[No public or meaningful name is available]

Endpoint summary

Description of key information

RDT oral (OECD guideline 408), rat NOAEL ≥ 1000 mg/kg bw/day (males/females)
RDT oral (OECD guideline 407), rat NOEL = 300 mg/kg bw/day (males/females); NOAEL ≥ 1000 mg/kg bw/day (males/females) 
Waiving – RDT inhalation 
Waiving – RDT dermal 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2 due to read-across) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

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

Repeated dose toxicity: oral route (90 days)

No data on subchronic repeated dose toxicity is available for Amides, C18, branched and linear. Therefore, read-across from the structurally related substance (Z)-docos-13-enamide (erucamide, CAS 112-84-5) was applied. A subchronic repeated dose toxicity study (90-days) with CAS 112-84-5, which serves as key study, was performed according to OECD TG 408 and in compliance with GLP (Takawale, 2015). In the available study the test substance was investigated for toxic effects after repeated administration via the oral route with a particular focus on fertility parameters and reproductive organs. Groups of 10 Wistar rats (Crl:WI(Han)) per sex per dose were administered doses of 100, 300 and 1000 mg/kg bw/day (nominal dose) via oral gavage. Animals treated with the vehicle (corn oil) served as controls. Treatment was carried out once daily (7 days per week) for 90 consecutive days. Animals were observed for mortalities and general clinical observations twice daily (except weekends). Detailed clinical observations were performed once before the first administration and at least once a week thereafter. Body weight was recorded once before the assignment to the experimental groups, on the first day of administration and weekly during the treatment period. Ophthalmological examinations using an ophthalmoscope were made on all animals before the first administration and in the last week of the treatment period. Haematology and clinical chemistry parameters as well as urinalysis were examined at the end of the treatment period prior to or as part of the sacrifice of the animals. Gross pathology and histopathology were performed one day after the last administration when all surviving animals were sacrificed. Examination of fertility parameters was performed daily over a period of 8 days. The estrous cycle of all female animals was examined 4, 8 and 12 weeks after the first administration. At necropsy the left epididymis, left testis and left vas deferens were separated and used for evaluation of sperm parameters. Epididymal sperm motility and testicular sperm count were evaluated in all male animals. Moreover, the wet weight of the organs of all sacrificed animals was recorded as soon as possible. No mortality occurred in the control or any of the dose groups during the treatment period of this study. No test item related clinical signs were observed in any male and female animal during the entire study period. During the weekly detailed clinical observation, no significant changes or differences between the groups were found. In males, mean body weight increased with the progress of the study in all groups and mean body weight gain did not differ significantly from that in the control group which was also correlated with the food consumption. In females, mean body weight increased with the progress of the study in all groups and no test item related effect was observed on body weight and body weight gain in treatment groups during the entire study period. No test item related or statistically significant effect on food consumption was observed in males and females during the whole study period. No ophthalmologic findings were observed in any of the animals of this study. In males and females, no test item related effect on haematological and blood coagulation parameters was observed in treated groups except decrease in PLT count in LD and MD males when compared with the controls. However, all individual and group mean values were within the historical control data range. Due to lack of dose dependency and consistency, this finding was not considered to be toxicologically relevant and was considered to have no biological relevance. In male animals, a marginally but statistically significantly lower value for cholesterol (Chol) was noted in the male MD group compared to the control group. As group mean and individual values for cholesterol were within the normal range of variation and due to lack of dose dependency, this is considered as incidental. In female animals, total bile acids (TBA) were marginally higher in the MD and HD group compared to the control group. This cannot be considered related to the treatment with the test item as the difference was statistically insignificant and values were within the normal range of variation and the historical control data range. Slightly higher leukocyte levels were found in the urine of a few male animals of all groups including the control animals. In males and females, all other urinary parameters were in the normal range of variation and no test item-related differences between the dose groups and control group were observed. No relevant effects were observed in any of the parameters of the functional observation battery at the end of the treatment period. There were no biologically relevant differences in body temperature between the groups. A marginal, but statistically significant lower body temperature of male HD animals before initiation of the treatment period was observed when compared to the respective controls. This effect on body temperature was considered to be incidental as it was observed before initiation of the treatment. In males, at the end of the treatment period, absolute and relative (to brain weight and body weight) thymus weights were slightly higher in MD and HD group than in the respective controls without achieving statistical significance. In females, absolute and relative (to brain weight and body weight) spleen weights were higher in all treatment groups although statistical significance was only achieved for absolute spleen weight in the HD group and relative (to brain weight) spleen weights in the LD and the HD group when compared with the controls. The absolute and relative (to brain weight and to body weight) thymus weights in females were also higher in the LD and the HD group without achieving statistical significance when compared with the controls. In the light of absence of histopathological findings in the spleen and thymus and as this increase was marginal, it was not considered to be adverse. A few spontaneous gross pathological findings were observed in males and females and as such not considered to be a systemic effect due to test item administration. Histopathologically, these gross lesions were not related to treatment with the test item. No test item related effect on epididymal sperm motility or testicular sperm count was noted at the end of the treatment of this study. The statistical analysis showed no statistically significant changes between the control group and any of the dose groups in the testicular number of sperms/g testis. However, a statistically significantly lower percentage of motile, rapidly moving epididymal sperms and significantly higher static count was observed in the LD group when compared with the controls. These significant values in the LD group were attributed to low sperm motility and high static count in animal number 12 and 14. Due to lack of dose dependency and consistency, and in the absence of histopathological findings, this effect on sperm parameters is not considered to be of toxicological relevance. Evaluation of sperm morphology did not reveal any indicator for toxicity induced by the test item, and percentages of normal and abnormal sperms in treatment groups were comparable with the controls. The test material had no biologically significant effect on the estrous cycle analyzed 4, 8 and 12 weeks after the first administration. In summary, the 90-Day Repeated Dose Oral Toxicity study with CAS 112-84-5 in male and female Wistar rats, with dose levels of 100, 300, and 1000 mg/kg bw/day, revealed no major toxicity or mortality. No effects of the test material were found at the dose level of 1000 mg/kg bw/day. Therefore, the NOAEL is considered to be 1000 mg/kg bw/day.

Repeated dose toxicity: oral route (28 days)

A supporting repeated dose toxicity study with Amides, C18, branched and linear is available and was performed according to OECD TG 407 and in compliance with GLP (McRae, L., 2015). In this subacute toxicity study groups of five Wistar rats of each sex per dose were administered nominal doses of 100, 300 or 1000 mg/kg bw/day once daily for 28 consecutive days via oral gavage. Appropriate control animals were concurrently administered the vehicle (arachis oil) in the same way. Animals were examined for overt signs of toxicity, ill-health, mortality or behavioral change at least twice daily. Detailed clinical observations were performed before treatment and on Day 7, 14, 21, and 25. Body weights, food consumption and neurobehavioural examination were recorded. No mortality and no severe clinical signs of toxicity were observed throughout the study period. Salivation was observed in animals of either sex in all dose groups but was not considered to be a sign of adverse systemic toxicity. No treatment-related effects on body weight, body weight gain, and food water consumption could be recorded. No toxicologically significant effects of treatment were detected on the hematology and blood chemistry parameters measured. Males treated with 1000 mg/kg bw/day showed a statistically significant increase in hematocrit and a statistically significant reduction in mean corpuscular hemoglobin concentration when compared to controls. Females at all dose levels showed a lower eosinophil count when compared to controls but these effects were considered not to be toxicologically significant. Furthermore, no treatment-related changes in the measured behavioural parameters were recorded. Animals of either sex treated with 1000 mg/kg bw/day had a statistically significant reduction in spleen weight, both absolute and relative to terminal body weight. No such effects were detected in animals of either sex treated with 100 or 300 mg/kg bw/day. Gross pathology revealed no macroscopic abnormalities, but there was a minor decrease in the amount of hematopoiesis in the spleen of females given 1000 mg/kg bw/day. This correlated with the weight decrease noted at necropsy. In summary,the 28-Day Repeated Dose Oral Toxicity study with Amides, C18, branched and linear in male and female Wistar rats, with dose levels of 100, 300, and 1000 mg/kg bw/day, revealed a reduction in spleen weight observed at 1000 mg/kg bw/day for both sexes along with alterations in hematology parameters for males and microscopic changes in the spleen of females, which was considered to represent an adaptive response to treatment. Therefore, the No Observed Effect Level (NOEL) for systemic toxicity was considered to be 300 mg/kg bw/day for animals of either sex. The No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg bw/day for animals of either sex.

  

In summary, the available data on repeated dose toxicity of the structurally-related substance (Z)-docos-13-enamide (CAS 112-84-5, erucamide) and on repeated dose toxicity of Amides, C18, branched and linear does not reveal any substance-related signs of toxicity. Therefore, a subchronic NOAEL of 1000 mg/kg bw/day was derived from the 90-Day Repeated Dose Toxicity Study.

 

According to Regulation (EC) No 1907/2006, Annex IX, 8.6.2, column 1, a subchronic toxicity study (90 day) has to be performed in one species (rodent, male and female) via the most appropriate route of administration, having regard to the likely route of human exposure. Therefore, no subchronic inhalation toxicity study needs to be performed according to the criteria outlined in Regulation (EC) No 1907/2006, Annex IX, 8.6.2, column 2, since the vapour pressure of the substance is very low and the possibility of human exposure is not expected under normal conditions of handling. Furthermore, a 90-day toxicity study via the oral route is available for the structurally related substance (Z)-docos-13-enamide (CAS 112-84-5, erucamide).

 

According to Regulation (EC) No 1907/2006, Annex IX, 8.6.2, column 1, a subchronic toxicity study (90 day) has to be performed in one species (rodent, male and female) via the most appropriate route of administration, having regard to the likely route of human exposure. Therefore, no subchronic dermal toxicity study needs to be performed according to the criteria outlined in Regulation (EC) No 1907/2006, Annex IX, 8.6.2, column 2, since the physicochemical properties (high log Pow and low water solubility) of the test substance do not suggest a significant absorption through the skin. In addition, the acute dermal toxicity and skin irritation studies conducted with Amides, C18, branched and linear did not show systemic effects or evidence of absorption through the skin. Furthermore, a 90-day toxicity study via the oral route is available for the structurally related substance (Z)-docos-13-enamide (CAS 112-84-5, erucamide).

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Hazard assessment is conducted by means of read-across from a structural analogue/surrogate. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose.

Justification for classification or non-classification

The available data on the repeated dose toxicity of Amides, C18, branched and linear and of the structurally-related substance (Z)-docos-13-enamide (CAS 112-84-5, erucamide) do not meet the criteria for classification according to Regulation (EC) No 1272/2008 or Directive 67/548/EEC; therefore, Amides, C18, branched and linear is not expected to exert toxicity after repeated exposure, and the data are thus conclusive but not sufficient for classification.