Fatty acids, C16-22, lithium salts

Endpoint summary

Description of key information

In vitro studies on dermal irritation have been conducted on C14, C16, and C18 fatty acid lithium salts. No irritant responses leading to classification were observed.
In vitro and in vivo studies on ocular irritation were conducted on C14, C16 and C18 fatty acid lithium salts. No classifiable irritant responses were observed for C16 and C18 fatty acid lithium salts, but irritation was seen for C14 (lithium myristate). This result was not read across to the category since the C16 and C18 results were negative.

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The substances in the category are considered to be similar on the basis that they have common structures of a lithium ion varying only by the length of the fatty acid chain and the presence of unsaturated and/or hydroxyl functional groups. REACH Annex V, Entry 9, groups fatty acids and their potassium, sodium, calcium and magnesium salts, including C6 to C24, predominantly even-numbered, unbranched, saturated or unsaturated aliphatic monocarboxylic acids. Provided that they are obtained from natural sources and are not chemically modified, the substances included in REACH Annex V, Entry 9 are exempt from registration, unless they are classified as dangerous (except for flammability, skin irritation or eye irritation) or they meet the criteria for PBT/vPvB substances. The fatty acid components of the category members are therefore not expected to be hazardous. As all category members are lithium salts, any toxicity is expected to be driven by the lithium ion. Due to the close structural similarity and the narrow range of carbon chain numbers covered in this category, irritation potential is expected to be similar or show a predictable trend across the category.

Although fatty acids C18 (unsaturated) lithium salts is not in the list of substances being registered, this substance falls within the definition of the lithium salts of fatty acids C14-C22 category (see Appendix 1 – Category Justification Document) by virtue of its chemical structure and therefore read across from data on fatty acids C18 (unsaturated) lithium salts to other members of the category is considered to be justified (see below).

Published reviews consider that the irritant/corrosivity properties of fatty acids are chain length dependent, where the lower carbon chain lengths, < C9 are corrosive, C10 – C12 are irritant, and chain lengths from C14 are not irritating (HERA 2002, referencing Briggs et al, 1976 and CIR, 1987).

Key in vitro skin irritation studies on lithium myristate (C14) and Fatty acids C18 (unsaturated) lithium salts gave negative results. Since under REACH, in vitro studies are sufficient for compliance with Annexes VII and VIII, no key in vivo study(ies) has been conducted. A number of in vivo supporting studies in rabbits for skin irritation using greases formulated with lithium 12-hydroxystearate have been conducted. However, since these were performed several decades previously on formulated greases containing other (unknown) performance additives, the results from the in vitro skin irritation tests on isolated C14 and C18 fatty acid lithium salts are considered to be more relevant and indicative of no classification for this endpoint.

Lithium palmitate (C16), and Fatty acids C18 (unsaturated) lithium salts were subjected to in vitro eye irritation studies using the isolated rabbit eye or reconstituted human corneal epithelium models, and in vivo eye irritation studies in rabbits according to OECD 405 (key studies). For both substances, no classifiable irritation was observed. Several supporting studies where grease containing approximately 5 to 13% lithium 12-hydroxystearate was tested in rabbit eyes are reported and where the test materials were found to be ‘not irritating’.

One reliable study (Klimisch 1) is referenced in the API Robust Summary document (2008) where lithium complex grease (containing 13.1% lithium 12-hydroxystearate and 2.6% dilithium azelate) was applied to the right eye of six rabbits. This was reported as non-irritant in the API hazard summary. The Cosmetic Ingredient Review Panel (CIR 1982) concludes that certain metal stearates (Mg, Na, Zn) were non-irritant to rabbit eye. No quality review of the data was reported and the data were either unpublished proprietary studies or from literature publications before 1960.

Lithium myristate (C14) was also tested in an OECD 405 rabbit eye irritation study. The results from this study showed ocular irritation, reversible within the 14-day observation period. Since both C16 and C18 fatty acid lithium salts gave negative results in the ocular irritation tests, the positive irritant response from lithium myristate (C14) was further reviewed. The initial substance for testing was prepared by reacting lithium hydroxide with myristic acid and washing the reaction product with isopropyl alcohol. Following substance analysis, the presence of small concentrations of residual lithium hydroxide (a strong ocular irritant) could not be excluded, and the aqueous pH (10% preparation) taken before and after the rabbit eye irritation study showed values of 10.1 drifting to 11.1 after 20 minutes. A new sample of lithium myristate was prepared, taking care to remove residual lithium hydroxide using water to wash the final product. The pH of a 10% preparation of this sample was ca 9.5 (and pH ca 8 from a sample moistened with water). Because of the modification of the synthesis, elemental analysis, and the consequent lower pH values (indicating little or no residual lithium hydroxide), it was considered appropriate to subject this sample to repeat in vitro and in vivo eye irritation studies. However, the results obtained were very similar to those from the first sample and consequently lithium myristate is considered to be classified as an ocular irritant.

The irritant/corrosivity properties of free fatty acids are chain length dependent, where the lower carbon chain length < C9 are corrosive, C10 – C12 are irritant and C14 above are non-irritant. No ocular irritation was observed in the studies with C16 and C18 lithium salts. It is therefore concluded that the positive eye irritation results obtained with lithium myristate (C14) represents a worst case and are not indicative of a category response for the longer chain length substances. The positive results are not read across to the other category members which are considered not to be eye irritants. 

References

API (American Petroleum Institute) (2008) Robust Summary of Information on Grease Thickeners (Creation date: October 11, 2003. Printing date: February 20, 2009. Last update: October 20, 2008. Document date: January 11, 2005)

Briggs GB, Doyle RL, Young JA (1976) Safety studies on a series of fatty acids. American Industrial Hygiene Association Journal, vol. 37, pp. 251-252

CIR (Cosmetics Ingredients Review) (1982). Final report of the safety assessment of lithium stearate, aluminum distearate, aluminum stearate, aluminum tristearate, ammonium stearate, calcium stearate, magnesium stearate, potassium stearate, sodium stearate and zinc stearate. Journal of the American college of toxicologists, vol. 1, issue 12, pp. 143-177.

CIR (Cosmetics Ingredients Review) (1987) Final report on the safety assessment of oleic acid, lauric acid, palmitic acid, myristic acid and stearic acid. Journal of American Toxicologists, vol. 6, issue 3, pp. 321-401

HERA (Human Health and Environmental Risk Assessment on ingredients of European household cleaning products) (2002) Fatty Acid Salts (Soap) Environmental and Human Health Risk Assessment

Justification for selection of skin irritation / corrosion endpoint:
This substance is representative of the lithium salts of C14 - C22 fatty acids and can be read across to other category members

Justification for selection of eye irritation endpoint:
This substance is representative of the lithium salts of C14 - C22 fatty acids and can be read across to other category members with the exception of lithium myristate (C14).

Justification for classification or non-classification

Skin irritation: Not classified. All studies were negative.

Eye irritation: C16 -C22 fatty acid lithium salts not classified (studies were negative). C14 fatty acid lithium salts classified as eye irritant category 2.