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Description of key information

Subchronic gavage application to rats of the C12 alkyl chain analogue caused signs of early or ongoing myocarditis at doses of 1000 mg/kg bw (OECD 408 with minor deviations, GLP). Findings were reversible within the 4-week recovery period. The NOAEL is 350 mg/kg bw and the NOEL is 125 mg/kg bw.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
350 mg/kg bw/day
Study duration:
subchronic
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

The assessment of subchronic toxicity is based on valid experimental data obtained with a structural analogue. This analogue substance has two C12 alkyl chain instead of two C18 alkyl chain and this structural difference is considered acceptable for the assessment of subchronic toxicity because both are long-chain fatty acids that undergo initial metabolism in the peroxisomes. The study was performed according OECD testing guideline 408 and GLP. The following deviations to the current version of the testing guideline were noted: No data on sensory reactivity to stimuli of different types, assessment of grip strength, and motor activity; blood clinical chemistry did not include urea; urinalysis did not include osmolality or specific gravity.

Oral (gavage) administration to Sprague-Dawley rats for 13 weeks at a dose level of 1000 mg/kg/day was associated with a minor increase in serum cholesterol concentrations in females, increased serum ALAT and ASAT activities and decreased urinary pH in both sexes. Microscopic findings in the heart of these animals suggested an ongoing myocarditis. All these changes were reversible after weeks without treatment. At a dose level of 350 mg/kg/day there was no evidence for any microscopic change in the heart and no other differences to indicate an adverse effect of the test article. Non-adverse changes in haematology and biochemistry were recorded. This dose level is therefore considered to be the no observed adverse effect level (NOAEL). There were no changes considered to represent an effect of the test article at 125 mg/kg/day and therefore this dose level is considered to be the no observed effect level (NOEL).

A follow-up analysis showed that all treated and untreated animals had the same organelle distribution in hepatocytes (Persohn 1994). In particular treatment with dilauryl thiodipropionate was without an effect on the number and size of peroxisomes and therefore, a peroxisome proliferating potential is excluded.

 

The following describes details on the study described above. In order to evaluate the possible regression a 4 week treatment-free period was included for the control group (1% carboxymethylcellulose in water) and the highest dose groups. Tested doses were 125, 350 and 1000 mg/kg bw. Stability and homogeneity of the preparations were verified by a validated HPLC method.

Treatment-related microscopic lesions were seen in the heart of high dose animals. The lesion was described as small foci of degenerated or necrotic fibres associated with minimal to moderate mononuclear cell infiltration. This association suggested early or ongoing myocarditis. These lesions were not present in animals previously treated at the high dose level but allowed a 4 week period without treatment before being necropsied. There were no other treatment-related microscopic lesions.

Mortality/morbidity checks were performed twice daily. Clinical examinations were performed daily. A full clinical examination was performed weekly. Individual body weights were recorded weekly. Food consumption was measured weekly for each cage of animals. Ophthalmological examination was performed pre-test and during week 13, clinical pathology investigations were performed after weeks 4, 13 and 17. All animals were killed and necropsied after weeks 13 or 17; selected organs were weighed and tissue samples were fixed and preserved at necropsy. Selected tissues from designated animals killed after weeks 13 and 17 were examined by histopathology.

There were no unscheduled deaths, no eye lesions and no treatment-related clinical signs. Body weight gain and food consumption were unaffected by the treatment. Although high dose males tended to have higher haemoglobin concentrations (Hb), packed cell volumes (PCV) and red blood cell counts (RBC) than controls after 13 weeks of treatment and treated females higher Hb concentrations, the individual values were within the normal background range and in females there was no dose-relationship. These small changes were therefore considered not to represent an adverse effect of the test article.

None of the other small differences in the haematological parameters was considered to represent an adverse effect of treatment. High dose females had slightly higher serum cholesterol concentrations at the end of the treatment period but the change was completely reversible after 4 weeks without treatment. Similarly, high dose animals tended to have slightly elevated alanine and aspartate aminotransferase (ALAT, ASAT) activities than controls. However, there were no differences when these parameters were measured at the end of the treatment-free period. There were no other differences in the clinical chemistry parameters to indicate an effect of treatment. Although the urine of high dose animals was slightly more acidic than that of controls in week 13, after 4 weeks without treatment there were no significant differences between the groups. Other urine parameters were unaffected by treatment.

When compared with the control group, the mean liver weight was higher for high dose group males when expressed relative to body weight and for females when expressed in absolute terms and relative to body weight. In addition, when compared with controls, the mean testes weight was lower for high dose group (absolute and relative to brain weight). High dose group females also had a lower mean ovarian weight when expressed relative to brain weight. When compared with the control group, the mean liver weight was higher for high dose group males when expressed relative to body weight and for females when expressed in absolute terms and relative to body weight. In addition, when compared with controls, the mean testes weight was lower for high dose group (absolute and relative to brain weight). High dose group females also had a lower mean ovarian weight when expressed relative to brain weight. In the absence of any microscopic lesions in these organs the weight changes were considered to be of doubtful toxicological significance. At the end of the treatment-free period, the mean absolute brain weight for high dose group males was higher than the control mean and this group also had a statistically significantly higher mean (absolute and relative to brain weight) prostate and epididymides weight than the control. In the absence of any microscopic lesions in these organs the weight changes were considered to be of doubtful toxicological significance. No historical control data for organ weights was included in the study. Macroscopic pathological changes were considered to be either agonal or incidental in origin or unrelated to treatment with the test article.

Justification for classification or non-classification

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

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. No serious or irreversible effects were observed at doses of 100 mg/kg bw or less. As a result the substance is not considered to be classified for repeated dose toxicity under Regulation (EC) No. 1272/2008.