Fatty acids, C16-22, lithium salts

Endpoint summary

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:

Guideline study conducted to GLP.

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. 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 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, the reproductive toxicity is expected to be similar 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).

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. The test material was administered at dose levels of 0, 100, 300 and 1000 mg/kg/day nominal, equating to 111.25, 345 and 1089.75 mg/kg/day by analysis, and 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/day.

Overall, on the basis of the category justification for the C14 to C22 fatty acid lithium salts, and supporting evidence, the lack of reproductive and developmental toxicity when C18 (unsaturated) lithium salts was administered to rats can be read across to other members of the category, and no classification for this endpoint is required.

The consideration concerning the margin of safety between the human therapeutic dose and the NOAELs found in the relevant studies is presented in the Repeated Dose Toxicity section above. The same proposals regarding the use of the human data for DNEL derivation are applicable for the developmental toxicity endpoint.

Annex IX requires the consideration of a two-generation general fertility and reproductive toxicity study if the subacute toxicity study indicates adverse effects on reproductive organs or tissues. Since no such effects on the male or female reproductive system were seen in the key OECD 422 study on the representative lithium fatty acid salt (fatty acids C18 (unsaturated) lithium salts), the conduct of a two-generation reproductive study has been waived.

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 screening study provides relevant experimental data on this endpoint. The tested substance is representative of the lithium salts of C14-C22 fatty acids and can be read across to other category members.

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/developmental 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:

Guideline study conducted to GLP.

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. 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 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, the developmental toxicity is expected to be similar 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).

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. The test material was administered at dose levels of 0, 100, 300 and 1000 mg/kg/day nominal, equating to 111.25, 345 and 1089.75 mg/kg/day by analysis, and 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/day.

A supporting dermal developmental toxicity study in rats using a grease containing ca 8% lithium 12-hydroxystearate in base oil, together with other additives, is reported. This showed no adverse reproductive or developmental effects. The NOAEL (developmental) was 2000 mg/kg bw/day, and the NOAEL (maternal) was 500 mg/kg bw/day of the grease (160 and 40 mg/kg bw/day of lithium 12-hydroxystearate respectively).

Overall, on the basis of the category justification for the C14 to C22 fatty acid lithium salts, the lack of developmental toxicity when C18 (unsaturated) lithium salts and grease containing lithium 12-hydroxystearate were administered to rats can be read across to other members of the category, and no classification for this endpoint is required.

The consideration concerning the margin of safety between the human therapeutic dose and the NOAELs found in the relevant studies is presented in the Repeated Dose Toxicity section above. The same proposals regarding the use of the human data for DNEL derivation are applicable for the developmental toxicity endpoint.

The use of lithium in bipolar disorder has been reviewed by Horton et al (2012). This disease is more prevalent in women and is often concurrent with peak reproductive age. This review considers a therapeutic regimen based on PBPK modelling, simulating the concentration of lithium in the organs and tissues of a pregnant woman and her foetus. In the USA, lithium has been classified as a Class D drug (legal to use during pregnancy, but may cause birth defects). The maximum dosage regimen suggested by the modelling based on avoidance of any adverse developmental sequelae was 400 mg lithium carbonate, three times per day (1200 mg/day). This is slightly higher than the lithium carbonate treatment levels of 450 – 900 mg/day referred to in the Repeated dose toxicity discussion, section 5.6.3. Therefore, this paper presents further evidence, based on PBPK modelling, that the use of human therapeutic data is a valid approach for consideration of a human NOAEL and DNEL based on serum concentrations during long-term therapy.

As indicated in the first paragraph of this section and in the Category Justification Document, the fatty acid anions are not considered to be hazardous under anticipated exposure conditions, and under certain conditions would be exempt from registration. Any hazard would be expected to be driven by the lithium cation. On this basis, prenatal developmental toxicity data generated on a soluble inorganic lithium salt would be appropriate to read across to the lithium fatty acid salts in the C14-C22 category. It is known that a proprietary prenatal developmental toxicity study according to OECD Guideline 414 has been conducted by the registrant(s) of lithium carbonate, and used for the REACH registration of this substance. This study is considered relevant to fulfil the developmental toxicity endpoint for the lithium fatty acid salts for the reasons described above. Since this information is not in the public domain and therefore not available to the lithium fatty acid salts registrants, it is proposed that post-registration access to the Robust Study Summary is negotiated with the data owner.

Reference

Horton, S., et al (2012). Maximum recommended dosage of lithium for pregnant women based on a PBPK model for lithium absorption. Advances in Bioinformatics, vol. 2012, pp 1 - 9

Justification for selection of Effect on developmental toxicity: via dermal route:
This study provides relevant experimental data on this endpoint. The tested substance is representative of the lithium salts of C14-C22 fatty acids and can be read across to other category members.

Justification for classification or non-classification

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