpoint summary

Description of key information

Repeat dose toxicity: 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:

After treatment at 500 mg/kg bw/day, a minimal increase in fore limb grip strength was observed in both sexes and a slightly different habituation profile in males only, as expressed by a higher number of movements and ambulations during the first part of motor activity testing. Due to the low magnitude of the changes in grip strength and motor activity, the results were still within the normal limits for these parameters in rats of this age and strain. Therefore, these findings at the dose level of 500 mg/kg bw/day were considered to be non-adverse.

Treatment-related changes at 500 mg/kg bw/day were observed as statistically significant lower body weights and food consumption, changes in several clinical biochemistry parameters, including increases in ALAT and ASAT, and glucose and a decrease in total protein. The changes in glucose and total protein were considered to be non-adverse, based on the low magnitude of change. Minimal increases in liver weights were observed in these high dose animals, still remaining within normal limits. In addition, a low severity of hepatocellular hypertrophy was recorded in the females at 500 mg/kg bw/day, which was considered to be a non-adverse finding in the absence of any degenerative findings in the liver of these animals. Whereas the increases in the enzyme levels ALAT and ASAT and liver weights were slightly more pronounced in males than in females, the hepatocellular hypertrophy was only seen in females. Although the increased enzyme levels might be indicative of liver damage, this was not confirmed by histopathology in the males. Therefore, also the changes in enzyme levels and liver weight were considered to be non-adverse.

Histopathological examination revealed squamous cell hyperplasia and edema in the stomach of males at 500 mg/kg bw/day, which were considered to represent non-adverse mild local reaction to the test item. No treatment-related changes were noted after treatment at 500 mg/kg bw/day in the other parental parameters investigated in this study (i.e. clinical appearance, haematology investigations, sperm staging (in males) and estrous cycle (in females)). Any changes in the various study parameters after treatment at 50 and 150 mg/kg bw/day were considered no signs of treatment related parental toxicity.

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.

Based on these results, a NOAEL parental toxicity of 150 mg/kg bw/day is derived.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

subacute

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available (further information necessary)

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Phytantriol is not classified for Specific Target Organ Toxicity - Repeated Exposure (STOT-RE) based on the results of a

combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422).

The reduced body weight gain and food consumption observed at 500 mg/kg bw/day are effects not considered to support classification for STOT-RE, as they do not themselves indicate 'significant toxicity'.

In addition, these effects were observed at 500 mg/kg bw/day, which is above the CLP guidance value range, 30 to 300 mg/kg bw/day for significant toxic effects for a 28-day study.