Registration Dossier

Administrative data

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:
experimental study
Adequacy of study:
weight of evidence
Study period:
2012-09 to 2013-01
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study under GLP
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories, B.V.
- Age at study initiation: 11 x wks
- Weight at study initiation: (P) Males: 326 to 358 g (mean: 343 g); Females: 188 to 220 g (mean. 201 g)
- Housing: Standard laboratory conditions; Individually in Makrolon type-3 cages with wire mesh tops and sterilized standard softwood bedding with paper enrichment
- Use of restrainers for preventing ingestion (if dermal): no
- Diet (e.g. ad libitum): ad libitum; Pelleted standard Harlan Teklad 2914C
- Water (e.g. ad libitum): ad libitum; Community tap-water
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG 300
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

DOSE FORMULATION
- Rate of dose formulation (frequency): weekly
- Storage temperature of dose formulations:20 ± 5 °C
Based upon the results of stability analyses performed within the non-GLP Harlan Laboratories study D57357 (Implementation and validation of an analytical method for dose formulation analysis), dose formulations were stable for at least four weeks when stored in these conditions.

VEHICLE

- Concentration in vehicle: 0, 8, 40, 200 mg/ml
- Amount of vehicle (if gavage): 5 ml/kg
- Lot/batch no. (if required): BCBG8285V
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: 14 days maximum until - the daily vaginal smear was sperm positive, or- a copulation plug was observed.
- Proof of pregnancy: vaginal smear was sperm positive, or a copulation plug was observed. referred to as day 0 of pregnancy
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): individually
- Any other deviations from standard protocol: no
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical Standard:
The test item as described in the main report was used as analytical standard.
Study Samples and Storage:
Representative samples were dispatched to the analytical laboratories internally (under ambient conditions) and stored frozen at -20 ± 5 °C until analysis.
Preparatin of standard solutions:
Stock solutions of test item in acetone were prepared for external standard calibration. For example, 22.74 mg of the test item was exactly weighed into a 50 mL volumetric flask and approximately 40 mL of acetone was added. Then, the mixture was sonicated for at least 5 minutes and the flask was brought to volume with acetone to yield a solution with a concentration of 454.8 μg/mL. Aliquots of this stock standard solution were used to prepare working standard solutions in acetone with a concentration range of 10.01 to 100.1 μg/mL. On each occasion standard solutions derived from two stock standard solutions were used for calibration.
Analysis of Samples:
The samples received were dissolved in acetone by sonication for at least 5 minutes and then diluted to volume with acetone. Where necessary, sample solutions were further diluted with acetone into the calibration range.
Duration of treatment / exposure:
Males: Minimum 4 weeks; Females: Approximately 7 weeks
Frequency of treatment:
once per day
Details on study schedule:
- Age at mating of the mated animals in the study:14 weeks
Remarks:
Doses / Concentrations:
40 mg/kg/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
200 mg/kg/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
11
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels were selected based on a previous dose range-finding toxicity study in Han Wistar rats, Harlan Laboratories Study D57357.
- Rationale for animal assignment (if not random): random
- Other:
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily, during acclimatization and up to day of necropsy

BODY WEIGHT: Yes
- Time schedule for examinations: daily from treatment start to day of necropsy.

FOOD CONSUMPTION:
- Food consumption for each animal determined; males: weekly during pre-pairing and after pairing periods; females: Pre-pairing period days 1 - 8 and 8 - 14;
gestation days 0 - 7, 7 - 14 and 14 - 21.
- No food consumption was recorded during the pairingperiod.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OTHER:The litters were examined for litter size, live births, still births and any gross anomalies. The sex ratio of the pups was recorded. Pups were weighed
individually (without identification) on days 0 (if possible), 1 and 4 post partum
Estrous cyclicity (parental animals):
no
Sperm parameters (parental animals):
Parameters examined in male parental generations:
[testis weight, epididymis weight, sperm morphology, other: Sperm staging]
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
litter size, live births, still births, any gross anomalies, the sex ratio ofthe pups , body weight

GROSS EXAMINATION OF DEAD PUPS:
[yes, for external and internal abnormalities]
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals after treatment
- Maternal animals: All surviving animals on day 4 post partum

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations

HISTOPATHOLOGY / ORGAN WEIGHTS
Testes, epididymides, lungs, kidneys, prostate, seminal vesicles, thymus, ovaries, uterus were prepared for microscopic examination and weighed, respectively.
Postmortem examinations (offspring):
SACRIFICE
- All animals were sacrificed on day 4 post partum.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations
Statistics:
The following statistical methods were used to analyze food consumption, body weights and reproduction data:
• Means and standard deviations of various data were calculated.
• The Dunnett-test [see References (2)] (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
• The Steel-test [see References (3)] (many-one rank test) was applied instead of the Dunnett-test when the data could not be assumed to follow a normal distribution.
• Fisher's exact-test [see References (4)] was applied if the variables could be dichotomized without loss of information.
Reproductive indices:
Mating perfomance, fertility, duration of gestation, corpora lutea count, implantation rate and post-implantation loss were investigated.
Offspring viability indices:
Litter size was measured at first litter check; post natal loss day 0-4 post partum was recorded
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not specified
Reproductive function: estrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
At 1000 mg/kg/day, one male was found dead on Day 7 of the preparing period. One male treated with 40 mg/kg/day was found dead on Day 11 of the prepairing period. One control male was found dead on Day 1 of the pairing period. All males treated with 200 mg/kg/day and all other males survived until scheduled necropsy.
One female treated with 1000 mg/kg/day and one control female were killed on their respective day 25 of the gestation period (four days after the scheduled litter date). All females treated with 200 mg/kg/day survived until scheduled necropsy. One femaletreated with 40 mg/kg/day was found dead on day 4 of the prepairing period
Soft feces was noted throughout the dosing period in control as well as test item-treated males and females, and was ascribed to the use of PEG 300 as vehicle. Salivation (sometimes also with reddish discoloration) was noted after dosing some test itemtreated males and females at all dose levels. In this study, increased salivation was considered likely to result from the taste of the test item formulations. This increased salivation often resulted in discoloration or staining of the fur on the lower mandible. In isolated cases, noticeable breathing noises were observed, but these findings were largely transient.
These findings were not considered to be of toxicological relevance.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
The mean daily food consumption of the test item treated males was similar to that of the control males during pre-pairing period.
The mean daily food consumption of the females was unaffected by treatment during the prepairing, gestation and lactation periods.
During the pre-pairing and pairing periods, the mean body weights of the test item-treated males were generally similar to those of the control males.Minor differences in the mean body weight gain values were noted in males at 40 mg/kg/day and 1000 mg/kg/day that occasionally attained statistical significance (p>0.05 or p<0.01) but these differences did not exceed 4% when compared to the body weight gain of the control males. Therefore, these differences were considered to be of no toxicological relevance.
During the pre-pairing period, the mean body weights of the test item-treated females compared favorably with those of the control females. During the gestation period, the mean body weights of the test item-treated mated females were similar to those of the control females. During the lactation period, the mean body weights of the test item-treated females that gave birth were unaffected by treatment.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
The mean precoital time of the females treated with 1000 mg/kg/day was slightly longer than that of the other treated females and the control females. No effects on fertility (% mating, fertility index and conception rate) were observed at any dose level.
The duration of gestation was similar at all dose levels.
The number of corpora lutea observed at all dose levels compared favorably (or exceeded that) of the controls.
The implantation rate of the test item-treated and control groups compared favorably. The mean post-implantation loss of the test item-treated females was unaffected.
When compared with the control females, the mean litter sizes were unaffected by the treatment with the test item.
The post-natal loss of the test item-treated females was unaffected.

ORGAN WEIGHTS (PARENTAL ANIMALS)
In males, the mean absolute and relative organ weights were unaffected by the treatment with the test item.

GROSS PATHOLOGY (PARENTAL ANIMALS)
Findings in decedents:
One male of the control group had incompletely collapsed lungs, unilateral size reduction of the testes and epididymides (the latter of which also had a tan nodule), whereas one male treated with 1000 mg/kg/day had dark red inflated lungs, unilateral size reduction of the testes and epididymides, and reddish foci on the thymus. All premature decedents were considered to be incidental or accidental, and were deemed not to be due to adverse events caused by treatment with the test item. One male and one female (40 mg/kg/day) showed no macroscopical changes.
Males:
In the survivors, there were no gross lesions that could be attributed to treatment with the test item. All findings recorded were considered to be within the range of normal background alterations.
Females:
There were no macroscopical finding in any dam treated with 40 mg/kg/day or 1000 mg/kg/day. Discoloration of the ovaries was noted in one female treated with 200 mg/kg/day.

HISTOPATHOLOGY (PARENTAL ANIMALS)
Findings in Decedents:
In one male treated with 1000 mg/kg/day, bronchial watery contents containing inflammatory cells and desquamated bronchial epithelial cells as well as diffuse alveolar edema and congestion were recorded in the lung. These were considered to be due to an accidental influx of the dosing solution into respiratory tracts and to be the cause of death. In one male of the control group, alveolar edema with flocculent materials and congestion were
recorded, and these were also considered be due to an accidental influx of the dosing solution into respiratory tracts and to be the cause of death.
The remainder of findings recorded in these two males were within the range of normal background lesions which may be recorded in animals of this strain and age. No findings of toxicological relevance were observed in one male and one female (both treated with 40 mg/kg/day). Although only a limited number of organs/tissues were examined in these animals, there were no deaths which could be attributed to adverse events caused by the
test item in animals treated with 200 or 1000 mg/kg/day. Therefore, these deaths were considered to be of incidental or accidental as well, and were deemed not to be associated with the treatment with the test item.
Findings in Surviving Rats:
There were no histomorphologic lesions that could be attributed to treatment with the test item. All microscopic findings recorded were within the range of normal background lesions which may be recorded in animals of this strain and age. In one female of control group, a necrotic tissue debris mass probably derived from necrotic placenta and fetus was observed in the uterus. The ovary of this animal showed a normal histologic appearance of a pregnant female. This was considered to be a spontaneous fetal death. No microscopical findings of toxicological relevance were observed in the ovary of female no. 86.
Testes - Detailed Examination Including Sperm Staging:
The stages were checked on completeness of cell populations, completeness of stages and degenerative changes. There were no abnormalities on the completeness of stages or cell populations of the testes examined in this study. All histologic findings recorded were within the range of normal
background lesions which may be recorded in animals of this strain and age. As a result of the detailed examination of the testis, it was judged that there were no test itemrelated effects on the testicular histomorphology, including spermatogenesis and interstitial cell structure.
No microscopical findings of toxicological relevance were observed in testes of animal no. 2 (control) and no. 42 (1000 mg/kg/day), which were mated with female nos. 46 and 86, respectively, but did not litter.

Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effect related to the test item
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 specified
Gross pathological findings:
no effects observed
Histopathological findings:
not specified
VIABILITY (OFFSPRING)
Blue discoloration of the abdomen or extremity was noted in a small number of pups at 40 mg/kg/day and 1000 mg/kg/day. One pup of a dam treated with 200 mg/kg/day was missing the tail apex. The low incidence and type of these findings suggested incidental occurrence.

BODY WEIGHT (OFFSPRING)
The mean body weights of the pups on day 4 post partum were considered to be unaffected by the treatment with the test item

GROSS PATHOLOGY (OFFSPRING)
There were no test item-related macroscopical findings in any pup necropsied on day 4 post partum at any dose level.

Others
No effectThe sex ratios at first litter check were within the range of typical variation.
Dose descriptor:
NOEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effect related to the test item
Reproductive effects observed:
not specified
Conclusions:
The NOEL (No Observed Effect Level) and the NOAEL (No Observed Adverse Effect Level) for general toxicity in males and females and for reproduction/developmental toxicity was considered to be 1000 mg/kg/day.
Executive summary:

Soribtan caprylate was administered to male rats for at least 28 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 post partum. The dose levels applied are 40, 200, and 1000 mg/kg body weight/day, and controls received the vehicle PEG 300 only. There were no effects upon mean daily food consumption or body weight development of parent animals, no effects upon mean absolute or relative organ weights of males, and no macroscopical or microscopical findings of toxicological relevance. No effects on mating performance, fertility, corpora lutea count, duration of gestation, implantation rate and post-implantation loss as well as litter size and post-natal loss were noted at any dose level. No test item-related findings in pups or effects on pup body weights were noted at any dose level. Although one male treated with 1000 mg/kg/day and one male treated with 40 mg/kg/day were found dead during the pairing period, these were considered to be unrelated to any systemic toxicity. One female treated with 1000 mg/kg/day was killed four days after the scheduled litter date and one female treated with 40 mg/kg/day was found dead on day 4 of the prepairing period. These deaths were also considered to be unrelated to any systemic toxicity.

The NOEL (No Observed Effect Level) and the NOAEL (No Observed Adverse Effect Level) for general toxicity in males and females and for reproduction/developmental toxicity was considered to be 1000 mg/kg/day.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
reliable and robust; 3 studies / reports are available on target or source chemicals
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The reporoduction toxicity of sorbitan caprylate was derived from experimental studies and analogue approaches using sorbitan stearate as source chemical.

The analogue approach using sorbitan stearate as source chemical is justified:

Both chemicals are of comparable structures with minor deviations and can be characterized as an ester of sorbitan and a fatty acid. Compared to the source chemical, the target chemical has a shorter alkyl chains that affect its physicochemical properties. But based on the kinetic / metabolic investigations on both chemicals, the length of the alkyl chain is not considered to have significant impact on the metabolic pathway or toxicological mode of action. Oral gavage studies in rats administered C14 labeled sorbitan stearate in oil solutions have demonstrated that about 90% of the substance was absorbed and hydrolyzed to stearic acid and sorbitan. The metabolic fate of sorbitan caprylate was investigated using a lipase assay. The hydrolysis mediated by porcine pancreas lipase was quantitatively determined. The target chemical sorbitan caprylate is proved to be hydrolyzed and caprylic acid was formed . These findings suggest that metabolism of the sorbitan occur initially via enzymatic hydrolysis, leading to sorbitan and the corresponding natural acids.

Based on the above mentioned information, it is reasonable to consider that these two substances are comparable in their metabolic fate and thereby toxicological profiles. Hence, the source chemical is considered as “suitable with interpretation” analog.

According to the available toxicity studies, the findings are also comparable for target and source chemicals:

·        The findings in acute toxicity studies are comparable. Both chemicals are of no acute toxicity.

·        The findings in subacute dose toxicity studies are comparable. No treatment effects were observed in 28-day repeated toxicity studies in Wistar rats. The same NOEL of 1000 mg/kg bw/d was derived for both chemicals.

·        The findings in genetic toxicity are comparable. Both chemicals did not induce gene mutations in Ames tests, but induced structural chromosomal aberrations in cell lines of Chinese Hamster.

·        The findings in reproduction / developmental toxicity studies are comparable.

The reproduction toxicity potential of sorbitan caprylate was investigated in a reproduction/developmental toxicity screening test in rats accoring to OECD 421. The substance was administered to male rats for at least 28 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 post partum. The dose levels are 0, 40, 200, 1000 mg/kg body weight/day using PEG 300 as a vehicle. No effect on mating performance or fertility was observed at any dose level. There were no findings at first litter check or during the lactation period that were indicative of a test item-related effect. On day 4 post partum, there were no abnormal findings noted in surviving pups at any dose level. The mean body weights of the pups on day 4 post partum were considered to be unaffected by the treatment with the test item. There were also no test item-related macroscopical findings in any pup necropsied on day 4 post partum or in pups found dead at first litter check. Based on the results, The NOEL and the NOAEL for general toxicity in males and females and for reproduction/developmental toxicity was considered to be 1000 mg/kg/day.

 

The reproduction toxicity potential of the source chemical sorbitan stearat was investigated in a combined repreated dose toxicity study with the reproduction/developmental toxicity screening test. In this subacute toxicity test, the test item was administered daily by oral gavage to Sprague-Dawley rats of both sexes at dose levels of 40, 200 and 1000 mg/kg body weight/day. A control group was treated similarly with the vehicle only. The study comprised a reproductive/developmental toxicity screening test, intended to provide information on possivle effects on male and female reproductive performance and also on the development of the F1 offspring from conception to day 4 post-partum. Clinical signs, outside cage observation, food consumption and body weights were recorded periodically. At the end of the dosing and the treatment-free recovery period, blood samples were withdrawn for hematology and plasma chemistry analyses. Evaluation of the mating, pregnancy, parturition and post-partal periods, and relevant parameters and/or indices were performed and/or calculated. All animals were killed, necropsied and examined post mortem. Histological examinations were performed on organs and tissues. Based on the results of this study, 1000 mg/kg body weight/day of the test item was established as the no-observed-effect-level (NOEL) for repeated toxicity, reproductive and developmental effects.

The toxicity of sorbitan stearate was investigated in a 2 -year study with 4 generations.Wistar rats (25 groups consisting of 12 males and 20 females/dose; F0 generation) were administered with sorbitan monostearate in the diet at 0, 5, 10 or 20% (~ 0, 2500, 5000 or 10,000 mg/kg-bw/day) for two years (spanning four generations). During the course of the study, observations were made of physical appearance, behavior, reproduction, and lactation through three successive generations, and gross and histologic evaluations were made at termination. Growth was normal, except for males in the 20 percent group. These animals had reduced weight gains. Fertility and gestation parameters for the initial generation were similar for control and test groups. Infant deaths for the 10 and 20 percent ester groups were higher than for the control group which was considered to be due to maternal neglect and reduced milk production. Reproduction and lactation data were also recorded for the F1 and F2 generations. The proportions of matings resulting in pregnancy were lower in the 20 percent dietary ester group, as was the proportion of nurselings surviving the lactation period. Based on the result, it was concluded:

LOAEL (reproductive toxicity) ~ 10,000 mg/kg-bw/day (based on decreased reproductive performance and pregnancy rate)

NOAEL (reproductive toxicity) ~ 5,000 mg/kg-bw/day

The same results could be also expected for sorbitan caprylate due to the structrual similarities.


Short description of key information:
Oral:
NOEL (OECD 421, gavage, rat): 1000 mg/kg bw

Oral (read-across using sorbitan stearate as source chemical):
NOEL (OECD 422 , gavage, rat): 1000 mg/kg bw
NOAEL (2 years, feed, rat): 5000 mg/kg bw

Justification for selection of Effect on fertility via oral route:
Guideline study under GLP

Effects on developmental toxicity

Description of key information
Oral (read-across using sorbitan stearate as source chemical):
NOAEL (2 years, feed, rat): 5000 mg/kg bw
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
reliable and robust; 2 studies / reports are available on target or source chemicals
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

The developmental toxicity of sorbitan caprylate was derived from analogue approaches using sorbitan stearate as source chemical.

The analogue approach using sorbitan stearate as source chemical is justified:

Both chemicals are of comparable structures with minor deviations and can be characterized as an ester of sorbitan and a fatty acid. Compared to the source chemical, the target chemical has a shorter alkyl chains that affect its physicochemical properties. But based on the kinetic / metabolic investigations on both chemicals, the length of the alkyl chain is not considered to have significant impact on the metabolic pathway or toxicological mode of action. Oral gavage studies in rats administered C14 labeled sorbitan stearate in oil solutions have demonstrated that about 90% of the substance was absorbed and hydrolyzed to stearic acid and sorbitan. The metabolic fate of sorbitan caprylate was investigated using a lipase assay. The hydrolysis mediated by porcine pancreas lipase was quantitatively determined. The target chemical sorbitan caprylate is proved to be hydrolyzed and caprylic acid was formed . These findings suggest that metabolism of the sorbitan occur initially via enzymatic hydrolysis, leading to sorbitan and the corresponding natural acids.

Based on the above mentioned information, it is reasonable to consider that these two substances are comparable in their metabolic fate and thereby toxicological profiles. Hence, the source chemical is considered as “suitable with interpretation” analog.

According to the available toxicity studies, the findings are also comparable for target and source chemicals:

·        The findings in acute toxicity studies are comparable. Both chemicals are of no acute toxicity.

·        The findings in subacute dose toxicity studies are comparable. No treatment effects were observed in 28-day repeated toxicity studies in Wistar rats. The same NOEL of 1000 mg/kg bw/d was derived for both chemicals.

·        The findings in genetic toxicity are comparable. Both chemicals did not induce gene mutations in Ames tests, but induced structural chromosomal aberrations in cell lines of Chinese Hamster.

·        The findings in reproduction / developmental toxicity studies are comparable.

The toxicity of sorbitan stearate was investigated in a 2 -year study with 4 generations.Wistar rats (25 groups consisting of 12 males and 20 females/dose; F0 generation) were administered with sorbitan monostearate in the diet at 0, 5, 10 or 20% (~ 0, 2500, 5000 or 10,000 mg/kg-bw/day) for two years (spanning four generations). During the course of the study, observations were made of physical appearance, behavior, reproduction, and lactation through three successive generations, and gross and histologic evaluations were made at termination. Growth was normal, except for males in the 20 percent group. These animals had reduced weight gains. Fertility and gestation parameters for the initial generation were similar for control and test groups. Infant deaths for the 10 and 20 percent ester groups were higher than for the control group which was considered to be due to maternal neglect and reduced milk production. Reproduction and lactation data were also recorded for the F1 and F2 generations. The proportions of matings resulting in pregnancy were lower in the 20 percent dietary ester group, as was the proportion of nurselings surviving the lactation period. Based on the result, it was concluded:

LOAEL (reproductive toxicity) ~ 10,000 mg/kg-bw/day (based on decreased reproductive performance and pregnancy rate)

NOAEL (reproductive toxicity) ~ 5,000 mg/kg-bw/day

The same results could be also expected for sorbitan caprylate due to the structrual similarities. Further testing on a second species (e.g. rabbit) is unjustified considering scientific as well as animal welfare reasons.

 


Justification for selection of Effect on developmental toxicity: via oral route:
Guideline study under GLP

Justification for classification or non-classification

Based on the available data no classification is warranted according to the criteria laid down in the EU Dangerous Substances Directive (67/548/EEC) and in the EU Classification Labelling and Packaging Regulation (1272/2008/EC).