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Diss Factsheets

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data is from OECD SIDS

Data source

Reference
Reference Type:
secondary source
Title:
SIDS Initial Assessment Profile- Calcium stearate
Author:
Organization for Economic Cooperation and Development
Year:
2012
Bibliographic source:
CoCAM 2, 17-19 April 2012

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
Reproductive and developmental toxicity screening test of Calcium distearate in rats
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Calcium distearate
EC Number:
216-472-8
EC Name:
Calcium distearate
Cas Number:
1592-23-0
Molecular formula:
C18H36O2.1/2Ca
IUPAC Name:
calcium dioctadecanoate
Constituent 2
Reference substance name:
Calcium Stearate
IUPAC Name:
Calcium Stearate
Test material form:
solid
Details on test material:
Name of test material (as cited in study report): Calcium StearateMolecular formula : C36H70CaO4 Molecular weight: 607.04 g/mole Smiles notation :C(CCCCCCCCCCC)CCCCCC(=O)[O].C(CCCCCCCCCCC)CCCCCC(=O)[O].[Ca+2]InChl:1S/2C18H36O2.Ca/c2*123456789101112131415161718(19)20;/h2*217H2,1H3,(H,19,20);/q;;+2/p2Substance Type: OrganicPhysical State: Solid
Specific details on test material used for the study:
- Name of test material (as cited in study report): Calcium distearate- Molecular formula (if other than submission substance): C36H70O4.Ca- Molecular weight (if other than submission substance): 607.023 g/mole- Substance type: Organic- Physical state: White powder

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS- Source: Crl:CD(SD) Rat- Age at study initiation: (P) 8 wk- Weight at study initiation: (P) Males: 230.4-275.9 g;Females: 184.3-212.5 g- Housing:- Quarantine and acclimatization : The five animals per cage were housed in stainless steel cages- Administration : The two animals per cage were housed in stainless steel cages- Mating period : One female to one male were housed in stainless steel cages- Gestation and lactation period : Maternal rats and fetuses were housed individually in polycarbonate cages- Diet : ad libitum- Water : ad libitum- Acclimation period: 7 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 22.3 - 23.7 °C- Humidity (%): 50.0 - 55.7 %- Air changes (per hr): 10- 15 times/hr- Photoperiod (hrs dark / hrs light): 12 hours light/dark cycle (light during 8:00-20:00) at 150 to 300 Lux.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on mating procedure:
- M/F ratio per cage: One female to one male- Length of cohabitation: 7 days- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy- After 7 days of unsuccessful pairing replacement of first male by another male with proven fertility.- Further matings after two unsuccessful attempts: [no / yes (explain)] -- After successful mating each pregnant female was caged (how): Each pregnant female was caged individually in cage- Any other deviations from standard protocol:-
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
-Male : Two weeks before mating to the end of the mating period, for at least 28 or more days-Female : Two weeks before mating to day 3 of lactation including the mating and gestation period
Frequency of treatment:
once a day, 7 days a week
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
Total: 800 mg/kg bw/day: 10 male, 10 female 250 mg/kg bw/day: 10 male, 10 female 500 mg/kg bw/day: 10 male, 10 female 1000 mg/kg bw/day: 10 male, 10 female
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: In the preliminary toxicity study (KTR Study No. : TBH-902), at a dose level of 1000 mg/kg bw/day in SD rats, there was no treatment-related changes. Based on above results, 1000 mg/kg bw/day was selected as the high dose for the reproduction/developmental toxicity screening study and two lower doses were added with 2 fold interval.- Rationale for animal assignment: The animal strain was chosen because the SD rats are commonly used for reproductive toxicity testing and abundant background data are available to assist evaluation of the results.
Positive control:
not specified

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS:No data - Time schedule: - Cage side observations checked in table [No.?] were included. DETAILED CLINICAL OBSERVATIONS: Yes - Time schedule: BODY WEIGHT: Yes - Time schedule for examinations: FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): - Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day:No data - Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data - Time schedule for examinations: OTHER: No data
Oestrous cyclicity (parental animals):
Yes
Sperm parameters (parental animals):
No data
Litter observations:
No data
Postmortem examinations (parental animals):
GROSS PATHOLOGY: yesHISTOPATHOLOGY: yes
Postmortem examinations (offspring):
GROSS PATHOLOGY: yesHISTOPATHOLOGY: yes
Statistics:
No data
Reproductive indices:
no data
Offspring viability indices:
no data

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Alopecia was observed in the vehicle control and treatment groups of both sexes. In males, 2 [1104, 1107] and [ R1201] animals were observed of 0 and 250 mg/kg bw/day groups, respectively. In females, 1 [2106], 1 [2201], 1 [2308] and 2 [2404, 2405] animals were observed of 0, 250, 500 and 1000 mg/kg bw/day groups, respectively. Cannibalism, 1 [2107 : 1 death/140 total fetus (group)], 1 [2207 : 1 death/134 total fetus (group)] and 1 [2409 : 2 death/137 total fetus (group)] were observed of 0, 250 and 1000 mg/kg bw/day groups, respectively.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
No mortality were observed in treated male and female rats.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There were no statistically significant changes in body weights were observed in treatment groups.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Statistically significant decrease in food consumption was observed at 2 weeks in 1000 mg/kg bw/day group.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
In all reproductive organs in control and high dose groups, the lesion related with the test article was not observed.Adrenocortical necrosis was observed in 1 female of the 250 mg/kg bw/day group
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
TThere was no statistically significant difference in Estrus Cycle among the groups.
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
There was no statistically significant difference in mating, fertility and pregnant index among the groups.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
gross pathology
histopathology: non-neoplastic
reproductive function (oestrous cycle)
reproductive performance
other: No effect observed

Target system / organ toxicity (P0)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Alopecia occurred in some parent animals, but this was thought to be a sporadically occurring sign due to a genetic and/or environmental factor specific to the SD rats, not related to the test article.
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Description (incidence and severity):
No effect on survival of pups were observed as compared to control.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No treatment-related changes were observed of Calcium distearate in body weight during the prenatal, postnatal and lactation period
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Decrease of food consumption at 2 weeks after administration of 1000 mg/kg bw/day group was considered to be incidental since it was transient during the study period.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No treatment-related changes were observed of Calcium distearate in organ weights during the prenatal, postnatal and lactation period
Gross pathological findings:
no effects observed
Description (incidence and severity):
Splenomegaly was observed in male of the control group. This was considered to be a sporadically occurring sign.Cannibalism was observed in treatment groups, which was occurred commonly in normal parturition and lactation period, because of behavior or environment factor
Histopathological findings:
no effects observed
Description (incidence and severity):
Testicular atrophy was observed in male of the 1000 mg/kg/day group, however, there was no toxic effect of the test article on these organs in histopathology; therefore, this was considered to be a sporadically occurring sign. Discoloration of adrenal gland in female of the 250 mg/kg bw/day group was not considered to be toxicological significance, since no treatment-related change was found in histopathological examination.
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality
body weight and weight gain
food consumption and compound intake
gross pathology
histopathology: non-neoplastic

Target system / organ toxicity (F1)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Any other information on results incl. tables

No statistically significant differences were seen in the following parameters examined: gestation period, the number of corpora lutea and implantation, delivery index, the number of live and dead pups, the percentage of live and dead pups to implantations, pre-implantation loss, post-implantation loss, sex ratio, viability ratio, number of neonates with external anomalies, and body weights of pups on post-natal day 0 and day 4.

Applicant's summary and conclusion

Conclusions:
NOAEL of Calcium distearate was considered to be 1000 mg/kg bw/day for reproduction/developmental toxicity in parent animals and for F1 pups.
Executive summary:

In a reproductive and developmental toxicity screening test, Sprague-Dawley male and female rats were treated with Calcium distearate in the concentration of 0, 250, 500 and 1000 mg/kg bw orally by gavage. No effect on survival of treated male and female rats was observed as compared to control. Alopecia was observed in the vehicle control and treatment groups of both sexes. In males, 2 and animals were observed in 0 and 250 mg/kg bw/day groups, respectively. In females, 1, 1, 1 and 2 animals were observed at 0, 250, 500 and 1000 mg/kg bw/day groups, respectively. Cannibalism, 1 [1 death/140 total fetus (group)], 1 [ 1 death/134 total fetus (group)] and 1 [2 death/137 total fetus (group)] were observed at 0, 250 and 1000 mg/kg bw/day groups, respectively. No effect on body weight of treated rats was observed as compared to control. Statistically significant decrease in food consumption was observed at 2 weeks in 1000 mg/kg bw/day group. Similarly, No effect on reproductive parameters such as Estrus Cycle, mating, fertility and pregnant index of treated rats. Splenomegaly and testicular atrophy were observed in 1 male of the 0 and 1000 mg/kg bw/day groups, respectively. Discoloration of adrenal gland was observed in 1 female of the 250 mg/kg bw/day group. In all reproductive organs in control and high dose groups, the lesion related with the test article was not observed. Adrenocortical necrosis was observed in 1 female of the 250 mg/kg bw/day group. In addition, no effect on viability and body weight of pups on day 0 and 4 were observed. Decrease of food consumption at 2 weeks after administration of 1000 mg/kg bw/day group was considered to be incidental since it was transient during the study period. No effect on organ weight of treated pups was observed as compared to control. Cannibalism was observed in treatment groups, which was occurred commonly in normal parturition and lactation period, because of behavior or environment factor. Testicular atrophy was observed in male at 1000 mg/kg/day group, however, there was no toxic effect of the test article on these organs in histopathology; therefore, this was considered to be a sporadically occurring sign. Discoloration of adrenal gland in female of the 250 mg/kg bw/day group was not considered to be toxicological significance, since no treatment-related change was found in histopathological examination. Therefore, NOAEL was considered to be 1000 mg/kg bw for P and F1 generation when Sprague-Dawley male and female rats were treated with Calcium distearate orally.