Calcium(2+) 12-hydroxyoctadecanoate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

2010-2011

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: According to or similar to guideline study OECD 422; GLP

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: approx. 8 weeks
- Weight at study initiation: Males - 266-311g; Females (nulliparous and nonpregnant) - 191-222g
- Housing: Individually housed in suspended, stainless steel, wire-mesh type cages, except during pairing, near parturition and during lactation. P females moved to plastic caging with wood chip bedding from GD20 - LD 4. Animal enrichment per SOP-ACU-89
- Diet (e.g. ad libitum): Lab Diet Certified Rodent Diet #5002, PMI Nutrition International, Inc., ad libitum.
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 64-79
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12 h /12 h

IN-LIFE DATES: From: 30 November 2010 To: 1 Febraury 2011

Route of administration:

dermal

Vehicle:

water

Details on exposure:

TEST SITE
- Area of exposure: dorsal surface; equivalent to approx. 10% of the total body surface area
- Type of wrap if used: gauze dressing and non-absorbent cotton covered with self-adhesive take and athletic tape.
- Time intervals for shavings or clipplings: As required

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Wypall wet with distilled water.
- Time after start of exposure: 6 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.5 mL/kg
- Concentration (if solution): equivalent to 0; 100; 300; 1000 mg/kg/day (nominal)
- Constant volume or concentration used: yes


VEHICLE
- Distilled deionised tap water
- Concentration (if solution): N/A
- Lot/batch no. (if required): not available
- Purity: not available

USE OF RESTRAINERS FOR PREVENTING INGESTION: no

Details on mating procedure:

After 2 weeks of treatment, P animals (Groups 1 to 4), each female was housed in cage of a male from the same treatment group.
- M/F ratio per cage: 1
- Length of cohabitation: Until evidence of copulation was established (max 14 days). Housed individually during daytime 6-hour exposure period.
- Proof of pregnancy: vaginal plug and / or vaginal lavage with the presence of sperm; referred to as gestation day (GD) 0
- After 14 days of unsuccessful pairing females were returned to individual cages.
- After successful mating each pregnant female was caged individually for the remainder of the study.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentrations of Fatty acids C18-(unsaturated) lithium salts in 52 dosing formulation samples was established by determining lithium content by Inductively Couple Plasma Optical Emission Spectroscopy (ICP-OES). Samples were processed by microwave aided acid digestion (DIN 51460-2) before submitting to ICP-OES (EN ISO 11885).

Duration of treatment / exposure:

Males dosed for at least 43 days, beginning 14 days prior to mating (Groups 1-4).
Dosing of the females beginning 14 days prior to mating and continuing through mating, up to and including GD 19 (Groups 1-4). Another set of animals (Groups 5 and 6) dosed for a total of 43 days before beginning a 14-day (non-treated) recovery period.

Frequency of treatment:

Daily, once per day for 6 hours.

Details on study schedule:

- Age at mating of the mated animals in the study: approximately 10 weeks of age

Remarks:

Doses / Concentrations:
0; 100; 300; 1000 mg/kg bw
Basis:
nominal conc.

Remarks:

Doses / Concentrations:
0; 111.25; 345.00; 1089.75 mg/kg bw
Basis:
analytical conc.

No. of animals per sex per dose:

Terminal Groups (Groups 1 to 4): 10 animals per sex per dose
Recovery Groups (Groups 5 and 6): 5 animals per sex per dose

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The dose levels were selected on the basis of available data from a previous dose ranging study (MPI Study No. 1883-001). Animals were dosed dermally once a day at 0, 525, 1050 and 2100 mg/kg/day (water based Fatty acids C18-(unsaturated) lithium salts) and for two weeks at 2106 mg/kg/day with oil-based Fatty acids C18-(unsaturated) lithium salts. The results of this study identified significant dose responsive dermal effects, based on maximized erythema and eschar scores at dose levels =1050 mg/kg/day Fatty acids C18-(unsaturated) lithium salts. A slight decrease in mean body weight was noted in males during the last week of
dosing, however, not other adverse body weight or food consumption effects were observed at the dose levels tested. A nominal high-dose level of 1000 mg/kg/day (at a slightly lower concentration based on dose volume) was selected for the defintive study to insure some morbidity. The nominal low dose level (100 mg/kg/day) was selected with 10-fold decrease to insure a no effect level, and a nominal mid-dose level of 300 mg/kg/day was selected to be about 3 times higher than the low-dose level and about 3 times lower than the high-dose level.
- Rationale for animal assignment (if not random): All animals placed on study will have body weights that fall within 20% of the mean bodyweight for each sex. Animals considered suitable for study will be weighed prior to treatment. After the appropriate number of animals with the highest and lowest body weights has been excluded, the remaining required number of animals on study will be randomized, by sex, into treatment groups using a standard, by weight, measured value randomization procedure.

- Rationale for selecting satellite groups: As above.

- Post-exposure recovery period in satellite groups: 14-day non treatment period.

- Section schedule rationale (if not random): Randomized.

Positive control:

Not included

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least twice a day, 7 days a week, for morbidity, mortality, injury, and availability of food and water. Towards end of gestation period, P females examined twice daily for signs of parturition.
- Cage side observations recorded are not reported, but are maintained in the study file.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily during the study (after wrap removal on dose days).

DERMAL IRRITATION: Yes
- Time schedule for examinations: Prior to first dose and daily during the study (after wrap removal on dosing days).

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly during the study. Mated females weighed on GD 0, 7, 14 and 20 and on LD 0 and 4 and at termination.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

WATER CONSUMPTION: No

OTHER:
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination / at recovery
- Anaesthetic used for blood collection: Yes (CO2)
- Animals fasted: No
- How many animals: 5 per sex per group (P animals) in Groups 1-4 at Termination (same animals designated for behavioral testing). 5 per sex per group in Groups 5 and 6 at Recovery
- Parameters checked:
¿ leukocyte count (total and absolute differential); ¿ erythrocyte count; ¿ hemoglobin; ¿ hematocrit; ¿ mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration (calculated); ¿ absolute reticulocytes; ¿ platelet count; ¿ blood cell morphology

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination / at recovery
- Animals fasted: No
- How many animals: 5 per sex per group (P animals) in Groups 1-4 at Termination (same animals designated for behavioral testing). 5 per sex per group in Groups 5 and 6 at Recovery
- Parameters checked:
¿ alkaline phosphatase; ¿ total bilirubin (with direct bilirubin if total bilirubin exceeds 1 mg/dL); ¿ aspartate aminotransferase; ¿ alanine aminotransferase; ¿ gamma glutamyl transferase; ¿ sorbitol dehydrogenase; ¿ urea nitrogen; ¿ creatinine; ¿ total protein; ¿ albumin; ¿ globulin and A/G (albumin/globulin) ratio (calculated); ¿ glucose; ¿ total cholesterol; ¿ triglycerides; ¿ electrolytes (sodium, potassium, chloride); ¿ calcium; ¿ phosphorus

Oestrous cyclicity (parental animals):

Not determined

Sperm parameters (parental animals):

Parameters examined in P male parental generations:
testis weight, epididymis weight

Litter observations:

Litters were examined as soon as possible after delivery(LD 0) and on LD 4.

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
Litter size, number of stillborn and liveborn pups, survival, number of males and females, individual body weights, abnormal behaviour, and gross abnormalities of the pups.

GROSS EXAMINATION OF DEAD PUPS:
yes, for external abnormalities. Offspring found dead on LD 0 had lungs removed and placed in tap water to determine whether live/stillborn.

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals on day 44 (Groups 1-4) and day 57 (groups 5 and 6)
- Maternal animals: All surviving animals on LD 4 (groups 1-4) and day 57 (groups 5 and 6)

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cranial, thoracic, and abdominal viscera, and recorded number of total implantation scars and number of corpora lutea on each ovary.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table 1 were prepared for microscopic examination and weighed, respectively.

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring sacrificed on LD 4.
- These animals were subjected to postmortem external examinations.

GROSS NECROPSY
- Gross necropsy consisted of external examinations.

Statistics:

The raw data were tabulated within each time interval, and the mean and standard deviation were calculated for each endpoint by sex and group. For each endpoint, treatment groups were compared to the control group using: Group pair-wise comparisons; Cochran Manzel Haenszel test; log transformation / group pair-wise comparisons; Fisher's exact test; Arcsin-square root transformation, and; Covariate analysis, as presented in Table 2.

Reproductive indices:

Male and female mating index; fertility index and fecundity index.

Females Delivering Litters (%) = (No. females delivering litters / No. females pregnant) x 100

Females with All Stillborn (%) = (No. litters with all stillborn pups / No. females delivering litters) x 100

Females with Stillborn Pups (%) = (No. litters with at least 1 stillborn pup / No. females delivering litters) x 100

Fertility Index - Males (%) = (No. males impregnating a female / No. males paired) x 100

Fertility Index - Females (%) = (No. females pregnant / No. females paired) x 100

Offspring viability indices:

Live Birth Index (%) = (No. live pups at birth / No. pups born) x 100

Stillborn Index = No. stillborn pups / No. pups born

Viability Index – Day 4 (%) = (No. pups surviving 4 days (preculling) / No. live pups at birth) x 100

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

345 and 1089.75 mg/kg bw/day: localized scabbed area on dorsal surface and scabbed area in the thoracic region (related to test site) during dosing period. Recovery animals indicated trend towards recovery after cessation of dosing.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Trend to decreasing mean body weight in males at 1089.75 mg/kg bw/day - though not statistically significant. Mean body weight change was statistically decreased in treated males at 1089.75 mg/kg bw/day during the premating interval from Weeks 1 to 3.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Trend to decreasing mean body weight in males at 1089.75 mg/kg bw/day - though not statistically significant. Mean body weight change was statistically decreased in treated males at 1089.75 mg/kg bw/day during the premating interval from Weeks 1 to 3.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Test article-related microscopic findings in skin: minimal/moderate erosion/ulceration, epidermal hyperplasia and exudate, minimal/mild acute/subacute/chronic inflammation, minimal edema. 1000 mg/kg/day: secondary adaptive findings in thymus and spleen.

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

male/female fertility and fecundity indices and copulatory intervals unaffected by treatment.

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
300 and 1000 mg/kg bw/day animals: localized scabbed area on dorsal surface and scabbed area in the thoracic region (related to test site) during dosing period. These were dose-responsive, being most pronounced at the high dose level of 1000 mg/kg bw/day in both males and females. Recovery animals indicated trend towards recovery after cessation of dosing, although these dermal fndings remained evident. [See attached Parental Summary Tables 1-4; and Recovery Summary Table 32]

DERMAL IRRITATION SCORES
Daily dermal scoring (edema, as well as erythema and eschar) during the course of the dosing period in treated male and female animals, revealed dose responsive effects, particularly at 300 and 1000 mg/kg bw/day, with controls being devoid of any significant adverse dermal effects. [See attached Parental Summary Tables 8-11]
The results of the dermal scoring in the animals at 100 mg/kg/day were generally comparable to the controls. Edema in the males at 300 mg/kg/day was limited to very slight effects during the start of dosing, which progressed to slight edema, with a few instances of moderate edema at a little over 5 weeks into dosing. Edema in the males at 1000 mg/kg/day started at very slight effects right after dosing, which became slight edema after about a week of dosing and progressed to moderate edema by 3 weeks of dosing. Edema in the females at 300 mg/kg/day was similar to the males up to the time of mating. At 1000 mg/kg/day, edema also progressed to slight edema by Day 2 of dosing, prior to mating. During gestation, edema was very slight in the 100 mg/kg/day group; it was slight in appearance at 300 mg/kg/day and moderate at 1000 mg/kg/day. During lactation edema was limited to very slight effects at 300 and 1000 mg/kg/day.
The evaluation of erythema and eschar (to be referred to as erythema) showed more significant dermal scoring in the treated animals. Erythema in the males at 300 mg/kg/day was generally very slight starting about a week of dosing and continued during the dosing period (Days 1 to 44). Erythema in the males at 1000 mg/kg/day started with very slight to well-defined effects, and by the first week of dosing progressed from well defined to moderate erythema, with a few instances of severe edema. By three weeks of dosing, most of the males at 1000 mg/kg/day had moderate to severe findings. Erythema in the females at 300 mg/kg/day during the premating period started with very slight findings and some well defined effects about 5 days into dosing and this progressed to well-defined findings by two weeks of treatment until mating. Erythema at 1000 mg/kg/day for females during the premating period started with very slight to well defined findings, which progressed to well defined, moderate, and in a few instances severe erythema by two weeks of dosing, prior to mating.
These localized dermal effects at 300 and 1000 mg/kg/day were considered to be test article related. In the designated recovery animals the dermal scores were similar to the terminal animals, but there was a decreasing trend in severity and incidence after cessation of dosing. [See attached Recovery Summary Table 34]

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
There was a trend of decreasing mean body weight in the males at 1000 mg/kg/day, though, the values were not statistically identified. Mean body weight change was statistically decreased in the treated males at 1000 mg/kg/day during the premating interval from Weeks 1 to 3. Mean body weight and body weight gain in the treated females were generally similar to the controls and did not show any definitive treatment related effects over the
dosing period. [See attached Parental Summary Tables 16-27]
In the designated recovery animals, mean body weight at 1000 mg/kg/day was statistically decreased in the males during Weeks 3, 4, 5, 6, and 7, which correlated to the decreases in body weight gain in these animals during weekly study intervals 1-2, 2-3, 3-4, 4-5, and 1-7. Mean body weight at 1000 mg/kg/day continued to be significantly lower than controls during the recovery period; however, the mean body weight gain was comparable to the controls, indicating a reversal of the body weight effects after cessation of dosing. The designated recovery females did not show any statistically significant body weight changes, as compared to the controls. [See attached Recovery Summary Table 35-36]

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Male and female fertility and fecundity indices and copulatory intervals unaffected by treatment. [See attached Reproductive Summary Table 28.]
Natural delivery and Litter Data un affected by treatment. [See attached Reproductive Summary Table 29.]

ORGAN WEIGHTS (PARENTAL ANIMALS)
Possible test article-related organ weight differences at the terminal necropsy were present in the spleen. [See attached Pathology Summary Table 2; Recovery Pathology Summary Table 6]
At the terminal necropsy, the mean spleen weight (relative to body weight) was statistically significantly increased in males at 1000 mg/kg/day versus controls. The increased spleen/body weight ratio may have been associated with the lower mean body weight of males at this dose level compared to controls and/or the increased mean absolute spleen weight that may have reflected increases in extramedullary hematopoiesis noted microscopically.
Additional statistically significant organ weight differences at the terminal necropsy were limited to the increased mean adrenal gland weight (relative to body weight) of females at 1000 mg/kg/day compared to controls. There was no microscopic correlate for this effect, and the relationship to test article administration was unclear.

GROSS PATHOLOGY (PARENTAL ANIMALS)
Test article-related macroscopic findings were limited to the dose site in the skin. At the terminal necropsy, minimal to moderate abrasion/scab formation was identified in the dose site in the skin in control males and treated animals of both sexes with a dose-related increase in the incidence and/or severity in males at 300 and 1000 mg/kg/day and in females at all dose levels compared to controls. This reflected the test article-related erosion/ulceration noted microscopically in treated skin (see Microscopic section). At the recovery necropsy, the incidence and overall severity of abrasion/scab formation was reduced in animals at 1000 mg/kg/day, indicating partial resolution of this finding over the recovery period.
Other macroscopic findings were infrequent and typical of those commonly identified in rats of this strain and age. [See attached Pathology Summary Table 1; Recovery Pathology Summary Table 5]

HISTOPATHOLOGY (PARENTAL ANIMALS) - NON-NEOPLASTIC
Test article-related microscopic findings were present in treated skin, and possible test article effects were also noted in the thymus and spleen. Test article-related increases in the incidence and/or severity of microscopic findings in treated skin were present in males at 300 and 1000 mg/kg/day and in females at all dose levels versus controls at the terminal necropsy. These findings were generally present with a dose-related increase in incidence and severity, however, treated skin was not examined in all mid-dose animals (microscopic examination limited to animals with gross lesions). Test article-related microscopic findings in treated skin included minimal to moderate erosion/ulceration, epidermal hyperplasia and exudate, minimal to mild acute to subacute/chronic inflammation, and minimal edema. At the recovery necropsy, test article-related microscopic findings in treated skin in animals at 1000 mg/kg/day were similar, although they occurred at a lower incidence and severity indicating partial resolution of these findings over the recovery period. Minimal to mild cortical lymphoid depletion was noted in the thymus in animals of both sexes at 1000 mg/kg/day at the terminal necropsy while this finding was not identified in control animals. However, notably, there were no statistically significant differences in the mean thymus weight and the thymus was not examined microscopically for all control and treated animals. Thymic lymphoid depletion in animals at 1000 mg/kg/day may have been a secondary finding due to stress associated with the test article-related lesions in treated skin as evidenced by self-mutilation and hypersensitivity to touch noted clinically in males at this dose level. The thymus was not examined microscopically at the recovery necropsy. At the terminal necropsy, there was a slight increase in the incidence and severity of extramedullary hematopoiesis in the spleen in animals at 1000 mg/kg/day versus controls. The severity of splenic extramedullary hematopoiesis was generally increased in both control and treated females, likely due to recent parturition, but the slight increase in the incidence of this finding in animals at 1000 mg/kg bw/day may have also reflected an adaptive response secondary to test article-related inflammation in treated skin. The spleen was not examined microscopically at the recovery necropsy. [See attached Pathology Summary Table 3; Recovery Pathology Summary 7]

OTHER FINDINGS (PARENTAL ANIMALS)

Dose descriptor:

NOAEL

Effect level:

> 1 089.75 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Reproductive parameters (male/female fertility and fecundity indices, and copulatory intervals) were unaffected by treatment. No statistically significant changes in delivery data and pup development / survival.

Dose descriptor:

other: NOAEL non-reproductive systemic effects

Effect level:

345 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: body weight

Dose descriptor:

other: NOAEL local effects

Effect level:

111.25 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

There were no treatment-related effects at any dose level on any of the reproductive parameters evaluated in this study including offspring survival (gestation and postnatal survival indices, percent pre- and post-implantation loss), pup body weight and pup sex ratio. There were also no treatment-related effects on any of the developmental parameters evaluated including external abnormalities, number of live and still births, mortality, sex determination and weights of pups. [See attached Reproductive Summary Tables 30 and 31.]

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

> 1 089.75 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No reproductive effects or definitive test-article related changes in the development or survival of the offspring.

Reproductive effects observed:

not specified

See attached documents.

Conclusions:

Dermal application of Fatty acids C18-(unsaturated) lithium salts to the dorsal surface of Parental male and female rats at dose levels of 100, 300, and 1000 mg/kg/day did not result in any adverse reproductive effects or any definitive test article-related changes in the development or survival of the offspring.

Executive summary:

Dermal application of Fatty acids C18-(unsaturated) lithium salts to the dorsal surface of Parental male and female rats at dose levels of 100, 300, and 1000 mg/kg/day did not result in any adverse reproductive effects or any definitive test article-related changes in the development or survival of the offspring.

In addition, results from the clinical pathology evaluations and neurobehavioral testing did not reveal any definitive effects that could be attributed to treatment at the dose levels tested. Test article-related dermal changes were limited to local effects at the test site for Parental animals at 300 and 1000 mg/kg/day, which showed a decreasing trend following cessation of dosing in the designated recovery animals. Microscopic evaluation of the skin at the test site showed minimal to moderate erosion/ulceration, epidermal hyperplasia and exudate, minimal to mild acute to subacute/chronic inflammation and minimal edema, which confirmed the macroscopic findings. At recovery necropsy, test article-related microscopic findings in treated skin in animals at 1000 mg/kg/day were morphologically similar, although they occurred at a lower incidence and severity indicating partial resolution of these findings following the recovery period. Microscopic findings of splenic extramedullary hematopoiesis and thymic lympoid depletion noted at 1000 mg/kg/day were considered to be secondary adaptive responses to parturition and localized dermal effects.

Systemic effects were limited to changes in body weight and organ weight at 1000 mg/kg/day, the highest dose level tested.

In summary, 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 daya, the NOAEL for developmental toxicity was >1089.75 mg/kg bw/day and the NOAEL for reproductive toxicity was also >1089.75 mg/kg bw/day.

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.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP-compliant, guideline study, available as an unpublished study report. Acceptable for assessment.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: approx. 8 weeks
- Weight at study initiation: Males - 266-311g; Females (nulliparous and nonpregnant) - 191-222g
- Housing: Individually housed in suspended, stainless steel, wire-mesh type cages, except during pairing, near parturition and during lactation. P females moved to plastic caging with wood chip bedding from GD20 - LD 4. Animal enrichment per SOP-ACU-89
- Diet (e.g. ad libitum): Lab Diet Certified Rodent Diet #5002, PMI Nutrition International, Inc., ad libitum.
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 64-79
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12 h /12 h

IN-LIFE DATES: From: 30 November 2010 to 1 Febraury 2011

Route of administration:

dermal

Vehicle:

water

Details on exposure:

TEST SITE
- Area of exposure: Dorsal surface; equivalent to approx. 10% of the total body surface area
- Type of wrap if used: Gauze dressing and non-absorbent cotton covered with self-adhesive tape and athletic tape.
- Time intervals for shavings or clipplings: As required

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Wypall wet with distilled water.
- Time after start of exposure: 6 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.5 mL/kg
- Concentration (if solution): equivalent to 0; 100; 300; 1000 mg/kg/day (nominal)
- Constant volume or concentration used: Yes


VEHICLE
- Distilled deionised tap water
- Concentration (if solution): N/A
- Lot/batch no. (if required): Not available
- Purity: Not available

USE OF RESTRAINERS FOR PREVENTING INGESTION: No

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentrations of fatty acids C18-(unsaturated) lithium salts in 52 dosing formulation samples was established by determining lithium content by Inductively Couple Plasma Optical Emission Spectroscopy (ICP-OES). Samples were processed by microwave aided acid digestion (DIN 51460-2) before submitting to ICP-OES (EN ISO 11885).

Details on mating procedure:

After 2 weeks of treatment, P animals (Groups 1 to 4), each female was housed in cage of a male from the same treatment group.
- M/F ratio per cage: 1
- Length of cohabitation: Until evidence of copulation was established (max 14 days). Housed individually during daytime 6-hour exposure period.
- Proof of pregnancy: vaginal plug and / or vaginal lavage with the presence of sperm; referred to as gestation day (GD) 0
- After 14 days of unsuccessful pairing females were returned to individual cages.
- After successful mating each pregnant female was caged individually for the remainder of the study.

Duration of treatment / exposure:

Males dosed for at least 43 days, beginning 14 days prior to mating (Groups 1-4).
Dosing of the females began 14 days prior to mating and continued through mating, up to and including GD 19 (Groups 1-4). Another set of animals (Groups 5 and 6) were dosed for a total of 43 days and then began a 14-day (non-treated) recovery period.

Frequency of treatment:

Daily, once per day for 6 hours.

Duration of test:

Terminal Groups (Groups 1 to 4): Dosed for at least 43 days
Recovery Groups (Groups 5 and 6): Dosed for a total of 43 days before beginning a 14-day (non-treated) recovery period

Remarks:

Doses / Concentrations:
0; 100; 300; 1000 mg/kg bw
Basis:
nominal conc.

Remarks:

Doses / Concentrations:
0; 111.25; 345.00; 1089.75 mg/kg bw
Basis:
analytical conc.

No. of animals per sex per dose:

Terminal Groups (Groups 1 to 4): 10 animals per sex per dose
Recovery Groups (Groups 5 and 6): 5 animals per sex per dose

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The dose levels were selected on the basis of available data from a previous dose ranging study (MPI Study No. 1883-001). Animals were dosed dermally once a day at 0, 525, 1050 and 2100 mg/kg bw/day (water based Fatty acids C18-(unsaturated) lithium salts) and for two weeks at 2106 mg/kg bw/day with oil-based Fatty acids C18-(unsaturated) lithium salts. The results of this study identified significant dose responsive dermal effects, based on maximized erythema and eschar scores at dose levels =1050 mg/kg bw/day fatty acids C18-(unsaturated) lithium salts. A slight decrease in mean body weight was noted in males during the last week of dosing, however, not other adverse body weight or food consumption effects were observed at the dose levels tested. A nominal high-dose level of 1000 mg/kg bw/day (at a slightly lower concentration based on dose volume) was selected for the defintive study to insure some morbidity. The nominal low dose level (100 mg/kg bw/day) was selected with 10-fold decrease to insure a no effect level, and a nominal mid-dose level of 300 mg/kg bw/day was selected to be about 3 times higher than the low-dose level and about 3 times lower than the high-dose level.
- Rationale for animal assignment (if not random): All animals placed on study will have body weights that fall within 20% of the mean bodyweight for each sex. Animals considered suitable for study will be weighed prior to treatment. After the appropriate number of animals with the highest and lowest body weights has been excluded, the remaining required number of animals on study will be randomized, by sex, into treatment groups using a standard, by weight, measured value randomization procedure
- Rationale for selecting satellite groups: As above
- Post-exposure recovery period in satellite groups: 14-day non treatment period
- Section schedule rationale (if not random): Randomized

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least twice a day, 7 days a week, for morbidity, mortality, injury, and availability of food and water. Towards end of gestation period, P females examined twice daily for signs of parturition.
- Cage side observations recorded are not reported, but are maintained in the study file.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily during the study (after wrap removal on dose days).

DERMAL IRRITATION: Yes
- Time schedule for examinations: Prior to first dose and daily during the study (after wrap removal on dosing days).

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly during the study. Mated females weighed on GD 0, 7, 14 and 20 and on LD 0 and 4 and at termination.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

WATER CONSUMPTION: No

OTHER:
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At termination / at recovery
- Anaesthetic used for blood collection: Yes (CO2)
- Animals fasted: No
- How many animals: 5 per sex per group (P animals) in Groups 1-4 at Termination (same animals designated for behavioral testing). 5 per sex per group in Groups 5 and 6 at Recovery
- Parameters checked: Leukocyte count (total and absolute differential); erythrocyte count; hemoglobin; hematocrit; mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration (calculated); absolute reticulocytes; platelet count; blood cell morphology

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At termination / at recovery
- Animals fasted: No
- Number of animals: 5 per sex per group (P animals) in Groups 1-4 at Termination (same animals designated for behavioral testing). 5 per sex per group in Groups 5 and 6 at Recovery
- Parameters checked: Alkaline phosphatase; total bilirubin (with direct bilirubin if total bilirubin exceeds 1 mg/dL); aspartate aminotransferase; alanine aminotransferase; gamma glutamyl transferase; sorbitol dehydrogenase; urea nitrogen; creatinine; total protein; albumin; globulin and A/G (albumin/globulin) ratio (calculated); glucose; total cholesterol; triglycerides; electrolytes (sodium, potassium, chloride); calcium; phosphorus

Ovaries and uterine content:

No data reported

Fetal examinations:

Litters were examined as soon as possible after delivery(LD 0) and on LD 4. The F1 offspring sacrificed on LD 4 and these animals were subjected to postmortem external examinations.

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: Litter size, number of stillborn and liveborn pups, survival, number of males and females, individual body weights, abnormal behaviour, and gross abnormalities of the pups.

GROSS EXAMINATION OF DEAD PUPS: Yes, for external abnormalities. Offspring found dead on LD 0 had lungs removed and placed in tap water to determine whether live/stillborn.

Statistics:

The raw data were tabulated within each time interval, and the mean and standard deviation were calculated for each endpoint by sex and group. For each endpoint, treatment groups were compared to the control group using: Group pair-wise comparisons; Cochran Manzel Haenszel test; log transformation / group pair-wise comparisons; Fisher's exact test; Arcsin-square root transformation, and; Covariate analysis.

Indices:

Live Birth Index (%) = (No. live pups at birth / No. pups born) x 100
Stillborn Index = No. stillborn pups / No. pups born
Viability Index – Day 4 (%) = (No. pups surviving 4 days (preculling) / No. live pups at birth) x 100

Historical control data:

No data reported

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
- Clinical signs (parental animals): 345 and 1089.75 mg/kg bw/day: localized scabbed area on dorsal surface and scabbed area in the thoracic region (related to test site) during dosing period. Recovery animals indicated trend towards recovery after cessation of dosing.
- Body weight and food consumption (parental animals): Trend to decreasing mean body weight in males at 1089.75 mg/kg bw/day - though not statistically significant. Mean body weight change was statistically decreased in treated males at 1089.75 mg/kg bw/day during the premating interval from Weeks 1 to 3.
- Test substance intake (parental animals): Not examined
- Reproductive function: Estrous cycle (parental animals): Not examined
- Reproductive function: Sperm measures (parental animals): Not examined
- Reproductive performance (parental animals): Male/female fertility and fecundity indices and copulatory intervals unaffected by treatment.
- Organ weights (parental animals): Relative mean spleen weight increased in 1089.75 mg/kg/d males. Considered to be secondary adaptive response to localised dermal effects
- Gross pathology (parental animals): Test article-related macroscopic findings (terminal necropsy): minimal to moderate abrasion/scab formation in control males and treated animals of both sexes. Dose-related increase in incidence/severity in females (all doses) and males (345-1089 mg/kg/d)
- Histopathology (parental animals): Test article-related microscopic findings in skin: minimal/moderate erosion/ulceration, epidermal hyperplasia and exudate, minimal/mild acute/subacute/chronic inflammation, minimal edema. 1000 mg/kg/day: secondary adaptive findings in thymus and spleen.

Dose descriptor:

NOAEL

Remarks:

Generation P male/female

Effect level:

> 1 089.75 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Remarks:

Generation F1 male/female

Effect level:

> 1 089.75 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Dose descriptor:

NOAEL

Remarks:

Generation P male/female

Effect level:

111.25 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: other:

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
- Viability (offspring): No effects
- Clinical signs (offspring): No effects
- Body weight (offspring): No effects
- Sexual maturation (offspring): Not examined
- Organ weights (offspring): Not examined
- Gross pathology (offspring): No effects
- Histopathology (offspring): Not examined
- Details on results (offspring): There were no treatment-related effects at any dose level on any of the reproductive parameters evaluated in this study including offspring survival (gestation and postnatal survival indices, percent pre- and post-implantation loss), pup body weight and pup sex ratio. There were also no treatment-related effects on any of the developmental parameters evaluated including external abnormalities, number of live and still births, mortality, sex determination and weights of pups.

Abnormalities:

not specified

Developmental effects observed:

not specified

Dermal application of fatty acids C18-(unsaturated) lithium salts to the dorsal surface of Parental male and female rats at dose levels of 100, 300, and 1000 mg/kg bw/day did not result in any adverse reproductive effects or any definitive test article-related changes in the development or survival of the offspring.

In addition, results from the clinical pathology evaluations and neurobehavioral testing did not reveal any definitive effects that could be attributed to treatment at the dose levels tested. Test article-related dermal changes were limited to local effects at the test site for Parental animals at 300 and 1000 mg/kg bw/day, which showed a decreasing trend following cessation of dosing in the designated recovery animals. Microscopic evaluation of the skin at the test site showed minimal to moderate erosion/ulceration, epidermal hyperplasia and exudate, minimal to mild acute to subacute/chronic inflammation and minimal edema, which confirmed the macroscopic findings. At recovery necropsy, test article-related microscopic findings in treated skin in animals at 1000 mg/kg bw/day were morphologically similar, although they occurred at a lower incidence and severity indicating partial resolution of these findings following the recovery period. Microscopic findings of splenic extramedullary hematopoiesis and thymic lympoid depletion noted at 1000 mg/kg bw/day were considered to be secondary adaptive responses to parturition and localized dermal effects.

Systemic effects were limited to changes in body weight and organ weight at 1000 mg/kg bw/day, the highest dose level tested.

In summary, 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 daya, the NOAEL for developmental toxicity was >1089.75 mg/kg bw/day and the NOAEL for reproductive toxicity was also >1089.75 mg/kg bw/day.

Conclusions:

Dermal application of fatty acids C18-(unsaturated) lithium salts to the dorsal surface of Parental male and female rats at dose levels of 100, 300, and 1000 mg/kg bw/day did not result in any adverse reproductive effects or any definitive test article-related changes in the development or survival of the offspring.

Executive summary:

The developmental toxicity of fatty acids C18 (unsaturated) lithium salts was assessed in a combined repeated dose and reproductive toxicity screening test following OECD guideline 422 (MPI 2011). The parental generation was dermally administered daily for 6 hours per day with fatty acids C18 (unsaturated) lithium salts at concentrations of 100, 300 and 1000 mg/kg bw/day. The offspring of the treated rats were then assessed for survival (gestation and postnatal survival indices, percent pre- and post-implantation loss), pup body weight and sex ratio and external abnormalities.

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).

Reference

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.