9-Octadecenoic acid (Z)-, zinc salt, basic

Endpoint summary

Description of key information

Fourteen-day repeat dose toxicity study using the oral route by gavage in the rat, conducted according to a range-finder standard procedure under GLP, and followed by a twenty-eight day repeat oral (gavage) study in the rat. The NOAEL for systemic toxicity was found to be 1000 mg/kg bw/day (OECD 422).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 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

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

Additional information

Oral

 

Introduction

 

The study was designed to investigate the systemic toxicity and potential adverse effects of the test item on reproduction (including offspring development), to assess the ability of the animals to recover from any toxicity following the withdrawal of treatment and is designed to be compatible with the requirements of the OECD Guidelines for Testing of Chemicals No. 422 “Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test” (adopted 22 March 1996).

 

This study was also designed to be compatible with Commission Regulation (EC) No 440/2008 of 30 May 2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH).

 

Methods

 

The test item was administered by gavage to three groups, each of twelve male and twelve female Wistar Han™:RccHan™:WIST strain rats, for up to seven weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dose levels of 100, 300 or 1000 mg/kg bw/day. A control group of twelve males and twelve females was dosed with vehicle alone (Arachis oil BP). Two recovery groups, each of five males and five females, were treated with the high dose (1000 mg/kg bw/day) or the vehicle alone for forty-two consecutive days and then maintained without treatment for a further fourteen days.

 

Clinical signs, behavioral assessments, body weight change and food and water consumption were monitored during the study. Pairing of non-recovery animals within each dose group was undertaken on a one male: one female basis within each treatment group on Day 15 of the study, with females subsequently being allowed to litter and rear their offspring to Day 5 of lactation. During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size and offspring weights and assessment of surface righting reflex.

 

Extensive functional observations were performed on five selected non-recovery males from each dose group during the final week of treatment, and for five selected parental females from each dose group on Day 4 post partum. Urinalysis was performed on five non-recovery males per dose group during the final week of treatment and five non-recovery males and females from each dose group were selected for hematology and blood chemistry assessments prior to termination.

 

Adult non-recovery males were terminated on Days 43 or 44, followed by the termination of all females and offspring on Day 5 post partum. Any female which did not produce a pregnancy was terminated on Day 26 post coitum. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed.

 

Following forty-two days of treatment, recovery group animals were maintained without treatment for a further fourteen days. Urinalysis was performed on all recovery group males during the final week of the treatment period. In addition, hematological and blood chemical assessments were performed on all recovery group animals at the end of the treatment-free period. These animals were then subjected to a gross necropsy, but as there were no treatment-related histopathology findings, histopathological examinations of tissues from these animals was not performed.

 

Results

 

Mortality - There were no unscheduled deaths on the study.

 

Clinical Observations - Throughout the study, there were no clinical signs considered to be related to the toxicity of the test item.

 

Behavioral Assessment - There were no treatment-related changes in the behavioral parameters measured.

 

Functional Performance Tests - There was no effect of treatment with the test item at any dose level on functional performance in animals of either sex.

 

Sensory Reactivity Assessments - Sensory reactivity scores across all treated groups were similar to controls.

Body Weight - Body weight development for animals of either sex remained unaffected throughout the treatment and recovery period.

 

Food Consumption - No adverse effects on dietary intake were noted for males during the study or for females during the pre-pairing, gestation or lactation phases of the study. Dietary intake and food efficiency in recovery animals of both sexes was also unaffected.

 

Water Consumption - Visual inspection of water bottles did not indicate any differences in water intake for treated animals of either sex in comparison with controls.

 

Hematology - No toxicologically significant effects were detected in animals of either sex receiving the test item at any dose level.

 

Blood Chemistry - No toxicologically significant effects were detected in animals of either sex receiving the test item at any dose level.

 

Urinalysis - No toxicologically significant effects were detected in animals of either sex receiving the test item at any dose level.

 

Necropsy - No treatment-related macroscopic observations were detected at any dose level.

 

Organ Weights - At the end of the dosing period, group mean absolute and body weight-related liver weights in males given the test item at 1000 mg/kg bw/day were slightly but statistically significantly higher than controls. Group mean absolute and body weight-related thyroid weights in the females from this dose group were slightly but statistically significantly lower than controls at the end of the treatment and recovery periods. There were no histopathology correlates, and these observations along with any other statistically significant differences were considered to be of no toxicological relevance.

 

Histopathology - Microscopic examination of tissues from the control and high dose groups did not reveal any treatment-related findings.

 

Conclusion

 

The oral administration of the test item to rats by gavage, at dose levels of 100, 300 and 1000 mg/kg bw/day was well tolerated. The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was considered to be 1000 mg/kg bw/day, based on the absence of toxicologically significant or treatment-related findings.

 

Inhalation

 

According to REACH, Annex VIII, Section 8.6.1, short-term repeated dose toxicity should be investigated using one species and the most likely route of human exposure. The substance is a waxy solid with a vapour pressure of 0.001 Pa at 25°C and, based on evaluation of the life cycle of the substance, it is expected that inhalation exposure will be low and that the most likely route of exposure for workers and consumers is the dermal route. A repeated dose toxicity study via the inhalation route is, therefore, not appropriate

 

Dermal

 

According to REACH, Annex VIII, Section 8.6.1, short-term repeated dose toxicity should be investigated using one species and the most likely route of human exposure. However, no evidence of systemic toxicity was demonstrated during an acute study via the dermal route and, in order to minimise the number of vertebrate animals tested, oral dosing by gavage was considered most appropriate for a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) in rats.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
GLP guideline study performed on substance itself

Justification for classification or non-classification

No classification for repeat dose toxicity is required as there were no adverse effects up to and including the maximum recommended dose leverl of 1000 mg/kg bw/day.