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Description of key information

Dose responsive localized dermal effects at the test site (dorsal surface), consisting of scabbed post dose findings and elevated dermal scores. These findings were most pronounced at 1000 mg/kg bw/day and were seen most frequently at this dose level. The findings at 300 mg/kg bw/day were at a lower incidence and with lower dermal scores. Dermal scores and findings at 100 mg/kg bw/day were comparable to the controls.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
2 500 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
GLP-status not known, guideline not known, published in a regulatory document. Only a summary of the study is available, limitations in design and/or reporting but otherwise adequate for assessment.

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 adverse effect observed
Dose descriptor:
NOAEL
1 089.75 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
High

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
0.86 mg/cm²
Study duration:
subacute
Species:
rat
Quality of whole database:
High

Additional information

The substances in the category are considered to be similar on the basis that they have common structures of a calcium ion varying only by the length of the fatty acid chain and the presence of unsaturated and/or hydroxyl functional groups. As a result it is expected that the substances will have similar, predictable properties. 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 metal fatty acid substances in the category are therefore not expected to be hazardous. Due to the close structural similarity and the narrow range of carbon chain numbers covered in this category, the repeated dose toxicity properties are expected to be predictable across the category.

Since REACH Annex V groups together calcium, potassium, sodium and magnesium salts of C6 to C24 fatty acids as being potentially exempt from registration, these metal cations are therefore not considered to contribute to any health hazard. On this basis, relevant published or proprietary data on any potassium, sodium or magnesium salt within the fatty acid category range of C14 to C22 can be used to read across to the calcium salts of C14-C22 fatty acid category.

Lithium salts of fatty acids are not included in REACH Annex V as being potentially exempt from registration. For these salts it is expected that the lithium cation would be the species with the potentially higher toxicity profile when compared to calcium, potassium, sodium, and magnesium cations. However, the substance fatty acids C18 (unsaturated) lithium salts contains a fatty acid anion that falls within the C14-C22 category. Experimental data for the mammalian toxicity Annex VIII endpoints have been generated on this substance and the results obtained are relevant for read across to the calcium salts of C14-C22 fatty acids either in a weight of evidence approach or as key studies due to the structural similarity and its position within the category fatty acid range. This is clearly relevant when the results from the lithium fatty acid salts are negative.

The fatty acid salts in the category will ionise into the metal cations and fatty acid anions. It is generally considered that simple metal salts of fatty acids have the same hazard profile as the parent acid, with the exception of any potential local effects such as irritation/corrosivity. Since the acids are either naturally derived or equivalent to natural substances, the hazard profile of such substances is well-documented.Fatty acids are an endogenous part of every living cell and are an essential dietary requirement. They are absorbed, digested and transported in animals and humans. When taken up by tissues they can either be stored as triglycerides or can be oxidised via the mitochondrial ß-oxidation and tricarboxylic acid pathways. The ß-oxidation uses an enzyme complex for a series of oxidation and hydration reactions, resulting in a cleavage of acetate groups as acetyl CoA. The metabolic products can then be incorporated for example into membrane phospholipids. Long chain saturated fatty acids are less readily absorbed than unsaturated or short chain acids. Several investigators have found that increasing fatty acid chain length decreased their digestibility (see also Toxicokinetic section).

The UK Department of Health has 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). This equates to about 100 g of fatty acids per day or 1.7 g/kg bw/day (HERA 2002). Several of the fatty acids or salts are Generally Recognised as Safe by the US FDA. These include stearic acid, oleic acid and sodium palmitate. In 1974, the WHO set an unlimited Acceptable Daily Intake for the salts of myristic (C14), palmitic (C16) and stearic (C18) acids. It was 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 that 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).

Due to the widespread use of fatty acids and their simple metal salts in cosmetic/toiletry products and greases, many reviews on their safety have been published by e.g. API (2008), HERA (2002), CIR (1982, 1987). In addition a number of repeated dose toxicity studies have been conducted by the oral or dermal routes on substances relevant to the category, either as individual substances or as part of a grease formulation. The results of these studies by the dermal route show a variation in the NOAELs obtained which may have been related to the fact that the thickener was only a part of the total formulation applied, and the oil base and other additives may have influenced the tolerance of the animals to the test material, particularly on the skin. The key dermal study on fatty acids C18 (unsaturated) lithium salts – see below- were conducted on the isolated substance and provide the key NOAELs. It should be noted that skin irritation is minimal on short term exposure, but is more significant following repeated dose exposure.

Fatty acid containing oils are frequently used as vehicles in animal toxicity studies (e.g. corn oil) due to their innocuous nature and are routinely administered at volumes up to 10 mL/kg bw. These experimental data, together with the published information, are used to support the low hazard profile of the substances in the category.

Castor oil (C18 hydroxylated, unsaturated) can be considered representative of the fatty acid moieties within the C14-C22 category. Although it is a fatty acid triglyceride, it will first be hydrolysed into fatty acids and glycerol by pancreatic lipases secreted into the G.I. tract, then absorbed systemically and the fatty acids metabolised via mitochondrial ß-oxidation and tricarboxylic acid pathways. A 90-day feeding study in rats and mice on castor oil has been reported (NTP 1992). Diets containing up to 10% castor oil were provided to 5 groups of 10 males and 10 females, with a control group receiving untreated diet. The 10% concentration equated to ca. 5.8 g/kg bw/day for rats and ca. 15 g/kg bw/day for mice. Survival and bodyweight gains were not affected; neither were haematological parameters. Mild increases in total bile acids and serum alkaline phosphatase were noted in rats receiving the higher dietary concentrations. Liver weights were increased in male rats receiving 10%, and in male and female mice receiving 5 or 10%. The liver weight increases were considered as adaptive changes in response to the presence of xenobiotics as no histopathological changes were seen in association with these liver changes. There were no other compound-related morphological changes in any organ. No significant changes were noted in a screening for male reproductive endpoints, including sperm count and motility, and no changes were observed in the length of oestrous cycles of rats or mice given diets containing the castor oil. Thus, no significant adverse effects of castor oil administration were noted in these studies, with a NOAEL level of 10% in the diet (ca. 5.8 g/kg bw/day for rats and ca. 15 g/kg bw/day for mice).

Magnesium stearate (a C18 saturated fatty acid) was subjected to a 3-month dietary toxicity study in Wistar rats, with nominal concentrations of 5, 10 and 20% in the diet fed to groups of 20 males and 20 females. There was a reduction in weight gain during the first part of the study in males receiving 20% and slow and unsteady movements were seen concomitantly in these animals. Four males receiving 10% died within 2 months and stones were found in the lower urinary tract. No clinical effects were seen in females. At termination, changes were found in the renal pelvis and lower urinary tract in four males and one female receiving 20%. It was concluded by the authors that the high magnesium content of the diet has previously been associated with a greater incidence of lower urinary tract stone formation. When liver weight was used as a measure of adverse effect the NOAEL was estimated to be 5% magnesium stearate in the diet, corresponding to 2500 mg/kg bw/day.

A key 28-day toxicity and reproductive toxicity screen via dermal administration, using the OECD 422 study design, was conducted in rats on a fatty acid salt with a cation not within the category - fatty acids C18 (unsaturated) lithium salts. The test material was administered at dose levels of 0, 100, 300 and 1000 mg/kg bw/day nominal, equating to 111.25, 345 and 1089.75 mg/kg bw/day by analysis, and doses were based on local dermal effects from a dose range finding study. There was a 2-week post-dose observation period for satellite high dose level and control groups. No systemic toxicity directly related to the administration of the substance was observed, although dose-related local effects were seen in the skin of treated animals in the 300 and 1000 mg/kg bw/day groups. Since the highest dose of 1089.75 mg/kg bw/day was essentially equivalent to a ‘limit dose’ and was considered to be the systemic NOAEL, this lithium fatty acid salt is not considered to be systemically hazardous. A local NOAEL of 111.25 mg/kg bw/day was determined due to dermal changes seen at higher concentrations. This study is considered relevant to read across to the calcium fatty acid salts in the category as it is a representative fatty acid and the results demonstrate a lack of systemic toxicity despite an alternative cation (which in itself could be considered to be potentially more hazardous than the calcium metal cation in the category).

The calcium cation in the category is biologically relevant and necessary for normal cellular function. There is a wide margin of safety for this cation, although when present in significant excess it will have a specific known hazard profile. Nevertheless, it must also be considered that Annex V of REACH exempts calcium fatty acid metal salts from registration under specific conditions and therefore, by extrapolation, they represent a known and controllable hazard. Since the hazards identified in the experimental and published data on relevant substances are low and below the threshold for classification, there is no requirement to conduct a human risk assessment. On this basis a systemic DNEL for the substances in this category is not relevant and has not been calculated.

On the basis of the category justification for the C14 to C22 fatty acid calcium salts, the supporting data on magnesium stearate, and the lack of systemic toxicity when C18 (unsaturated) lithium salts was administered to rats for 28 days, no classification for specific target organ toxicity is required.  

Taking all the above available information into account, including the Annex V exemption considerations and the opinions of various authorities (UK DoH, WHO, JECFA), there is no scientific justification for conducting any further repeated dose toxicity studies on a member of the category since this will not provide any further information that is not already available. Thus the Annex IX requirement for a subchronic study is waived in accordance with Annex XI.

References

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

DoH (Department of Health ) (1991) Dietary reference values for food energy and nutrients for the United Kingdom: report of the panel on dietary reference values of the committee on medical aspects of food policy.Report on health and social subjects 41. London: HMSO. 1991

HERA (2002) Human and Environmental Risk Assessment on ingredients of European Household Cleaning Products. Fatty Acid Salts Human Risk Assessment, June 2002.

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

NTP (1992) NTP Technical Report on the Toxicity Studies of Castor Oil in F344/N rats and B6C3F1Mice. NIH Publication No. 92-3131

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


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Relevant study on a substance representative of the calcium salts of C14-C22 fatty acid

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
The data from this lithium fatty acid salt can be used to read across to members of the calcium C14-C22 fatty acid salts category

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
The data from this lithium fatty acid salt can be used to read across to members of the calcium C14-C22 fatty acid salts category

Justification for classification or non-classification

Based on the available information, classification with respect to systemic repeated Specific Target Organ Toxicity is not justified. No toxicologically significant systemic adverse effects were observed in repeated dose toxicity study on a number of relevant fatty acids salts.

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