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Description of key information

No repeated dose toxicity study with Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts is available, thus the repeated dose toxicity will be addressed with existing data on the moieties liberated upon dissolution, zinc and fatty acid, C14 -18 and C16 -18 unsatd.

In relevant and reliable repeated dose toxicity studies for the moiety zinc of Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts, and in peer-reviewed publicly available assessment reports for the assessment entity fatty acids, C14 -18 and C16 -18 unsatd, there were no toxicological findings reported that would justify a classification for specific target organ toxicity with repeated exposure.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available
Species:
guinea pig

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

Fatty acids, C14 -18 and C16 -18 unstd., zinc salts

Since no repeated dose toxicity study is available specifically for Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts, information on the moieties liberated upon dissolution, zinc and fatty acids, C14 -18 and C16 -18 unsatd., will be used for the hazard assessment and when applicable for the risk characterisation of Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts. For the purpose of hazard assessment of Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts, the point of departure for the most sensitive endpoint of each moiety will be used for the DNEL derivation. In case of zinc in Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts, the NOAEL of 0,83 mg/kg bw/day in repeated dose toxicity (human data) will be used.

However, zinc is essential for human growth and development, neurological functions and immunocompetence. The main clinical manifestations of zinc deficiency are growth retardation, delay in sexual maturation or increased susceptibility to infections (SCF, 2003). Health specialists recommend supplementing the diet with zinc in case human diet is zinc deficient. The maximum allowable daily intake has been established to be 50 mg zinc per day. There is no experimental sufficient evidence for specific target organ toxicity based on the reversibility of the ‘adverse’ effects demonstrated.

SCF 2003: Scientific Committee on Food, 2003. Opinion of the Scientific Committee on Food on the tolerable upper intake level of zinc (expressed on 5 March 2003). European Commission, Health and Consumer Protection Directorate-General, Directorate C - Scientific Opinions, C2 - Management of scientific committees; scientific co-operation and networks. [Accessed 2009 December 4]. Available from: https://ec.europa.eu/food/sites/food/files/safety/docs/sci-com_scf_out177_en.pdf

Read-across approach and conclusion are in line with the EU risk assessment carried out on the structurally similar substance Fatty acids, C16-18, zinc salts (i.e. zinc stearate) within the framework of EU Existing Chemicals Regulation 793/93 (EU RAR Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II–Human Health. EUR 21168 EN (http://echa.europa.eu/documents/10162/08799aec-42c5-44e0-9969-baa022c66db1):

“No data were provided on the repeated dose toxicity of zinc distearate. Data on other zinc compounds have been used, based on the assumption that after intake the biological activities of the zinc compounds are determined by the zinc cation.

Further testing is not required.

 

Please refer to the respective assessment entity section for data on the moieties zinc and fatty acids, C14 -18 and C16 -18 unsatd. In brief:

Zinc

From studies in which humans were supplemented with zinc (as zinc gluconate) it was concluded that women are more sensitive to the effects of high zinc intake and that a dose of 50 mg Zn/day is the human NOAEL. This corresponds to a daily exposure of 0.83 mg Zn/kg bw. At the LOAEL of 150 mg Zn/day, clinical signs and indications for disturbance of copper homeostasis have been observed. Studies conducted on animals are not discussed here, since information on human experience are considered of higher relevance for risk assessment purposes and should take precedence over animal studies.

Fatty acids, C164 -18 and C16 -18 unsatd.

Fatty acids, C14-18 and C16-18 unsatd., zinc salts is a mixture naturally occurring C14-18 saturated and C16-18 unsaturated fatty acids. They are naturally produced by a wide range of plants and organisms. They are naturally present in butter, cheese, milk and meat and some of them are common food additives or involved in essential biochemical processes. Thus, the following endpoint is covered by publicly available data on fatty acids with the same or similar structure.

According to a very recent ECHA report, non-branched aliphatic fatty acids (C5-C24) “are expected to be of low toxicity by their nature (similar to high purity fatty acids of natural origin which do not need to be registered as included in Annex V to REACH). […] From a human health perspective, substances in this group are considered to have a low systemic toxicity profile with no specific target organ toxicity or CMR properties. Some have irritant and/or corrosive properties that are reflected in the classification and labelling. Risk from these properties can be avoided by implementing risk management measures in supply chains based on the correct classification and labelling products. Therefore, there is no need for further action on the substances belonging to the group of aliphatic fatty acids non-branched (C5-C24)” (ECHA, 2020: Integrated Regulatory Strategy Annual Report May 2020).

In the UK and in several other countries, “the Department of Health have set dietary reference values for fatty acids and recommend that total fatty acid intake should average 30 % of total dietary energy including alcohol (DoH, 1991). The available data demonstrate the low toxicity of fatty acids and their salts, which is consistent with the long history of safe use in foods for both fatty acids and glycerides.

Several of the fatty acids are Generally Recognised as Safe (GRAS) by the U.S. Food and Drug Administration (US FDA). Substances that are listed as GRAS include: stearic acid; oleic acid and sodium palmitate. Stearic acid is also included by the Council of Europe (1974), at a level of 4000 ppm, in the list of artificial flavouring substances that may be added to foodstuffs without hazard to public health” (HERA, 2002 and references therein).

“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)” (HERA, 2002 and references therein).

 

Oral

“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)” (HERA, 2002 and references therein).

The results of various in vivo studies clearly demonstrate that fatty acids are not toxic via the oral route. “Fitzhugh et al. (1960) fed lauric acid (C12) to five male rats at the 10% level of their diet for 18 weeks. A control group of 5 males was fed concurrently. There were no observable clinical effects, no adverse effects on weight gain, nor was there any mortality. Gross organ pathology and comparison of individual organ weights showed no significant differences between the controls and test animals. In a 24-week oral study, rats were fed doses of 15% oleic acid (C18) (approximately 7.5 g/kg body weight per day). Normal growth and general good health was reported in the rats and the NOAEL was reported to be >7,500 mg/kg body weight per day (HERA, 2002 and references therein). Caprenin, a randomised triglyceride primarily comprising caprylic (C8), capric (C10), and behenic (C22) acids, was administered in a semi-purified diet to weanling Sprague-Dawley rats (25/sex/group) at dose levels of 5.23, 10.23 or 15.00% (w/w) for 91 days. Corn oil was added at 8.96, 5.91 and 3.00%, respectively, to provide essential fatty acids and digestible fat calories. Survival, clinical signs, body weight, feed consumption, feed efficiency, organ weights, organ-to-body-weight ratios, organ-to-brain-weight ratios, haematological values and clinical chemistry parameters were evaluated in all groups. Histopathology of a full complement of tissues was evaluated in the control group as well as the high-dose caprenin group. No significant differences in body weight gain were measured with the balanced caloric diets, although feed conversion efficiency was reduced in the high-dose caprenin group. No adverse effects from the ingestion of caprenin were detected. The authors concluded that the results establish a no-observable-adverse-effect level (NOAEL) of more than 15% (w/w) caprenin in the diet (or more than 83% of total dietary fat), which is equal to a mean exposure level of more than 13.2 g/kg/day for male rats and more than 14.6 g/kg/day for female rats (Webb et al. 1993)” (HERA, 2002 and references therein).

“Albino rats (10 animals of both sexes and mixed strain per group) were given a rice diet with 10% (equivalent to 9,000 mg/kg bw per day) capric-, lauric- or palmitic acid for a maximum of 150 days (Mori, 1953). Interim sacrifices were performed throughout the experiment and stomachs were examined for gross lesions. According to the author, no remarkable changes were detected in the forestomach or glandular stomach” (EFSA NDA Panel, 2017).

Overall, it was concluded by the EFSA NDA Panel “that there was no evidence for toxic effects of fatty acids in subchronic toxicity feeding studies at dose levels up to 10% in the diet (equivalent to 9,000 mg/kg bw per day).“

The available data demonstrate the low toxicity of fatty acids and their salts, which is consistent with their long history of safe use in foods and the fact that many of the fatty acids are listed as Generally Recognised as Safe (GRAS) by the U.S. Food and Drug Administration (US FDA).

 

Dermal

“In a subchronic study, no adverse effects were produced from topical application of myristic acid (C14) to rabbit skin. One-half ml of a 30% preparation of myristic acid in ether and propylene glycol (solvents at a 1:1 ratio in concentration) was massaged into the depilated skin of the flanks of 5 rabbits daily for 30 days. The opposite flank of the rabbits was depilated and treated with solvent only. No significant macroscopic changes were observed. Microscopic lesions included thinning of collagen fibres in the superficial layer of the dermis after 10 days and a loose dermal infiltrate of lymphomononuclear cells and histocytes after 20 and 30 days (CIR, 1987). A formulation “bath soap and detergent” containing 10-25% sodium stearate (C18) was used to conduct a dermal toxicity study in rabbits. Formulations at a dose of 2.0 g/kg were applied for 3 months to the skin by syringe daily, five days a week. No “untoward reactions” were observed (CIR, 1982)” (HERA, 2002 and references therein).

The available data demonstrate the low toxicity of fatty acids and their salts, which is consistent with their long history of safe use in foods and the fact that many of the fatty acids are listed as Generally Recognised as Safe (GRAS) by the U.S. Food and Drug Administration (US FDA).

Justification for classification or non-classification

In relevant and reliable repeated dose toxicity studies for the assessment entity zinc of fatty acids, C14 -18 and C16 -18 unsatd., zinc salts, and in peer-reviewed publicly available assessment reports for the assessment entity fatty acids, C14 -18 and C16 -18 unsatd., there were no toxicological findings reported that would justify a classification for specific target organ toxicity with repeated exposure. Hence, no classification for Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts as STOT, RE via the oral route is required.

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