Registration Dossier

Administrative data

Description of key information

No effects observed.

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
1 940 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Acceptable and well documented publications

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 reaction product itself was not test with regard to repeated dose toxicity. The endpoint is discussed with studies obtained with the different constituents of the reaction product.

Sucrose Stearate:

a) chronic toxicity study

The principal objective of this chronic toxicity testing study, was to establish, under conditions of prolonged and repeated exposure, a general toxicological profile and assessment for the test substance (CAS 37318 -31 -3), permitting the determination of a maximum dose which produces no observed adverse effects through at least 12 months (NOAEL).

The test item was administered weekly in the feed of the Fischer rat (14 animals/sex/dietary level), at nominal dietary concentrations of 394, 1160 and 1970 mg/kg bw/day (males) and 480, 1440 and 2440 mg/kg bw/day (females). The feed mix was prepared every 9 weeks. Stability of the test item was checked after 3, 10 and 18 weeks by gas chromatographic analysis.

Body weight and food consumption determinations were done once a week for the first 13 weeks at least once every 4 weeks. Each animal was checked daily during the first 74 weeks and twice daily for survival, clinical signs and abnormalities of appearance and behaviour.

Ophthalmologic exams were conducted on 10 male and female rats from each test group before initiation and on 10 rats of each sex from the control and the high-dose group every 3 months and within 1 week before the end of treatment.

All animals placed on study were subject to a postmortem examination, which included (1) documenting and saving all gross lesions, (2) weighing designated organs, and (3) collecting representative tissue specimens for histopathologic evaluation. Significant decrease in weight gain in male rats of the high-dose group relative to controls was observed in weeks 3 to 6 and weeks 8, 10 and 17 to 49 after administration. The food consumption was clearly lower in the first week of administration in males of the high dose group. It was also lower in females of the medium and high dose groups relative to the respective controls.

Haematological examinations revealed elevated MCV (mean corpuscular hemoglobin) levels relative to the controls in females at 13 weeks (all dose groups), 39 weeks (highest dose group), 78 weeks (highest dose group) and 104 weeks (highest dose group). The relative weight of lungs was increased in females from the high dose group. In nonsurviving animals, approximately one-half of the animals in each group had large granular lymphocyte leukemia with associated macroscopic observations such as spleen enlargement and liver surface abnormalities.

The chronic study demonstrated that the test item was not toxic in Fischer rats. Differences in weight gain could be ascribed due to palatability. Hematology and clinical chemistry showed occasional statistical differences, but they were judged to be incidental. Leukemia and an associated increase in spleen weight were related to increased leukemia incidences in aging rats but not due to treatment.

The chronic study demonstrated that the test substance was not toxic in Fischer rats. Based on this result the NOAEL was determined to be 1970 mg/kg bw/day.

b) Subchronic Toxicity study in Fischer 344/DuCrj Rats 2000

The preliminary subchronic 13 week study was used to set the dose levels for the combined chronic and carcinogenicity study to assess the long-term toxicity and carcinogenic potential of the test substance (CAS 37318 -31 -3). The test item was administered weekly in the feed of the Fischer rat (20 animals/sex/dietary level), at nominal dietary concentrations of 636, 1900 and 3240 mg/kg bw/day (males) and 666, 1950 and 3430 mg/kg bw/day (females). The feed mix was prepared twice during the study (1 week before the start of administration and 5 weeks later). Stability of the test item was checked after 3, 10 and 18 weeks by gas chromatographic analysis. Body weight and food consumption determinations, as well as a detailed clinical examination of each animal, were conducted weekly throughout the study. Observations for moribundity and mortality were performed at least once daily. Standard hematologic and clinical chemistry were evaluated from blood shortly before sacrifice. Urine was taken from 10 female and 10 male animals 4 days (male) and 3 days (female) before completion of the dosing period. Ophthalmologic exams were conducted on 10 male and female rats from each test group before initiation. It was also conducted on 10 rats of each sex from the control and the high-dose group before the end of treatment. All animals placed on study were subject to a postmortem examination, which included (1) documenting and saving all gross lesions, (2) weighing designated organs, and (3) collecting representative tissue specimens for histopathologic evaluation. An increase in food consumption was noted in the male animals of the high-dose group near the end of the administration period. Haematological examinations showed a prolongation of APPT (activated partial thromboplastin time), observed in the female high-dose group. The Ketone bodies in the urine were decreased in male animals of the high-dose group. Male animals showed a significant decrease in absolute kidney weight in the medium- and high-dose groups and a decrease in relative kidney weights in all treated groups. A significant decrease of relative liver weight was also observed in the male high-dose group. Extramedullary hematopoesis of the spleen was observed. The effects described above were judged to be not based on compound related effects.

Conclusion

The subchronic study demonstrated that the test substance was not toxic in Fischer rats. Based on no-adverse compound related effects a NOAEL of 3240 mg/kg bw/day was established for rats.

Fatty acids, C16 -18 Methylester:

a) OECD 422

The near homolog Methyl laurate (CAS 111-82-0) was tested for oral toxicity in rats in an OECD 422 combined repeated dose and reproductive toxicity screening test under GLP conditions (MHLW, 2000). 12 male and female Crj:CD (SD) rats per dose were administered doses of 0, 250, 500 and 1000 mg/kg/day by gavage. The animals were mated. The test material was administered to females from 14 days before mating until day 3 of lactation and to males for 45 days. Terminal kill was on day 45 for males and on day 4 of lactation for females. The test substance showed no general toxicological effects in either sex. There were no clinical observations attributable to the administration of test substance and there was no mortality in any of the groups. No effects were observed in terms of body weights, food consumption, haematology, blood chemistry, organ weight, necropsy or histopathological findings. Therefore, under the experimental conditions of the study the NO(A)EL for methyl laurate for repeated dose toxicity after oral administration is 1000 mg/kg bw/day in both sexes.

 

b) 90 day study

A subchronic oral feeding study (Bookstaff, 2004) was performed with ethyl oleate (CAS 111-62-6, another homolog of Fatty acids, C16 -18, Methyl Ester) according to the 1993 FDA draft "Redbook II" guidelines (Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food). The study was performed equivalent to OECD Guideline 408. The purpose of the study was to determine the safety of ethyl oleate (EO) in a subchronic feeding study in Sprague-Dawley rats. EO was mixed into AIN-93G purified diet at levels of 0, 3.3, 6.7, and 10% by weight (approx. 0, 1900, 3800 and 6000 mg/kg bw/day). All diets were calorie- and fat-matched using high oleic safflower oil (HOSO) as the control fat. There were 20 male and 20 female rats per group. EO in the diet was well tolerated and there were no toxicologically significant findings in any of the measured parameters (clinical observations, body weight gains, appearance of the faeces, ophthalmic examinations, haematology, clinical chemistry, urinalysis, organ weights, histopathology, or male and female reproductive assessments). The subchronic oral NOAEL was determined to be 10% ethyl oleate, which corresponds to approximately 5500 mg/kg bw/day when administered by daily feeding to rats for 91-days.

Fatty Acids, C16-18 Methyl Ester and the test substances belong to the short chain methyl esters category (SCAE Me). A detailed justification for the grouping and read-across is provided in the Justification document (see Section 13).

Fatty acids, C16 -18:

In 1974, the WHO set an unlimited ADI for the salts of myristic (C14), palmitic (C16) and stearic (C18) acids. They stated that myristic, palmitic and stearic acid and their salts are normal products of the metabolism of fats and their metabolic fate is well established. Provided the contribution of the cations does not add excessively to the normal body load there is no need to consider the use of these substances in any different light to that of dietary fatty acids (WHO, 1974; JECFA, 1986).

It is worth noting when considering the oral toxicity of fatty acids and their salts, that due to their innocuous nature, fats and oils are commonly used as controls and as vehicles in animal toxicity studies. For example, OECD Guideline 408 (repeated dose 90-day oral toxicity study in rodents) recommends the use of “a solution/emulsion in oil (e.g. corn oil)” as a vehicle where an aqueous vehicle is not suitable (OECD, 1993).

JECFA (1986). 29thReport of the Joint FAO/WHO Expert Committee on Food Additives.WHO Technical Report Series No. 733.

OECD (1993) OECD Guidelines for the Testing of Chemicals. Volume 2, Organisation for Economic Co-Operation and Development, Paris.

WHO (1974) Toxicological evaluation of some food additives, including anticaking agents, antimicrobials, antioxidants, emulsifiers and thickening agents.WHO Food Additive Series, No. 5, World Health Organisation, Geneva.

Overall conclusion: none of the constituents of the reaction product showed any adverse effects after repeated oral exposure.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result the substance is not considered to be classified for repeated dose toxicity under Regulation (EC) No 1272/2008, as amended for the sixth time in Regulation (EC) No 1297/2014.