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Carcinogenicity

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Description of key information

104 week dermal carcinogenicity study in mice using grease formulated with 7.5%  lithium 12-hydroxystearate, at 50 mg/application. No guideline specified. Lithium 12-hydroxystearate is a member of the lithium salts of C14-C22 fatty acids category. The NOAEL of the grease was 408 – 714 mg/kg bw/day, and 31 – 54 mg/kg bw day for the lithium 12-hydroxystearate.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP, non-guideline study. Only summary available, taken from a published regulatory review. Limitations in design and/or reporting but otherwise adequate for assessment.
Principles of method if other than guideline:
- Method: 50 mg lithium 12-hydroxystearate in a grease base was applied to the shorn interscapular region of male and female mice twice weekly for 104 weeks or until a horny lesion on the skin surface reached 1 mm3.
GLP compliance:
yes
Species:
mouse
Strain:
C3H
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Animal preparation: The interscapular region was shorn
- Age at test initation: 6-8 weeks
Route of administration:
dermal
Vehicle:
unchanged (no vehicle)
Details on exposure:
No data reported
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data reported
Duration of treatment / exposure:
- Duration of exposure: Twice weekly for 104 weeks or until a horny lesion on the skin surface reached 1 mm3.
Frequency of treatment:
- Frequency of application: Twice weekly for 104 weeks
Post exposure period:
No data reported
Remarks:
Doses / Concentrations:
50 mg/application
Basis:
nominal conc.
No. of animals per sex per dose:
- Number of animals: 100 animals per treatment group, positive control, vehicle control and untreated controls
- Number of animals per sex: 50 males, 50 females
Control animals:
yes, concurrent no treatment
yes, concurrent vehicle
Details on study design:
No data reported
Positive control:
- Positive control: 50 mg of 0.05% solution of BaP in toluene
Observations and examinations performed and frequency:
- Observations: Daily observations of clinical signs of toxicity were made throughout the study
Sacrifice and pathology:
- Observations: At test termination, post-mortem examinations were carried out on all animals that died or were killed during the study because they were moribund, or were sacrificed at test termination. During the post-mortem examination, the size and location of all skin neoplasms was recorded; chest, cranial and abdominal cavities were exmained; and the gross appearance of organs was noted.
- Microscopic examination: H&E sections of the skin and mammary glands, subcutaneous lymph nodes and tissues from each organ underwent microscopic examination.
Other examinations:
- Skin lesion observations: The appearance of skin lesions, and where appropriate their transition to an "advanced tumor" (rapid growth, invasion of surrounding tissue or ulceration and/or necrosis) were recorded. Treatment was continued till the end of the study if the tumor regressed, unless another tumor developed (the appearance of which was used to determine the average latency period).
Statistics:
No data reported
Details on results:
- Results: A malignant tumor was observed in one female and benign tumors in two males of the treatment group
- Control results: A malignant tumor was observed in one female and benign tumors in two females of the untreated control
- Conclusion: The was not considered to be a skin carcinogen in this study.
Relevance of carcinogenic effects / potential:
No data reported
Basis for effect level:
other: The review concluded that the grease (lithium 12-hydroxystearate at 7.5 % in a base oil) was not a skin carcinogen.
Conclusions:
In this study, it was concluded that grease containing 7.5 % lithium 12-hydroxystearate in base oil is not a skin carcinogen.
Executive summary:

In this study, it was concluded that grease containing 7.5 % lithium 12-hydroxystearate in base oil is not a skin carcinogen. The skin carcinogenicity of lithium 12 -hydroxystearate grease to mice is taken from regulatory review documents (US EPA 2011, API 2008) citing a proprietary test (Barkley and Stemmer). No guideline was stated but a standard procedure was used. Only a summary of the study is available, but as the results are taken from a regulatory document, the data are considered adequate for use for this endpoint.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
mouse
Quality of whole database:
Limited. The study is taken from a regulatory review documents (US EPA 2011, API 2008) citing a proprietary test. No guideline was stated but a standard procedure was used. Only a summary of the study is available, but as the results are taken from a regulatory document, the data are considered reliable and relevant for use for this endpoint.

Justification for classification or non-classification

Not classified for carcinogenicity. No treatment-related increase in tumour incidence.

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 carcinogenicity potential is expected to be similar across the category.

A supporting 104-week dermal carcinogenicity study on a lithium complex grease containing 7.5% lithium 12-hydroxystearate and other additives on mice is reported. 50 mg of the grease was applied to the backs of mice twice weekly. Using an average mouse weight of 20 – 35 g (Derelenko, 2008), the NOAEL of the grease was 2857 – 5000 mg/kg/week or 408 - 714 mg/kg bw/day. Correcting this for the lithium 12-hydroxystearate concentration, this gives a dose of 31 – 54 mg/kg bw/day for the lithium salt. This grease was not found to be a carcinogen under the conditions of the test. On the basis of long history of safe use of fatty acid soaps in greases, the substances in the category are not considered to be carcinogens.

Lithium or lithium salts have not been classified for carcinogenicity by the US EPA in humans or animals (University of Tennessee, 1997). Target organ toxicity from chronic human lithium treatment has been well documented, but with no reports of carcinogenicity mentioned (EFSA, 2010).

References

Derelenko (2008) The toxicologists' Pocket Handbook. 2nd Edition.

EFSA (2010). European Food Standards Agency. Technical Report: Selected trace and ultratrace elements: Biological role, content in feed and requirements in animal nutrition – Elements for risk assessment. http://www.efsa.europa.eu/en/supporting/doc/68e.pdf

University of Tennessee (1997). Risk Assessment Information System – Formal toxicity summary for Lithium.http://rais.ornl.gov/tox/profiles/lith.html


Justification for selection of carcinogenicity via dermal route endpoint:
Supporting study conducted on grease formulation containing 7.5% lithium 12-hydroxystearate and other additives.

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