Registration Dossier

Administrative data

Description of key information

It is considered from the results that all the substances in the category of lithium salts of C14-C22 monocarboxylic acids exhibit a similar lack of acute oral and dermal toxicity potential across the entire category. There is no evidence of a relevant intrinsic acute oral or dermal toxicity requiring classification or substance specific RMMs. An estimate of the inhalative dust/mist toxicity by route-to-route extrapolation result in an ATE well above the cut-off values for classification for acute inhalation toxicity hazard.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
6 December 2012 to 3 January 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-compliant, guideline study, available as an unpublished report.
Qualifier:
according to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
- Source: Harlan laboratories UK Ltd., Oxon, UK. Animals were 8 to 12 weeks old and nulliparous and non-pregnant.
- Acclimatisation: On receipt, animals were randomly assigned to cages. After at least 5 days acclimatisation, animals were selected at random and marked with a unique identifier for the test in indelible ink.
- Housing: Animals were housed in groups of four in suspended solid-floor polypropylene cages furnished with woodflakes. With the exception of an overnight fast immediately before doing and for approximately 3 to 4 hours after dosing, the animals had free access to mains drinking water and food.
- Environmental conditions: Temperature and relative humidity were set to achieve limits of 19 to 25 deg C, and 30 to 70% humidity. Rate of air exchange was at least 15 changes per hour and the lighting controlled by a time switch to give 12 hours light/12 hours darkness. Animals were provided with enrichment items.
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
- Preparation: The lithium myristate did not dissolve or suspend in distilled water, it was freshly prepared as a suspension in arachis oil BP and applied to the test system within 2 hours of formulation. As an exception with regard to GLP, the homogeneity, concentration or stability or the formulation were not analysed but it was assumed that the formulation was stable for the duration until use.
- Dosing: Animals were dosed once only by gavage with 10 mL/kg dose volumes using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to the fasted body weight at the time of dosing.
Doses:
In the absence of data regarding the toxicity of lithium myristate, a preliminary study with a single animal was conducted at 300 mg/kg bw. As no effects were observed, an additional animal was treated at 2000 mg/kg bw. In the absence of evident toxicity at a dose level of 2000 mg/kg bw, four additional animals were dosed sequentially at this dose level.
No. of animals per sex per dose:
Five female rats were treated at a single dose concentration.
Control animals:
no
Details on study design:
- Observations: Clinical observations were made at 30 mins, 1, 2 and 4 hours after dosing, then daily for 14 days. Morbidity and mortality checks were made twice daily and individual body weights were recorded on days 0, 7 and 14. At the end of the exposure, animals were killed by cervical dislocation and subject to gross necropsy by external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded but no tissues were retained.
Statistics:
Evaluation of data included identification of the number of animals which died or were killed for humane reasons and the determination of the nature, severity, onset and duration of the toxic effects. The mortality data obtained were used to estimate the acute oral median lethal dose.
Preliminary study:
In the preliminary study at 300 mg/kg bw with a single animal, there was no death and no signs of systemic toxicity during the observation period and at test termination, no abnormalities were noted at necroscopy. The animal showed the expected gains in bodyweight over the observation period.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
During the definitive study, there were no deaths.
Clinical signs:
at 2000 mg/kg bw/day the initial treated animal showed diarrhoea two hours after dosing but there were no signs of systemic toxicity noted in the remaining animals.
Body weight:
Animals showed expected bodyweight gains over the observation period, except for one animal which showed expected gain in bodyweight during the first week but no gain in the bodyweight during the second week.
Gross pathology:
During necropsy, hydrophrosis was noted of two animals. No abnormalities were noted at necropsy of the remaining animals.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral median lethal dose (LD50) of lithium myristate in the female Wistar strain rat was estimated to be greater than 2000 mg/kg bodyweight and therefore, lithium myristate is considered not to meet the criteria for classification under the CLP Regulation.
Executive summary:

The acute oral toxicity of lithium myristate to female Wistar rats was determined in a GLP-compliant, fixed-dose method study following OECD guideline 420. Five rats were treated once with 2000 mg/kg bw lithium myristate by oral gavage and observed for the following 14 days for mortality, systemic toxicity and bodyweight gain. No deaths or significant signs of toxicity were seen. The LD50 value is > 2000 mg/kg bw/day. The study is considered to be relevant and reliable for use for this endpoint.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
High. Reliable, adequate and relevant data available to fulfill the tonnage-driven data requirements of REACH. Tested substance is representative of the lithium salts of C14-C22 fatty acids category and can be read across to other category members

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
The study was performed between 12 May 2010 and 26 May 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Five male and five female Wistar (HsdRccHan:WIST) strain rats were supplied by Harlan Laboratories U.K. Ltd., Oxon, UK. On receipt the animals were randomly allocated to cages. The females were nulliparous and non pregnant. After an acclimatisation period of at least five days the animals were selected at random and given a number unique within the study by indelible ink-marking on the tail and a number written on a cage card. At the start of the study the animals weighed at least 200g, and were eight to twelve weeks of age. The weight variation did not exceed ± 20% of the mean weight for each sex.
The animals were housed in suspended solid floor polypropylene cages furnished with woodflakes. The animals were housed individually during the 24-hour exposure period and in groups of five, by sex, for the remainder of the study. Free access to mains drinking water and food (2014 Teklad Global Rodent diet supplied by Harlan Laboratories U.K. Ltd., Oxon, UK) was allowed throughout the study. The diet, drinking water and bedding were routinely analysed and were considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study.
The temperature and relative humidity were set to achieve limits of 19 to 25°C and 30 to 70% respectively. Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.

The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
On the day before treatment the back and flanks of each animal were clipped free of hair.
Using available information on the toxicity of the test material, a group of five male and five female rats was treated with the test material at a dose level of 2000 mg/kg bw.
The appropriate amount of test material, moistened with distilled water, was applied as evenly as possible to an area of shorn skin (approximately 10% of the total body surface area). A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self adhesive bandage. The animals were caged individually for the 24 hour exposure period. Shortly after dosing the dressings were examined to ensure that they
were securely in place.
Duration of exposure:
24 hours
Doses:
2000 mg /kg body weight
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
After the 24-hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with distilled water to remove any residual test material. The animals were returned to group housing for the remainder of the study period.
The animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days.
After removal of the dressings and subsequently once daily for fourteen days, the test sites were examined for evidence of primary irritation and scored according to the following scale from Draize J H (1977) "Dermal and Eye Toxicity Tests" In: Principles and Procedures for Evaluating the Toxicity of Household Substances, National Academy of Sciences, Washington DC p.31:

EVALUATION OF SKIN REACTIONS
Erythema and Eschar Formation Value
No erythema 0
Very slight erythema (barely perceptible) 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beef redness) to slight eschar formation (injuries in depth) 4
Oedema Formation
No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well-defined by definite raising) 2
Moderate oedema (raised approximately 1 millimetre) 3
Severe oedema (raised more than 1 millimetre and extending beyond the area of exposure) 4

Any other skin reactions, if present were also recorded.

Individual bodyweights were recorded prior to application of the test material on Day 0 and on Days 7 and 14.

At the end of the study the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.



Statistics:
No statistical analysis was performed.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 95% confidence limits not reported
Mortality:
No deaths occurred during the study.


Clinical signs:
No clinical signs were observed during the course of the study.
Body weight:
All animals showed expected gains in bodyweight over the study period.
Gross pathology:
No macroscopic findings were recorded at necropsy.
Other findings:
Individual dermal reactions are given in Table 2 and Table 3 in overall remarks section.
Well-defined erythema and very slight oedema were noted at the test site of one animal one day after dosing with very slight erythema noted two days after dosing. There were no signs of dermal irritation noted in the remaining animals.

Table 1              Individual Clinical Observations and Mortality Data

Dose Level

mg/kg

Animal Number and Sex

Effects Noted After Initiation of Exposure (Hours)

Effects Noted After Initiation of Exposure (Days)

½

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

1-0

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-1

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-2

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-3

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-4

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-1

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-2

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-3

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-4

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0


0 = No signs of systemic toxicity

See Overall remarks for Dermal Reactions Tables 2 and 3.

Table 4              Individual Bodyweights and Weekly Bodyweight Changes

Dose Level mg/kg

Animal Number and Sex

Bodyweight (g) at Day

Bodyweight Change (g) During Week

0

7

14

1

2

2000

1-0 Male

229

247

278

18

31

1-1 Male

241

262

293

21

31

1-2 Male

244

271

291

27

20

1-3 Male

236

259

293

23

34

1-4 Male

231

255

294

24

39

2-0 Female

208

212

223

4

11

2-1 Female

210

219

228

9

9

2-2 Female

200

201

219

1

1 8

2-3 Female

202

206

209

4

3

2-4 Female

201

209

218

8

9

Table 5              Individual Necropsy Findings

Dose Level

mg/kg

Animal Number
and Sex

Time of Death

Macroscopic Observations

2000

1-0

Male

Killed Day 14

No abnormalities detected

1-1

Male

Killed Day 14

No abnormalities detected

1-2

Male

Killed Day 14

No abnormalities detected

1-3

Male

Killed Day 14

No abnormalities detected

1-4

Male

Killed Day 14

No abnormalities detected

2-0

Female

Killed Day 14

No abnormalities detected

2-1

Female

Killed Day 14

No abnormalities detected

2-2

Female

Killed Day 14

No abnormalities detected

2-3

Female

Killed Day 14

No abnormalities detected

2-4

Female

Killed Day 14

No abnormalities detected

Interpretation of results:
practically nontoxic
Remarks:
Migrated information
Conclusions:
The acute dermal median lethal dose (LD50) of the test material in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.
s
Executive summary:
Introduction. The study was performed to assess the acute dermal toxicity of the test material in the Wistar strain rat. The method was designed to meet the requirements of the following:

OECD Guidelines for the Testing of Chemicals No. 402 “Acute Dermal Toxicity” (adopted 24 February 1987)

Method B3 Acute Toxicity (Dermal) of Commission Regulation (EC) No. 440/2008

Method. A group of ten animals (five males and five females) was given a single, 24 hour, semi occluded dermal application of the test material to intact skin at a dose level of 2000 mg/kg bodyweight. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality. There were no deaths.

Clinical Observations. There were no signs of systemic toxicity.

Dermal Irritation. Well-defined erythema and very slight oedema were noted at the test site of one animal. There were no signs of dermal irritation noted in the remaining animals.

Bodyweight. All animals showed expected gains in bodyweight over the study period.

Necropsy. No abnormalities were noted at necropsy.

Conclusion. The acute dermal median lethal dose (LD50) of the test material in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
High. Reliable, adequate and relevant data available to fulfill the tonnage-driven data requirements of REACH. Tested substance is representative of the lithium salts of C14-C22 fatty acids category and can be read across to other category members

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 acute toxicity potential 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 number of key acute oral and dermal toxicity studies in rats have been conducted on lithium salts of myristic (C14), 12-hydroxystearic (C18 hydroxylated), stearic (C18), C18 unsaturated, and behenic (C22) monocarboxylic acids. The results from these studies showed no evidence of acute toxicity up to the highest doses tested (2000 mg/kg or greater). In addition, several supporting acute toxicity studies on lithium 12 -hydroxystearate in rats and rabbits have also been considered which, on a weight of evidence basis, provide data which supports the lack of acute toxicity of the lithium salts of C14 -C22 monocarboxylic acids. Several of the latter studies were conducted on the substance contained within a grease base at lower concentrations. However, no conflicting results were seen, and the data also supports the low acute toxicity of the category members.

It is considered from the results that all the substances in the category of lithium salts of C14-C22 monocarboxylic acids exhibit a similar, lack of acute oral and dermal toxicity potential across the entire category. There is no evidence of a relevant intrinsic acute oral or dermal toxicity requiring classification or substance specific RMMs. An estimate of the inhalation dust/mist toxicity by route-to-route extrapolation using conservative standard default values results in an ATE of 10.4 mg/l/4hminimum. This value is well above the cut values for classification for acute inhalation toxicity hazard.


Justification for selection of acute toxicity – oral 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 acute toxicity – dermal 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 classification or non-classification

The oral and dermal LD50 values are greater than 2000 mg/kg bw. An estimate of the inhalation dust/mist toxicity by route-to-route extrapolation according to ECHA CLP TGD 3.1.3.3.4i results in an ATE well above the cut-off values for classification for acute inhalation toxicity hazard.