Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No study available

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 study available

Effects on developmental toxicity

Description of key information

No adverse developmental effects were observed.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
The analogue approach is used for the hazard assessment of toxicological endpoints for the registration of the target substance pentaerythritol ricinoleate (CAS 78-22-8) based on generation of different breakdown/metabolic products, resulting not only in similar physical and biological systems (Scenario 2 of the Read-Across Assessment Framework (RAAF, ECHA, 2015), but also consequently in similar physico-chemical and toxicological properties. The source compounds for read-across are fatty acids, C16-18, esters with pentaerythritol (CAS 85116-93-4) and trimethololpropane ricinoleate (CAS 67025-99-4). It is proposed that the different alcohols resulting from ester hydrolysis of the source compounds and the target substance will not result in significant variation in biological effects.
Neither target nor source compounds are classified for mammalian hazardous effects. The use of reliable experimental data, all evaluated as reliable according to Klimisch scores of 1 or 2, to estimate the toxicity of the registered substance is adequate for the purposes of fulfilling the data requirements of registration and classifying potential hazards. Similar grouping into categories has been accepted by other regulatory agencies (U.S. EPA, 2010; U.S. FDA for food notifications). Thus, this read-across approach is adequate for the purposes of risk assessment and classification and labeling.
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
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, Wiga GmbH, Sulzfeld, Germany
- Age at study initiation: 8, weeks
- Weight at study initiation: 195-199 g
- Fasting period before study: no data
- Housing: semi-barrier sustained animal room, individually in Markrolon type M3 cages
- Diet (e.g. ad libitum): Altromin No. 1324, Altromin GmbH, Lage, Germany, ad libitum
- Water (e.g. ad libitum): community tap water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 40-56
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To:
Route of administration:
oral: gavage
Vehicle:
other: arachidis oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): daily
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:

VEHICLE
- Justification for use and choice of vehicle (if other than water): optimal solubility
- Concentration in vehicle:
- Amount of vehicle (if gavage):
- Lot/batch no. (if required): arachidis oil, DAB 10
- Purity:PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle:
- Amount of vehicle (if gavage): 5 ml/kg body weight
- Lot/batch no. (if required):
- Purity:
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Animals were cohabitated 1:1, and females were examined every morning for the presence of sperm in the vaginal canal or a vaginal plug; this was designated GD0 of gestation.
Duration of treatment / exposure:
GD 6-15
Frequency of treatment:
once daily
Duration of test:
20 days
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
24
Control animals:
yes, concurrent vehicle
Details on study design:
Animals were randomly assigned to test groups using random tables. They were treated and euthanised (ether) on GD20 in accordance with Animal Welfare legislation and guidelines. Foetuses were removed by Caesarian section.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: GD0, 6, 16 and 20

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on GD20
- Organs examined: Gross macroscopic examination of all maternal organs, with emphasis on uterus, uterine contents, position of the foetuses and presence of corpora lutea, and pre- and post-implantations

OTHER:
Ovaries and uterine content:
Examination was made of each animal's uterus, uterine contents, position of the foetuses and presence of corpora lutea, and pre- and post-implantations. The pre-implantation and post-implantation loss and intrauterine resorption sites were evaluated. Intrauterine deaths were classified on the basis of the absence (early resorption) and of the presence (late resorption) of foetal or decidual tissue in addition to placental tissue.
Fetal examinations:
Living and dead foetuses were removed from the uterus. The living foetuses were sexed, weighed individually with placentae and examined for gross external abnormalities. Foetal soft tissue and skeletal developmen t were investigated. The Wilson technique was applied to half of the foetuses to evaluate potential visceral changes (Wilson and Warkany, 1965). The remaining foetuses were cleared in a solution of potassium hydroxide and stained with Alizarin Red according to Dawson (1926). Alterations in foetuses were classified according into four categories (Klimisch et al., I992).
Statistics:
If the variables could be assumed to follow a normal distribution, the Dunnett test, based on a pooled variance, was applied for the comparison between the treated groups and the control group. The Steel test was applied when the data could not be assumed to follow a normal distribution. Fisher's exact test for 2 x 2 tables was applied if the variables could be dichotomized without loss of information (Bonferroni - Holm corrected).
Indices:
not specified
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Details on results:
2-Ethylhexyl stearate did not cause adverse effect to the maternal rats at any time during the pregnancy. No mortalities occurred in the dams during the study, either in the vehicle control or in the groups exposed to 2-ethyl­hexyl stear te up to 1000 mg/kg body weight. The absolute and the corrected body weight (Table 2) and body weight gain was comparable between the groups. No deviation was observed during the treatment period. Gross macroscopic examination of the maternal organs including ovaries and uterus revealed no alterations. The no-adverse-effect dose of 1000 mg/ kg body weight corresponds to the NOAEL of the repeated dose toxicity data in rats.
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
In the 100 and 1000 mg/ kg body weight groups the post-implantation loss and total embryonic deaths were significantly decreased.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: no adverse effects
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
not examined
Details on embryotoxic / teratogenic effects:
The weights of live foetuses exhibited no significant differences on a litter and individual basis. In comparison with the control group, in the 100 and 1000 mg/ kg body weight groups the post-implantation loss and total embryonic deaths were significantly decreased. Non-dose-related findings were considered to be incidental, compared to control values. Mean foetal placental and uterus weights were not affected by treatment. Foetal sex ratio was comparable in all groups. A hydrops was noted in one control group foetus.

Incidences were also compared to the historical controls of the OECD guideline No. 414 studies using the same strain (Sprague-Dawley CD). Findings both on the individual foetus and on the litter basis did not differ from the historical control. From the visceral examinations, one hydrocephalus internus was found which has to be considered as an individual non-dose-related finding which also occurs in the historical data at a comparable level (0.4 %). All other changes were slight and also occurred in the control population. Concerning the skeletal examinations on the basis of the foetal incidence, there are differentiated results in some findings such as 'non-ossification' of sternebrae (retardation). However, the total frequency of the findings 'incomplete ossification' including 'non-ossification' of all sternebrae show no substantial differences between the untreated and treated groups.I
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
In a guideline OECD 414 developmental toxicity study of 2-ethylhexyl stearate in CD rats at 100, 300 and 1000 mg/kg bw/d in arachidis oil, no adverse maternal effects, fetotoxic effects or teratogenic effects or variations were observed. The NOAEL for maternal toxicity is > 1000 mg/kg bw/d, and the NOAEL for developmental toxicity is > 1000 mg/kg bw/d. The substance is not classified for developmental effects according to Regulation EC No. 1272/2008.
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
The analogue approach is used for the hazard assessment of toxicological endpoints for the registration of the target substance pentaerythritol ricinoleate (CAS 78-22-8) based on generation of different breakdown/metabolic products, resulting not only in similar physical and biological systems (Scenario 2 of the Read-Across Assessment Framework (RAAF, ECHA, 2015), but also consequently in similar physico-chemical and toxicological properties. The source compounds for read-across are fatty acids, C16-18, esters with pentaerythritol (CAS 85116-93-4) and trimethololpropane ricinoleate (CAS 67025-99-4). It is proposed that the different alcohols resulting from ester hydrolysis of the source compounds and the target substance will not result in significant variation in biological effects.
Neither target nor source compounds are classified for mammalian hazardous effects. The use of reliable experimental data, all evaluated as reliable according to Klimisch scores of 1 or 2, to estimate the toxicity of the registered substance is adequate for the purposes of fulfilling the data requirements of registration and classifying potential hazards. Similar grouping into categories has been accepted by other regulatory agencies (U.S. EPA, 2010; U.S. FDA for food notifications). Thus, this read-across approach is adequate for the purposes of risk assessment and classification and labeling.
Reason / purpose for cross-reference:
read-across source
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Crl:CD BR VAF/Plus, Charles River Laboratories, Inc. (Kingston, NY)
- Age at study initiation:
- Weight at study initiation:
- Fasting period before study:
- Housing: housed singly in stainless steel wire-bottomed cages
- Diet (e.g. ad libitum): Certified Rodent Diet 5002 (PMI Feeds Inc., St. Louis, MO)
- Water (e.g. ad libitum): Local water processed through reverse osmosis membrane with chlorine added as a bacteriostat.
- Acclimation period: yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 66-77
- Humidity (%): 30-70
- Air changes (per hr): 10 changes per hour through 99.97% HEPA filters
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To:
Route of administration:
dermal
Vehicle:
corn oil
Remarks:
Mazola (Best Foods Division, Englewood Cliffs, NJ)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: prepared daily, stirred continuously during use.
DIET PREPARATION
- Rate of preparation of diet (frequency): daily
- Mixing appropriate amounts with (Type of food): NA, dermal exposure
- Storage temperature of food: NA, made daily

VEHICLE
- Justification for use and choice of vehicle (if other than water): skin application
- Concentration in vehicle: 100, 300, 1000 mg/ml

The backs of the rats were clipped during the acclimation period using an Oster clipper. The clipped area (5 x 7 cm, approximately 10% of body surface area) extended from the shoulders to the hip joints and extended ventrolaterally from the dorsal midline on each side. A " map " of the clipped area was made for each animal, noting any areas of apparent hair tufts or natural differences in skin colorization. Each rat was fitted with an Elizabethan collar on the day after the rat arrived, which was worn continuously until day 2 of cohabitation and again continuously throughout pregnancy (DG 0- 20).
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused with males
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: maximum of 5 days
- After 5 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- Verification of same strain and source of both sexes: yes, sourced from same vendor
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
GD 6-15
Frequency of treatment:
daily
Duration of test:
6 hours
Dose / conc.:
200 mg/kg bw/day (nominal)
Dose / conc.:
600 mg/kg bw/day (nominal)
Dose / conc.:
2 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25 pregnant females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
- Rationale for animal assignment (if not random): weight-ordered randomization procedures.
Body weights were collected on GD0, these were collected and used to assign animals to treatment groups based on computer-generated (weight-ordered) randomization procedures, such that the mean body weights of each group were not statistically different at the 5% probability level using the Bartlett's Test for homogeneity of variances.

The backs of the rats were clipped during the acclimation period using an Oster clipper. The clipped area (5 x 7 cm, approxi­ mately 10% of body surface area) extended from the shoulders to the hip joints and extended ventrolaterally from the dorsal midline on each side. A " map " of the clipped area was made for each animal, noting any areas of apparent hair tufts or natural differences in skin colorization. Each rat was fitted with an Elizabethan collar on the day after the rat arrived, which was worn continuously until day 2 of cohabitation and again continuously throughout pregnancy (DG 0- 20).

The dosage volume of 2 mL/ kg was adjusted daily on the basis of the individual body weights recorded each day before the daily topical application. The dosage amount was applied directly to the clipped area on the dorsum of the rat at approximately the same time each d ay and spread uniformly over the area with a glass rod. The skin application site was occluded during treatment with a gauze pad secured with Vetrap'" or Micropore II tape to minimize loss of material from under the patch. After the 6-hr exposure period, the occlusive dressing was removed and the treatment area was wiped with a dermal wipe pad dampened with an aqueous 1% solution of soap and then patted dry with a second clean pad. The application site was also examined for residue of the test material prior to the daily rinse.

After dosing the rats were monitored for viability at least twice daily. Body weights and feed consumption values were recorded on GD0 and daily during the dosage and post-dosage period. Clinical signs were monitored once daily before treatment, and approximately 60 min post-dosage during the dosage period and once daily during the post-dosage period. Additionally, the dosing site was examined daily prior to application of the test material for signs of skin irritation and was graded for severity applying modifications of those described by Draize and the National Research Council (Draize et al., 1944; National Research Council, 1977). During the post-dosage period (GD 16- 20), the dosing site was examined for skin irritation once daily. Termination was by CO2 inhalation on GD20, when rats were Caesarian-sectioned; the gravid uterus was excised and weighed and the fetuses removed and placed in individual containers. Examinations were conducted “blind” to the treatment/dose. Live fetuses were sacrificed by ip injection of euthanasia solution (Beuthanasia-D Special, Schering-Plough Animal Health).
Maternal examinations:
All rats were monitored for viability twice daily; body weights and feed consumption values were recorded on GD0 and daily during the dosage and post-dosage period. Clinical signs were monitored once daily before treatment, approx. 60 min post-dosage during dosage period, and once daily during the post-dosage period. Dosing sites on skin were monitored daily prior to application of test material.
Ovaries and uterine content:
The number and distribution of corpora lutea, implantation sites, live and dead fetuses, and early and late resorptions were recorded for each female rat. An early resorption was defined as one in which embryonic structures were not grossly evident. A late resorption was defined as one in which embryonic structures were grossly evident. A live fetus was defined as a term fetus that responded to stimuli. Dead fetuses and late resorptions were differentiated by the degree of autolysis present; marked to extreme autolysis indicated a late resorption.

Fetal examinations:
Fetal observations included sex determination, gross external alterations, and body weights (of live fetuses). Approximately one half of the fetuses were examined for solf tissue alterations using a variation of the micro dissection technique of Staples (1974). The heads of these were fixed in Bouin solution and subsequently examined using a free-hand cross-sectioning technique (Wilson, 1965). Gross lesions found at visceral exam were retained in neutral buffered 10% formalin for future evaluation. The remaining fetuses in each litter were eviscerated, cleared, stained with alizarin red S and examined for skeletal alterations.
Statistics:
Clinical observation and other proportion data were analyzed using the Variance Test for Homogeneity of the Binomial Distribution (Snedecor and Cochran, 1967). Quantitative continuous data (e.g., maternal body weights, body weight changes, feed consumption values, litter averages for percent male fetuses, percent resorbed conceptuses, fetal body weights, fetal anomaly data, and fetal ossification data) were analyzed using Bartlett's Test for Homogeneity of Variance (Sokal and Rohlf, 1969) and the Analysis of Variance (ANOVA, Snedecor and Cochran, 1967) when Bartlett's Test was not significant (p> 0.05). If the ANOVA was significant (p ≤0.05), Dunnett' s Test (Dunnett, 1955) was used; if ANOVA was not appropriate, the Kruskal-Wallis Test (Sokal and Rohlf, 1969) was used when ≤ 75% ties were present. In cases where the Kruskal-Wallis Test was statistically significant (p ≤ 0.05), Dunn’s Method of Multiple Comparisons (Dunn, 1964) was used. If there were > 75% tied, Fisher’s Exact Test (Siegel, 1956) was used to analyze the data.
Count data obtained at Caesarian-sectioning of the dams were evaluated using the procedures described above for the Kruskal-Wallis Test.
Indices:
see above
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
Dose-dependent increases in incidence of erythema (Grades 1 and 2), flaking (Grades 1, 2 and 3), edema (Grades 1 and 2) and scabbing, were seen in the mid and high dose groups. Each of these were significant in the high dose group (p ≤ 0.01); there were no significant differences in skin irritation between the low dose group and vehicle controls. The vehicle resulted in Grade 1 flaking in 3 rats on GD16 or 18, persisting until necropsy. In-life clinical findings were also observed as skin flaking and scabbing related to the wearing of Elizabethan collars.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
2 rats in control group, and 1 in high dose group died within 6 h of application of the first dose (GD^) and were replaced. They appeared normal after examination and necropsy; no cause of death was established. All were pregnant. All other animals, including replacements, survived until sacrificed.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Necropsy findings were limited to skin flaking and scabbing related to wearing Elizabethan collars.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
effects observed, non-treatment-related
Description (incidence and severity):
1 dam in the mid dose group had a litter of all (7) resorptions. This was not considered test substance related. As this skewed distribution of data, statistical analyses were conducted with and without this dam/litter. No meaningful differeneces were obersed with or without this dam; therefore, only the analyses without this dam were included in results. 1 control litter included a late resorption.
Dead fetuses:
no effects observed
Description (incidence and severity):
No dead fetuses
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: systemic toxicity
Dose descriptor:
NOEL
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: dermal irritation
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: general developmental toxicity/teratogenic effects/fetotoxicity
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no

No clinical observations other than local skin irritation were associated with treatment. The assessment of devlopmental toxicity showed no difference across dosage groups up to 2000 mg/kg bw/d for any Caesarian-sectioning or litter parameters measured. Application of the test material did not cause gross external, soft tissue or skeletal malformations or variations. The number of litters with any alteration numbered 10, 8, 14 and 7, respectively, among the dosage groups 0, 200, 600 and 2000 mg/kg bw/d.

The number of fetuses with any alteration numbered 13, 10, 20 and 9, respectively, among the dosage groups 0, 200, 600 and 2000 mg/kg bw/d.

The litter averages for corpora lutea, implantations, litter size, live and dead fetuses, early and late conceptuses, fetal body weights (total, male and female), and percent live male fetuses were comparable among the 4 dosage groups and did not differ significantly. There were no dead fetuses, no dams with all conceptuses resorbed, and all placentae appeared normal.

Analyses of the average numbers of fetal ossification sites per litter did not reveal biologically important or statistically significant differences among the 4 dosage groups. The extent of ossification of the hyoid, vertebrae, ribs, sternum, forelimbs and hindlimbs was comparable in all groups.

Conclusions:
In a protocol according to or similar to an OECD 414 developmental toxicity study, a trimethylolpropane diglyceride ester (analogue) in a corn oil suspension was applied dermally under occlusive patch for 6 hour periods on gestation days 6-15 to mated CD gravid rats. After Caesarian delivery of dams on GD20, maternal animals and offspring were assessed. The exposure showed no systemic toxicity or developmental effects at any of the tested doses, although skin irritation was observed in a dose dependent manner. The NOAEL(maternal systemic toxicity) was 2000 mg/kg bw/d, and the NOAEL(developmental) was also 2000 mg/kg bw/d. These data are applicable to the target (registered) substance and fill the data requirements of REACH.
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:
adequate
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
2 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
adequate
Additional information

In a guideline OECD 414 developmental toxicity study of 2-ethylhexyl stearate (analogue) by the oral route in CD rats at 100, 300 and 1000 mg/kg bw/d in arachidis oil, no adverse maternal effects, fetotoxic effects or teratogenic effects or variations were observed at the higest dose tested.  The NOAEL for maternal toxicity is > 1000 mg/kg bw/d, and the NOAEL for developmental toxicity is > 1000 mg/kg bw/d.  

In a second OECD 414 developmental toxicity study, a trimethylolpropane diglyceride ester (analogue) in a corn oil suspension was applied dermally under occlusive patch for 6-hour periods on gestation days 6-15 to mated CD gravid rats.  The exposure showed no systemic toxicity or developmental effects at any of the tested doses. The NOAEL(maternal systemic toxicity) was 2000 mg/kg bw/d, and the NOAEL(developmental) was also 2000 mg/kg bw/d.  

Mode of Action Analysis / Human Relevance Framework

Not applicable

Justification for classification or non-classification

Esters of fatty acids are not known to be toxic to adults or developing offspring. The substance is not classified for developmental effects according to Regulation EC No. 1272/2008.

Additional information