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Description of key information

Based on existing datasets and structural ad chemical considerations, read-across from Fatty acids, C18-unsatd., dimers, polymers with oleic acid and triethylenetetramine to an available repeated dose toxicity study using Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine is appropriate to meet the REACH Annex VII-IX data requirements. In a combined repeated dose and reproduction/developmental toxicity screening test conducted in the rat according to OECD Test Guideline 422, the NOAEL for systemic toxicity was determined to be 1000 mg/kg bw/day (i.e. the highest dose tested). The repeated dose toxicity of the substance will be characterised further based on read-across to a proposed 90-day oral repeated dose toxicity study in the rat (OECD Test Guideline 408) using Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine. 

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
Quality of whole database:
Reliable screening study providing multiple endpoints.

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

No studies on the repeated dose toxicity of Fatty acids, C18-unsatd., dimers, polymers with oleic acid and triethylenetetramine are available. Read-across from the substance to a repeated dose toxicity study using Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine is appropriate to meet the REACH Annex VII-IX data requirements. Read-across is scientifically justified and also enables the REACH requirements to be adequately addressed, while avoiding unnecessary animal testing in accordance with EU Directive 86/609/EEC.

The sub-acute repeated dose oral toxicity of Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine was investigated in rats in a combined repeated dose and reproduction/developmental toxicity screening test conducted according to OECD Test Guideline 422 (Perks, 2013). In the study, groups of male and female Crl:WI(Han) rats (10 animals/group) were administered with the test substance orally by gavage, at dose levels of 100, 300 and 1000 mg/kg bw/day. Dose levels were selected based on the results of a 14-day range finding study. No concentration verification results were obtained in the study. Formulations were prepared and used daily for dose administration and dose preparations records showed that the formulations were accurately prepared. In-life data confirmed, indirectly, that a range of dose levels were used. In the absence of analytical conformation the dose levels specified for the main study were considered to be nominal values.

Male rats were dosed once daily for two weeks prior to pairing, during the pairing period and a further two weeks before necropsy. Males were treated for a minimum of 6 weeks prior to necropsy. Female rats were dosed for two weeks prior to pairing, during pairing and until Day 4 post-partum (i.e. approximately 7 weeks of dosing). The females were allowed to litter and rear their offspring to Day 4 post-partum. The following parameters were assessed during the study: clinical observations, body weight, food intake, functional observations and tests, locomotor activity, haematology, clinical chemistry, organ weights, gross pathology and histopathology.

There were no treatment related deaths during the study. One female treated at 1000 mg/kg bw/day was euthanised on Day 1 post-partum, but this death was not considered to be treatment related. While noisy respiration was observed on several occasions during the dosing period in males and females treated at 300 or 1000 mg/kg bw/day, it was considered that this finding was not a direct clinical effect of the test material. Occasionally, mouth rubbing, salivation and/or paddling of the forelimbs were noted in animals from immediately post-dose until the end of the day. The number of animals affected and the duration of the reactions were dose-related. These findings were considered to be a reaction to the taste of the test material and of no toxicological significance.

There was a statistically significant reduction in mean body weight gain over the first week of the dosing period in males treated at 1000 mg/kg bw/day. A lower mean body weight persisted throughout the dosing period and was associated during Week 1 and 2 with a lower mean food consumption (compared to controls). It was considered that these changes did not adversely affect the males as there were no other adverse effects observed, and no effect on behaviour (based on a battery of observational tests) or on mating behaviour. There was a statistically significant reduction in mean body weight gain during the last week of gestation in females treated at 1000 mg/kg bw/day, but in the absence of other effects this transient observation was considered not to be adverse. Group mean locomotor activity data were highly variable. Males in the 1000 mg/kg bw/day dose group showed statistically increased activity compared to the controls, but in the absence of other effects observed during behavioural tests and observations, this was considered unlikely to be of biological significance.

There was a statistically significant increase in alanine aminotransferase levels in males treated at 300 and at 1000 mg/kg bw/day and in females treated at 1000 mg/kg bw/day. There was also an increase in aspartate aminotransferase levels in males and in females treated at 1000 mg/kg bw/day; a finding that may indicate liver changes. There were also slight increases in inorganic phosphate and total cholesterol concentration, achieving a significant dose-response. In the absence of changes in liver weight and microscopic morphological liver changes, these findings were not considered to be adverse. There was a statistically significant reduction in mean urine volume and an increase in specific gravity in males treated at 1000 mg/kg/day, compared with the controls. With only a single measurement and with no visual observations of lower water consumption during the in-life phase, this finding was considered to be incidental.

In males treated at 1000 mg/kg/day, there was a statistically significant decrease in mean heart weight relative to body weight, when compared with the controls. There were no histopathological changes or functional changes (FOBs) and no statistically significant changes in female heart weight. In the mesenteric lymph node, increased histiocyte foci were present in all male and most female rats treated with the substance at 1000 mg/kg/day. Histiocyte foci were characterised by discrete aggregates of plump eosinophilic macrophages. These changes were considered to be not adverse.

Based on this study, The No-Observed-Adverse-Effect-Level (NOAEL) for the sub-acute repeated dose oral toxicity (general and systemic effects) of the substance in adult male and female rats was considered to be 1000 mg/kg bw/day (i.e. the highest dose tested).

The repeated dose toxicity of the substance will be characterised further based on read-across to a proposed 90-day oral repeated dose toxicity study in the rat (OECD Test Guideline 408) using Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine.

Waivers are proposed for repeated dose toxicity tests via the inhalation and dermal routes in accordance with Column 2 of Annex VIII of the REACH Regulation. The repeated dose toxicity of the substance will be adequately elucidated by the oral route, based on read-across to a proposed study on Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine. Further testing via the dermal and inhalation routes is not required.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Based on existing datasets and structural and chemical considerations, read-across from Fatty acids, C18-unsatd., dimers, polymers with oleic acid and triethylenetetramine to an available repeated dose toxicity study using Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine is appropriate to meet the REACH Annex VII-IX data requirements. In a combined repeated dose and reproduction/developmental toxicity screening test conducted in the rat according to OECD Test Guideline 422, the NOAEL for systemic toxicity was determined to be 1000 mg/kg bw/day (i.e. the highest dose tested).

Justification for classification or non-classification

The available data on Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine indicate that the substance does not cause effects that meet the criteria for classification for systemic or target organ toxicity after repeated sub-acute exposures. Based on read-across to these findings, Fatty acids, C18-unsatd., dimers, polymers with oleic acid and triethylenetetramine does not meet the criteria for classification for repeated dose toxicity according to Regulation 1272/2008/EC or Directive 67/548/EEC.