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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
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:
reliable, relevant and adequate.
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 reproduction 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 to 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.

As fully reviewed in the Repeated Dose Toxicity section above, the long history of safe use of these fatty acids, their triglycerides and food oils, as well as the GRAS status for several of the fatty acids and their salts indicate the low potential for reproductive toxicity of these substances. There have been some limited published reviews of fatty acid salt reproductive toxicity, particularly in HERA (2002), and CIR (1982). A three-generation study in rats with 8.6% crude Cuphea oil (76% capric acid – C10), although outside the category, provided no evidence of reproductive effects.

 

A key toxicity and reproductive toxicity screen, using the OECD 422 study design, was conducted in rats on fatty acids C18 (unsaturated) lithium salts via dermal administration. Although the category does not contain fatty acid salts with the lithium cation, it is considered relevant to read the data across to the calcium C14-C22 fatty acid category since the only difference is the metal cation, and in any case, the lithium ion could be expected to demonstrate a higher hazard profile than calcium (see above). 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 were no treatment-related effects at any dose level on any of the reproductive parameters evaluated in this study or in any of the developmental parameters evaluated. Based on these data, the NOAEL for reproductive and developmental toxicity was 1089.75 mg/kg bw/day.

 

Overall, on the basis of the category justification for the C14 to C22 fatty acid calcium salts, the biological requirements for the relevant metal cations and fatty acid anions, the long history of safe exposure to such materials and the lack of reproductive toxicity when C18 (unsaturated) lithium salts was administered to rats, it can be concluded that none of the substances in the category are considered to be reproductive toxicants. No classification for this endpoint is required.

Annex IX requires the consideration of a two-generation general fertility and reproductive toxicity study if a 28-day study indicates adverse effects on reproductive organs or tissues (REACH 8.7.2, Column 1). Since no effects on the male or female reproductive system were seen in the key OECD 422 study on a relevant lithium fatty acid salt (fatty acids C18 (unsaturated) lithium salts) or as a reported side effect from other metal fatty acid salts in the published literature, the conduct of a two-generation reproductive study has been waived (under REACH Annex XI – Testing does not appear to be scientifically necessary, section 1.2 Weight of evidence).

References

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.

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


Short description of key information:
A dermal reprotoxicity screening study in rats conducted according to OECD 422 in which no adverse effect was seen in any of the reproductive parameters examined at any dose.

Justification for selection of Effect on fertility via dermal route:
This substance is a representative fatty acid salt that can be read across to the calcium salts of C14-C22 fatty acids category

Effects on developmental toxicity

Description of key information
A dermal reprotoxicity screening study in rats conducted according to OECD 422 in which no adverse effect was seen in any of the reproductive parameters examined at any dose.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
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:
reliable, relevant and adequate.
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 developmental 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 to 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.

As fully reviewed in the Repeated Dose Toxicity section above, the long history of safe use of these fatty acids, their triglycerides and food oils, as well as the GRAS status for several of the fatty acids and their salts indicate a low potential for developmental toxicity of these substances. There have been some limited published reviews of fatty acid salt reproductive toxicity, particularly in HERA (2002), and CIR (1982). It was concluded that available data do not provide evidence of significant developmental toxicity. The developmental toxicity study on a delayed-release vehicle containing magnesium stearate used to coat pharmaceutical tablets, at a single dose of 2.5 mg/kg bw post coitus, showed an absence of a treatment-related teratogenic effect.

A key toxicity and reproductive toxicity screen, using the OECD 422 study design, was conducted in rats on fatty acids C18 (unsaturated) lithium salts via dermal administration. Although the category does not contain fatty acid salts with the lithium cation, it is considered relevant to read the data across to the calcium C14-C22 fatty acid category since the only difference is the metal cation, and in any case, the lithium ion could be expected to demonstrate a higher hazard profile than calcium, magnesium, sodium or potassium (see above) 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 were no treatment-related effects at any dose level on any of the reproductive parameters evaluated in this study or in any of the developmental parameters evaluated. Based on these data, the NOAEL for reproductive and developmental toxicity was 1089.75 mg/kg bw/day.

 

Overall, on the basis of the category justification for the C14 to C22 fatty acid calcium salts, the biological requirements for the relevant metal cations and fatty acid anions, the long history of safe exposure to such materials and the lack of reproductive and developmental toxicity when C18 (unsaturated) lithium salts was administered to rats, it can be concluded that none of the substances in the category are considered to be developmental toxicants. No classification for these endpoints is required.

Annex IX requires the consideration of a prenatal developmental toxicity study. From the long history of safe use of these substances and their potential exemption from registration under Annex V, there is no justification for the conduct of a prenatal developmental toxicity study on a member of the category and this endpoint has been waived (under REACH Annex XI – Testing does not appear to be scientifically necessary, section 1.2 Weight of evidence).

References

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.

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


Justification for selection of Effect on developmental toxicity: via dermal route:
This substance is a representative fatty acid salt that can be read across to the calcium salts of C14-C22 fatty acids category

Justification for classification or non-classification

Not classified. No adverse reproductive or developmental toxicity effects observed.

Additional information

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