Reaction product with n-butanol of high-boiling stream resulting from the hydroxylation, oxidative cleavage and hydrolysis of vegetable oil saturated and unsaturated C16-C22 triglycerides.

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Reference 1

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:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP-guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Duration of treatment / exposure:

Males: 14 days before mating and for 28 days thereafter
Females: total of 42-53 days beginning 14 days before mating to day 3 of lactation

Frequency of treatment:

7 days /week

Remarks:

Doses / Concentrations:
100, 300, 1000 mg/kg
Basis:
actual ingested

No. of animals per sex per dose:

13

Control animals:

yes, concurrent vehicle

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily, before and after administration

BODY WEIGHT: Yes
- Time schedule for examinations: Males on Days 1, 8, 15, 22, 29, 36 and 43, females on Days 1, 8 and 15 of treatment, Days 0, 7, 14 and 20 of gestation and Days 0 and 4 of lactation

FOOD CONSUMPTION: not examined

Oestrous cyclicity (parental animals):

Observed

Sperm parameters (parental animals):

Parameters examined in parental animals:
testis weight, epididymis weight, other: histopathology

Litter observations:

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals on Day 43
- Maternal animals: All surviving animals on Day 4 of lacation

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
Organ weight: kidneys and spleen of both sexes and testes and epididymides of males.
Microscopic observation: testes and epididymides of males; ovary and uterus of females

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring were sacrificed at 4 days of age.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations.
Statistics

Reproductive indices:

copulation index (no. of copulated rats/no. of mated rats x 100),
fertility index (no. of pregnant females/no. of females with successful copulation x 100),
gestation index (no. of females with live pups/no. of pregnant females x 100),
implantation index (no. of implantation sites/no. of corpora lutea x 100),
delivery index (no. of pups born/no. of implantation sited x 100)

Offspring viability indices:

birth index (no. of live pups on day 0/no. of implantation sites x 100),
live birth index (no. of live pups on Day 0/no. of pups born x 100),
viability index (no. of pups alive on Day 4 of lactation/no. of pups born x 100)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Dose-dependent increase in number of rats with salivation after dose administration in both sexes.

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:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

no effects observed

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

300 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: organ weights: kidney weights increased

Dose descriptor:

NOAEL

Remarks:

reproduction

Effect level:

>= 1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: NOAEL for reproductive parameters is corresponding to the highest dose tested

Clinical signs:

no effects observed

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

Pup viability on PND 4 was decreased.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

pup weight on PND 0 and 4 was slightly decreased (without reaching statistical significance)

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

300 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: pup weight; viability index

Reproductive effects observed:

not specified

Table 1: Number of animals showing salivation upon treatment [male/female]

	Dose [mg/kg bw/day]
Days of treatment	0	100	300	1000
1-7	-	-	-	12/9
18-14	-	-/1	4/4	13/13
15-21	-	3/2	7/9	13/13
22-28	-	-	2/1	12/13
29-35	-	-	6/4	13/13
36-42	-	-	6/3	13/12
43	-	-	-	-
Total	-	3/3	11/9	13/13

 

Table 2: Organ weights

Males after 42 days of treatment		Dose [mg/kg bw/day]
Kidney		0	100	300	1000
absolute weight [g]	mean	2.96	3.12	3.04	3.08
	SD	0.39	0.34	0.32	0.35
relative weight [% of mean body weight]	mean	0.6	0.61	0.63	0.65*
	SD	0.05	0.04	0.06	0.06
Spleen
absolute weight [g]	mean	0.79	0.95	0.84	0.9
	SD	0.14	0.19	0.11	0.2
relative weight [% of mean body weight]	mean	0.16	0.18*	0.17	0.19**
	SD	0.02	0.03	0.02	0.03
Females at Day 4 of lactation
Kidney
absolute weight [g]	mean	1.95	1.97	2.1	2.11
	SD	0.15	0.19	0.22	0.17
relative weight [% of mean body weight]	mean	0.6	0.58	0.62	0.65
	SD	0.04	0.03	0.05	0.07
Spleen
absolute weight (in g)	mean	0.59	0.74*	0.65	0.68
	SD	0.08	0.16	0.13	0.09
relative weight (% of mean body weight)	mean	0.18	0.22	0.19	0.21
	SD	0.03	0.04	0.03	0.03

 

Table 3: Reproductive parameters

Dose [mg/kg bw/day]		0	100	300	1000
No.of female animals:		13	13	13	13
No. of mated pairs:		13	13	13	13
No. of copulated pairs:		13	13	13	13
Copulation index [%]		100	100	100	100
No. of pregnant females		12	12	12	12
Fertility index [%]		92.3	92.3	92.3	92.3
Pairing day until copulation
	mean	4.1	2.6	3	2.7
	SD	3.3	0.8	2.3	1
Frequency of vaginal estrus
	mean	1.1	1	1.2	1
	SD	0.3	0	0.6	0
No. of pregnant females with pups alive:		12	12	12	12
Gestation index (%)		100	100	100	100
Gestation length (days)
	mean	22.3	22.1	22.2	22.2
	SD	0.5	0.3	0.4	0.4
No. of corpora lutea
	mean	15.7	15.6	17	16.9
	SD	2	1.6	1.9	1.7
No.of implantation site
	mean	14.8	14.7	15.8	15.5
	SD	2.6	2.1	3.1	2.1
Implantation index [%]
	mean	94.2	94	92.2	91.5
	SD	7.8	8.4	14.1	7.5
Day 0 of lactation
No.of pups born
	mean	13.6	14.2	15	14.6
	SD	2.4	1.9	2.9	2.3
Delivery index [%]
	mean	91.8	96.7	95.5	93.9
	SD	6.5	3.4	5.7	5.9
No.of pups alive
	mean	13.3	13.9	14.3	13.7
	SD	2.4	1.9	2.6	3.3
Birth index (%)
	mean	90.1	95.2	91.8	88.2
	SD	6.1	6	8.8	16.8
Live birth index (%)
	mean	98.2	98.4	96.2	93.6
	SD	4.6	4.1	8.4	15.2
Pups weight [g]
Male	mean	6.5	6.4	6.2	6.1
	SD	0.7	0.6	0.8	0.7
Female	mean	6.1	6	5.8	5.8
	SD	0.6	0.6	0.7	0.5
Sex ratio on day 0 of lactation [no. of male pups/total no. of pups]
	mean	47.6	41.4	49.4	48.6
	SD	13	7.7	12.7	11.9
Day 4 of lactation
No.of pups alive
	mean	13.3	13.8	13.1	13.3
	SD	2.4	1.7	4.8	3.5
Viability index [%]
	mean	100	99.5	90.6	96.1*
	SD	0	1.7	28.6	5.3
Pups weight [g] on day 4 of lactation
Male	mean	10.6	10.8	10.2	9.9
	SD	1.8	1.2	1.7	1.9
Female	mean	10.1	10.1	9.7	9.3
	SD	1.7	1.2	1.6	1.4

SD standard deviation

* significant difference from control, p<0.05

** significant difference from control, p<0.01

Conclusions:

The NOEL for reproduction was considered to be 1,000 mg/kg/day in male and female rats and 300 mg/kg/day for the F1 generation.
The NOEL for general toxicity of this chemical in parent animals was considered to be 300 mg/kg/day.

Executive summary:

Copulation, ovulation, fertility, maintenance of pregnancy, and parturition and lactation were not affected by the test compound.

Reproductive parameters (i.e., duration of gestation, number of corpora lutea, implantations and resorptions, litter size, and sex ratio distribution) were comparable among all four groups including controls. In the 1,000 mg/kg group, pup weight on postnatal days 0 and 4 was slightly decreased along with viability on postnatal day 4. Thus the NOEL was considered to be 1,000 mg/kg/day for reproduction in male and female rats and 300 mg/kg/day for the F1 generation. Concerning maternal and paternal general toxicity, no mortalities occurred in any group. There were no toxic effects of this chemical on the

general condition of male and female animals. Slight suppression of body weight gain was observed in males in 1,000 mg/kg group, while body weight change in females and food consumption in male and female animals in all compound treated groups were comparable to those in the controls. Macroscopic findings at necropsy and histological findings for the internal genitalia showed no abnormalities,. Kidney weights were increased in males and females of the 1,000 mg/kg groups as compared to

the control values. Thus the NOEL for general toxicity of this chemical in parent animals was considered to be 300 mg/kg/day.

Reference 2

Endpoint:

fertility, other

Remarks:

based on test type (migrated information)

Type of information:

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

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable published study, basic data given.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Groups of 20 males and 20 female rats were dosed with the test substance via the diet for 10 weeks and then mated. Date of parturition and number of young in each litter were recorded. Litters were weaned 21 days port partum, and the weight of the weanlings was determined. 24 male and 24 female weanlings were selected at random and for the next 21 days these young were fed the same diet as had been ingested by their parents. Diet intakes and body weights were recorded daily. 21 Days after weaning, the rats were killed and autopsies were performed.

GLP compliance:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: (P) 5-6 weeks
- Weight at study initiation: Control group: (F1) Males: 44 ± 8 g; Females: 43 ± 9 g; Treatment group: (F1) Males: 38 ± 5 g; Females: 36 ± 5 g

Route of administration:

oral: feed

Details on mating procedure:

After successful mating each pregnant female was caged: Pregnant females were transferred to individual breeding cages.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

(P) Males and Females: 10 weeks before mating
(F1) 24 males and 24 females were chosen at random and 21 days post partum fed the same diet

Frequency of treatment:

Parental animals:
Daily for 10 weeks

F1 animals:
Daily for 21 days post partum

Details on study schedule:

- Parental animals were fed diets containing 6.25% test substance for 10 weeks and mated. A control group of 12 male and 12 female animals of the same age were fed the basal ratio for 10 weeks and mated.
- Litters were weaned 21 days post partum.
- 24 male and 24 female litters were chosen at random and 21 days post partum fed the same diet as had been ingested by their parents.

Remarks:

Doses / Concentrations:
6.25%
Basis:
nominal in diet
corresponding to about 6000 mg/kg bw/day

No. of animals per sex per dose:

Parental animals:
Control group: 12 males and 12 females
Treatment group: 20 males and 20 females

F1 animals:
Treatment group: 24 males and 24 females

Control animals:

yes, plain diet

Parental animals: Observations and examinations:

Examination of parental animals was focused on fertility.

Litter observations:

The following parameters were examined in [F1] offspring: number and sex of pups, litter size, survival of offspring, body weight (daily), weight gain.

Postmortem examinations (parental animals):

Not specified.

Postmortem examinations (offspring):

The F1 offspring were sacrificed 21 days after weaning and and were subjected to postmortem examinations.

Reproductive performance:

no effects observed

Administration of the test substance resulted in a retarded growth during the preweaning and postweaning periods. However, no gross pathological changes were found among young rats killed at the end of the 12-day postweaning period.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

ca. 6 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects were noted with respect to fertility.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

ca. 6 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Reproductive effects observed:

not specified

Executive summary:

Groups of 20 males and 20 female rats were dosed with the test substance via the diet for 10 weeks and then mated. Date of parturition and number of young in each litter were recorded. Litters were weaned 21 days post partum, and the weight of the weanlings was determined. 24 male and 24 female weanlings were selected at random and for the next 21 days these young were fed the same diet as had been ingested by their parents. Diet intakes and body weights were recorded daily. 21 Days after weaning, the rats were killed and autopsies were performed.

Dibutyl sebacate in dietary concentrations of 6.25% had no adverse effect on fertility or the number of viable young in the litter, however growth of young was slightly but significantly retarded.

Reference 3

Endpoint:

fertility, other

Remarks:

based on test type (migrated information)

Type of information:

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

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable published study, basic data given.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Groups of 20 males and 20 female rats were dosed with the test substance via the diet for 10 weeks and then mated. Date of parturition and number of young in each litter were recorded. Litters were weaned 21 days port partum, and the weight of the weanlings was determined. 24 male and 24 female weanlings were selected at random and for the next 21 days these young were fed the same diet as had been ingested by their parents. Diet intakes and body weights were recorded daily. 21 Days after weaning, the rats were killed and autopsies were performed.

GLP compliance:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: (P) 5-6 weeks
- Weight at study initiation: Control group: (F1) Males: 44 ± 8 g; Females: 43 ± 9 g; Treatment group: (F1) Males: 38 ± 5 g; Females: 36 ± 5 g

Route of administration:

oral: feed

Details on mating procedure:

After successful mating each pregnant female was caged: Pregnant females were transferred to individual breeding cages.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

(P) Males and Females: 10 weeks before mating
(F1) 24 males and 24 females were chosen at random and 21 days post partum fed the same diet

Frequency of treatment:

Parental animals:
Daily for 10 weeks

F1 animals:
Daily for 21 days post partum

Details on study schedule:

- Parental animals were fed diets containing 6.25% test substance for 10 weeks and mated. A control group of 12 male and 12 female animals of the same age were fed the basal ratio for 10 weeks and mated.
- Litters were weaned 21 days post partum.
- 24 male and 24 female litters were chosen at random and 21 days post partum fed the same diet as had been ingested by their parents.

Remarks:

Doses / Concentrations:
6.25%
Basis:
nominal in diet
corresponding to about 6000 mg/kg bw/day

No. of animals per sex per dose:

Parental animals:
Control group: 12 males and 12 females
Treatment group: 20 males and 20 females

F1 animals:
Treatment group: 24 males and 24 females

Control animals:

yes, plain diet

Parental animals: Observations and examinations:

Examination of parental animals was focused on fertility.

Litter observations:

The following parameters were examined in [F1] offspring: number and sex of pups, litter size, survival of offspring, body weight (daily), weight gain.

Postmortem examinations (parental animals):

Not specified.

Postmortem examinations (offspring):

The F1 offspring were sacrificed 21 days after weaning and and were subjected to postmortem examinations.

Reproductive performance:

no effects observed

Administration of the test substance resulted in a retarded growth during the preweaning and postweaning periods. However, no gross pathological changes were found among young rats killed at the end of the 12-day postweaning period.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

ca. 6 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects were noted with respect to fertility.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

ca. 6 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Reproductive effects observed:

not specified

Conclusions:

No adverse effects were observed with respect to fertility. Only the growth during the preweaning and postweaning periods was slightly retarded.

Executive summary:

Groups of 20 males and 20 female rats were dosed with the test substance via the diet for 10 weeks and then mated. Date of parturition and number of young in each litter were recorded. Litters were weaned 21 days port partum, and the weight of the weanlings was determined. 24 male and 24 female weanlings were selected at random and for the next 21 days these young were fed the same diet as had been ingested by their parents. Diet intakes and body weights were recorded daily. 21 Days after weaning, the rats were killed and autopsies were performed.

Butyl stearate in dietary concentrations of 6.25% had no adverse effect on fertility or the number of viable young in the litter, however growth of young was slightly but significantly retarded.

Reference 4

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Reproductive effects observed:

not specified

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

348.36 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Literature publications are available in which the reproductive toxicity of a number of read-across substances was described:

 

A reproduction / developmental toxicity screening was carried out on dibutyl adipate according to OECD guideline 421 (SIDS, 1996). The test substance was administered to male and female Sprague-Dawley rats by oral gavage at doses of 0, 100, 300 and 1000 mg/kg bw/d. Males were treated daily starting 14 days before mating and until 28 days thereafter. Females were treated daily for a total of 42-53 days, beginning 14 days before mating and up to day 3 of lactation.

No effects were observed for fertility and reproductive parameters at the low and middle dose group, neither were there any observations of general toxicity in the parental animals at these doses. Observed reproductive effects in the highest dose group were limited to a slight decrease in pup weight (postnatal day 4) and pup viability (postnatal days 0 and 4). Furthermore, in this dose group a slight suppression in male body weight was noted, as well as an increase in kidney weights in both males and females. These findings resulted in a NOEL for reproduction of 1000 mg/kg bw/d in male and female rats for the parent generation and 300 mg/kg bw/d for the F1 generation.

 

Furthermore, in a study by Smith (Smith, 1953), the effects of dibutyl sebacate and butyl stearate on reproductive parameters were assessed. In this study, groups of 20 male and female rats were dosed with the test substance via the diet for 10 weeks and then mated. A dietary concentration of 6.25% test material was used, which corresponded to a dose of ca. 6000 mg/kg bw/d. Litters were weaned 21 days post partum. Groups of 24 male and 24 female weanlings were fed the same diet as their parents for 21 days, after which they were sacrificed and autopsies were performed.

Both butyl stearate and dibutyl sebacate were found to have no adverse effects on fertility or on the number of viable young in the litter. Nevertheless, the growth of the young was slightly but significantly retarded. For both substances the NOAEL was considered to be ~6000 mg/kg bw.

 

Based on these data it can be reasonably assumed that FAV-ES will not exert distinct effects of reproductive toxicity. In accordance with the precautionary principle, the NOEL derived for dibutyl adipate (300 mg/kg bw/d) can be converted to a NOEL for FAV-ES. As FAV-ES is a UVCB substance, it has a broad molecular weight distribution, ranging from 300 to 1294 g/mol. Calculation of the NOEL for FAV-ES taking into account the lowest molecular weight of 300 g/mol yields a NOEL of 348.36 mg/kg bw/d, which is to be considered a (very) conservative value.

Justification for selection of Effect on fertility via oral route:
The read-across study with the lowest NOAEL was selected. Adverse effects were limited to a slight decrease in pup weight (post-natal day 4) and pup viability (post-natal day 0 and 4).

Effects on developmental toxicity

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Justification for type of information:

Data on a substance similar to several constituents of this UVCB are available. The source substance is an ester of stearic acid as some constituents of the target substance.

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

Minor deviations not imparting the validity of the study.

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Test animals: mated female Sprague-Dawley CD rats - specific pathogen free
- Source: Charles River, Wiga GmbH, Sulzfeld, Germany
- Age at study initiation: 8 weeks
- Housing: Makrolon type M3 cages
- Diet: commercial pelleted diet No. 1324, Altromin GmbH, Lage, Germany (analytically controlled by batch)
- Water: community tap water, ad libitum
- Acclimation period: 5 days

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

Route of administration:

oral: gavage

Vehicle:

arachis oil

Remarks:

DAB 10

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Dosing solutions were prepared daily before administration.

VEHICLE:
All groups received a dose volume of 5 mL/kg bw.
Test substance concentrations in the vehicle are calculated based on the body weight as determined on day 6 post coitum.

GAVAGE:
During the exposure period, the test solutions were administered each morning by gavage via a stainless-steel stomach tube.

Analytical verification of doses or concentrations:

no

Details on mating procedure:

For this tests, mated animals were obtained from the breeding facility. Therefore, no information on the mating procedure is available.

Duration of treatment / exposure:

Dams are dosed once daily from the 6th to the 15th day of gestation.

Frequency of treatment:

Once daily.

Duration of test:

On day 20 post coitum, the females were sacrificed.

No. of animals per sex per dose:

24 female animals per dose group

Control animals:

yes, concurrent vehicle

Details on study design:

On day 20 post coitum, the females were sacrificed by ether overdose and a caesarean section was carried out to obtain the foetuses.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily from day 0 to 20 of gestation

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily from day 0 to 20 of gestation

BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 6, 16 and 20 of gestation
- Body weight gain is calculated based on the body weight on day 0 of gestation

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: all maternal organs, with emphasis on the uterus

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes

Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Pre-implantation loss (in % of corpora lutea): Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Number of living foetuses: Yes
- Number of death foetuses: Yes
- Sex ratio: Yes
- Fetal weight: Yes (males, females and runts)
- Placental weight: Yes

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: No data

Statistics:

- Assumed normal distribution: Dunnett test based on a pooled variance
- No normal distribution assumed: Steel test
- Variables which could be dichotomized without loss of information: Fischer's exact test for 2x2 tables (Bonferroni-Holm corrected)

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
The dams tolerated the applied dose levels of up to 1000 mg/kg bw/d without lethality, nor was any other sign of maternal toxicity observed during the clinical and post-mortem examinations.

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No compound-related differences were noted between the mean reproduction data. Findings on the individual foetus as well as on the litter basis did not differ from historical control.

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: embryotoxicity

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

The following NOAELs were determined:
- Maternal toxicity NOAEL: 1000 mg/kg bw/d
- Embryo and foetotoxicity NOAEL: 1000 mg/kg bw/d
- Teratogenicity NOAEL: 1000 mg/kg bw/d

Executive summary:

A prenatal developmental toxicity study was carried out on 2-ethylhexyl stearate according to OECD guideline 414 (Aulmann, 2000). The test substance was administered to mated female Sprague-Dawley rats by oral gavage at doses of 0, 100, 300 and 1000 mg/kg bw/d from day 6 to day 15 of gestation. On day 20 post coitum, the females were sacrificed and the foetuses were removed following caesarean section. Investigations included clinical and post-mortem examinations of the dams, examination of uterine content and reproductive parameters, foetal soft tissue and skeletal development.

No maternal toxicity was observed in any of the dose groups. All examined reproduction parameters were comparable with the animals of the control group. No treatment-related malformations were detected during the visceral and skeletal examinations.

The following NOAELs were therefore determined:

- Maternal toxicity NOAEL: 1000 mg/kg bw/d

- Embryo and foetotoxicity NOAEL: 1000 mg/kg bw/d

- Teratogenicity NOAEL: 1000 mg/kg bw/d

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2004

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions; few details on test substance given, no analysis of the test compound

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

few details on test substance given, no analysis of the test compound

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: Charles River Laboratories, Kingston, NY
- Age at study initiation: young adult
- Weight at study initiation: Mean of the maternal body weight: 226 g (Vehicle), 225 g (200 mg/kg bw/day), 227 g (600 mg/kg bw/day), 226 g (2000 mg/kg bw/day)
- Fasting period before study: No
- Housing: Virgin females were cohabitated with singly-housed male rats, one male per female rat for a maximum of 5 days and returned to individual housing in stainless steel wire-bottomed cages after mating.
- Diet: Certified Rodent Diet No. 5002 (PMI Feeds Inc. St.Louis, MO), ad libitum
- Water: water passaged through a reverse osmosis membrane with chlorine added as a bacteriostat, ad libitum
- Acclimation period: yes, period not mentioned

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 30 - 70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

dermal

Vehicle:

corn oil

Details on exposure:

- Doses: 0, 200, 600, and 2,000 mg/kg/day.

- Dose formulation: 0 (vehicle only), 100, 300, and 1,000mg/mL

- Dosage volume: 2 mL/kg.

- Application of dose: The dosage amount was applied directly to the clipped area on the dorsum of the rat at approximately the same time each day and spread uniformly over the area with a glass rod. The skin application site was occluded during treatment with a gauze pad secured with Vetrapt or Micropores tape to prevent oral ingestion and to minimize loss of material from under the patch.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

Treatment on Gestation Days (GD) 6 - 15

Frequency of treatment:

daily

Duration of test:

Termination of the study by CO2 inhalation on GD 20.

No. of animals per sex per dose:

25 females per group

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dose dependent occurrence of skin irritation. Higher levels than 2000 mg/kg bw/day might be expected to produce marked irritation thereby compromising the interpretaion of developmental results.
- Rationale for animal assignment (if not random): Computer-generated randomization by weight (Barlett´s test for homogeneity) such that the groups were not statistically different (5% significance level) from each other.

Maternal examinations:

CAGE SIDE OBSERVATIONS
- Time schedule: Animals were checked for mortality twice daily during the treatment period and daily thereafter.


DETAILED CLINICAL OBSERVATIONS
- Time schedule: Animals were checked for signs of reaction to treatment and/or symptoms of illness once daily before treatment, approx. 60 min after treatment during the dosing period. The dosing site was examined daily prior to substance application for signs of skin irritation according to Draize.


BODY WEIGHT
- Time schedule for examinations: Recorded on GD 0 and daily during the treatment period.


FOOD CONSUMPTION AND COMPOUND INTAKE
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg b.w./day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No


POST-MORTEM EXAMINATIONS
- Sacrifice on gestation day # 20
- Organs examined: The uterus, uterine contents, position of the fetuses in the uterus and number of corpora lutea. Number and distribution of intrauterine implantations were classified as live or death fetuses, late intrauterine deaths (resorptions) and early intrauterine resorption sites. Live fetuses were sexed and further examined (see below).

Ovaries and uterine content:

- Gravid uterus weight
- Number of corpora lutea
- Number of implantations
- Number of early resorptions
- Number of late resorptions

Fetal examinations:

- External examinations: all per litter
- Soft tissue examinations: half per litter
- Skeletal examinations: half per litter
- Head examinations: half per litter (the heads of the animals used for soft tissue examinations)

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 (Snedecor and Cochran, 1967) when Bartlett’s Test was not significant (p40.05). If the Analysis of Variance was significant (pr0.05), Dunnett’s Test (Dunnett, 1955) was used to identify the statistical significance of the individual groups. If the Analysis of Variance was not appropriate, i.e., Bartlett’s Test was significant (pr0.05), 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 to identify the statistical significance of the individual groups. If there were 475% 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.

Clinical signs:

no effects observed

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: local irritation

Details on maternal toxic effects:
The two highest dose levels caused some local irritation at the site of application, but no decreases in maternal weight gain or feed consumption. Two animals in the control group and one animal in the high-dose group died within 6 h after first application; these were not considered to be treatment related and the animals were replaced. One dam of the mid-dose goup (1/25) having a litter consisting of seven early resorptions was pointed out as single non-dosage dependent event and to be within the ranges observed historically at the test facility.
Necropsy findings were limited to skin flaking and scabbing first identified in life and observations related to wearing the Elizabethan collar (local alopecia, chromorhinorrhea, and neck lesions).

Key result

Dose descriptor:

NOAEL

Effect level:

> 2 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Dose descriptor:

NOAEL

Remarks:

local

Effect level:

200 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Remarks on result:

not determinable due to absence of adverse toxic effects

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

2 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Fetal body weight changes:

no effects observed

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:

There were no significant differences from control in any of the developmental parameters measured, including embryo/fetal viability, fetal weight, malformations, or variations. The observed effects in fetuses were dose-independent and regarded to be sporadic.

Key result

Dose descriptor:

NOAEL

Effect level:

>= 2 000 mg/kg bw/day

Based on:

test mat.

Sex:

not specified

Basis for effect level:

fetal/pup body weight changes

changes in postnatal survival

external malformations

Remarks on result:

not determinable due to absence of adverse toxic effects

Abnormalities:

not specified

Developmental effects observed:

not specified

Table 1: Skin reaction observations

	0 mg/kg bw/d	200 mg/kg bw/d	600 mg/kg bw/d	2000 mg/kg bw/d
Maximum possible incidences^a	375/25	375/25	375/25	375/25
Erythema
Total	0/0	2/1	22/4	91/13^b
Grade 1	0/0	2/1	10/4	81/13^b
Grade 2	0/0	0/0	4/1	10/4^b
Flaking
Total	11/3	15/2	55/6	170/17^b
Grade 1	11/3	9/2	27/5	61/14^b
Grade 2	0/0	6/1	19/4	71/14^b
Grade 3	0/0	0/0	9/1	38/7 ^b
Edema
Total	0/0	0/0	23/4	83/11^b
Grade 1	0/0	0/0	18/4	59/11^b
Grade 2	0/0	0/0	5/1	24/6^b
Scab	0/0	0/0	6/2	19/4

a:       Maximum incidence : Days x rats from first treatment on GD 6 through sacrifice on GD 20 divided by the number of rats examined per group on GD 6-20

b:        Significantly different from vehicle control group value (p≤0.01)

 

Table 2: Maternal reproductive, litter, and fetal alteration observations: Caesarian-Section results on GD 20

	0 mg/kg bw/d	200 mg/kg bw/d	600 mg/kg bw/d	2000 mg/kg bw/d
Rats pregnant and sectioned on Day 20 of gestation (n)	25	23	22^b	24
Corpora lutea/dam	16.4	16.6	16.9	16.5
Implantation sites/litter	15.0	15.4	14.9	14.2
Litter size
Live fetuses/litter	14.6	14.6	14.0	13.3
Live fetuses (n)	364	335	308	320
Dead fetuses (n)	0	0	0	0
Resorptions	0.4	0.9	0.9	0.9
Early (n)	10	20	19	21
Late (n)	1	0	0	0
Dams with any resorptions n(%)	9 (36)	11 (48)	15 (68)	11 (46)
% resorbed/litter	2.9	5.4	5.8	5.0
% male/litter	51.3	50.8	48.1	47.7
Live fetal body weight (g/litter)	3.68	3.62	3.69	3.75
Male	3.77	3.68	3.82	3.85
Female	3.58	3.56	3.58	3.65
Fetuses evaluated (n)	364	335	308	320
Litters with any alterations observed n(%)	10 (40)	8 (35)	14 (64)	7 (25)
Fetuses with any alterations observed n(%)	13 (3.5)	10 (3.0)	20 (6.5)	9 (2.0)
% fetuses/litter with any alterations observed	3.5	2.9	6.8^c	2.7

b:       Excludes values for one dam, which had a litter consisting of seven early resorptions.

c:       Significantly different from vehicle control group value (p≤0.05)

Table 3: Fetal evaluations

	0 mg/kg bw/d	200 mg/kg bw/d	600 mg/kg bw/d	2000 mg/kg bw/d
Litters evaluated	25	23	22^b	24
Fetuses evaluated	364	335	308	320
Live	364	335	308	320
Fetal gross external alterations	364	335	308	320
Tail: kinked
Litter incidence, n (%)	0(0)	1 (4.3)	0(0)	0(0)
Fetal incidence, n (%)	0(0)	1(0.3)	0(0)	0(0)
Body: hematoma
Litter incidence, n (%)	1(4.0)	0(0)	0(0)	0(0)
Fetal incidence, n (%)	1 (0.3)	0(0)	0(0)	0(0)
Fetal soft tissue alterations, evaluations	174	162	149	155
Vessels: umbilical artery descended to the left of urinary bladder
Litter incidence, n (%)	2(8.0)	3(13.0)	2(9.1)	2(8.3)
Fetal incidence, n (%)	2(1.1)	3(1.8)	3(2.0)	2(1.3)
Vessels: apparent additional umbilical artery descended left of the bladder
Litter incidence, n (%)	0(0)	0(0)	1(4.5)	0(0)
Fetal incidence, n (%)	0(0)	0(0)	1(0.7)	0(0)
Fetal skeletal alterations, evaluations	190	173	159	165
Cervical vertebrae: cervical rib present at 7th cervical vertebrae
Litter incidence, n (%)	2(8.0)	1(4.3)	1(4.8)	0(0)
Fetal incidence, n (%)	2(1.0)	2(1.2)	1(1.2)	0(0)
Thoracic vertebrae: centrum, bifid
Litter incidence, n (%)	1(4.0)	1(4.3)	5(22.7)	0(0)
Fetal incidence, n (%)	1(0.5)	1(0.6)	5(3.1)^a	0(0)
Lumbar vertebrae: centrum, bifid
Litter incidence, n (%)	0(0)	1(4.3)	0(0)	0(0)
Fetal incidence, n (%)	0(0)	1(0.6)	0(0)	0(0)
Ribs: wavy
Litter incidence, n (%)	0(0)	0(0)	2(9.1)	1(4.2)
Fetal incidence, n (%)	0(0)	0(0)	2(1.2)	1(0.5
Sternal centra: 1st, not ossified
Litter incidence, n (%)	1(4.0)	0(0)	0(0)	2(8.3)
Fetal incidence, n (%)	1(0.5)	0(0)	0(0)	2(1.3)
Sternal centra: 1st, incompletely ossified
Litter incidence, n (%)	3(12.0)	3(13.0)	2(5.1)	1(4.2)
Fetal incidence, n (%)	4(2.1)	4(2.3)	2(1.2)	1(0.6)
Pelvis: pubis, incompletely ossified
Litter incidence, n (%)	3(12.0)	0(0)	4(18.2)	3(12.5)
Fetal incidence, n (%)	3(1.6)	0(0)	5(3.1)	3(1.8)
Pelvis: ischium, incompletely ossified
Litter incidence, n (%)	0(0)	0(0)	2(9.1)	0(0)
Fetal incidence, n (%)	0(0)	0(0)	2(1.2)	0(0)

a: Significantly different from vehicle control group (p≤0.01)

Conclusions:

TMPCC did not cause any developmental toxicity in the Sprague-Dawley rat at dermal dosages up to 2,000 mg/kg/day.

Executive summary:

The developmental toxicity potential of trimethylolpropane caprylate caproate (TMPCC, CAS no. 11138-60-6) was evaluated in rats. Sprague-Dawley rats were administered TMPCC in a corn oil suspension dermally at dose levels of 0, 200, 600, or 2,000 mg/kg/day on gestation days (GD) 6–15 (sperm positive day5GD 0). Caesarean sections were performed on GD 20 and fetuses were evaluated for viability, growth, and external, visceral, and skeletal abnormalities. Each group consisted of 25 females, with at least 22 per group being pregnant. The two highest dose levels caused some local irritation at the site of application, but no decreases in maternal weight gain. There were no differences from control in any of the developmental parameters measured, including embryo/fetal viability, fetal weight, malformations, or variations. TMPCC did not cause any developmental toxicity in the Sprague-Dawley rat at dermal dosages up to 2,000 mg/kg/day.

Reference 3

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)

Justification for type of information:

The source and the target substances share structural similarities with common functional groups, esters, and side chains varying in their lenght. Moreover, the side chains are chemically simple structures which have no structural alerts for toxicity and which are closely related to substances of known low toxicity.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Remarks on result:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Remarks on result:

other: Fetotoxicity

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Remarks on result:

other: embryotoxicity

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Remarks on result:

other: Teratogenotoxicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

The following NOAELs were determined:
- Maternal toxicity NOAEL: 1000 mg/kg bw/d
- Embryo and foetotoxicity NOAEL: 1000 mg/kg bw/d
- Teratogenicity NOAEL: 1000 mg/kg bw/d

Executive summary:

prenatal developmental toxicity study was carried out on 2-ethylhexyl stearate according to OECD guideline 414 (Aulmann, 2000). The test substance was administered to mated female Sprague-Dawley rats by oral gavage at doses of 0, 100, 300 and 1000 mg/kg bw/d from day 6 to day 15 of gestation. On day 20 post coitum, the females were sacrificed and the foetuses were removed following caesarean section. Investigations included clinical and post-mortem examinations of the dams, examination of uterine content and reproductive parameters, foetal soft tissue and skeletal development.

No maternal toxicity was observed in any of the dose groups. All examined reproduction parameters were comparable with the animals of the control group. No treatment-related malformations were detected during the visceral and skeletal examinations.

The following NOAELs were therefore determined:

- Maternal toxicity NOAEL: 1000 mg/kg bw/d

- Embryo and foetotoxicity NOAEL: 1000 mg/kg bw/d

- Teratogenicity NOAEL: 1000 mg/kg bw/d

Reference 4

Endpoint:

developmental toxicity

Remarks:

Developmental Toxicity model (CAESAR) 2.1.7

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Study period:

2017

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Qualifier:

according to guideline

Guideline:

other: Developmental Toxicity model (CAESAR) 2.1.7

Version / remarks:

2.1.7

Deviations:

not applicable

Principles of method if other than guideline:

The model implements a virtual library of toxicant compounds. The CAESAR QSAR model has been developed with the aim to minimize false negatives in order to make them more usable for REACH.

Compound SMILES: O=C(OCCCC)CCCCCCCCC(=O)CCCCCCCC

Experimental value: -

Predicted developmental toxicity activity: NON-Toxicant

Reliability: the predicted compound is into the Applicability Domain of the model

Remarks: none

Global AD Index

AD index = 0.912

Explanation: the predicted compound is into the Applicability Domain of the model.

Similar molecules with known experimental value

Similarity index = 0.831

Explanation: strongly similar compounds with known experimental value in the training set have been found.

Accuracy of prediction for similar molecules

Accuracy index = 1

Explanation: accuracy of prediction for similar molecules found in the training set is good.

Conclusions:

This constituent (the most present in terms of percentage) resulted non toxicant

Reference 5

Endpoint:

developmental toxicity

Remarks:

DART Scheme V. 1.0 (from QsarToolBox)

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Study period:

2017

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a (Q)SAR model, with limited documentation / justification, but validity of model and reliability of prediction considered adequate based on a generally acknowledged source

Principles of method if other than guideline:

Predicting developmental and reproductive toxicity of some constituents of this UVCB substance based on DART categorization tool and DART SAR model.
DART scheme is an adaptation of a framework for identifying chemicals with structural features associated with the potential to act as reproductive or developmental toxicants outlined in the journal of Wu S et all [1].
•It is implemented as a pilot endpoint specific scheme, developed on the basis of the combination of known modes of action (MOA) and associated structural features.
•DART scheme include 25 categories and 125 sub-categories organized as a decision scheme. Definition of the categories are based on a detailed review of 716 chemicals that have been evaluated for their DART potential effect. Mechanistic interpretation and reliability is provided for each category.
•DART scheme is implemented as a profiling/categorization tool and as a SAR model.
•It can be used both as a component of a screening system to identify chemicals of potential concern, and as part of weight of evidence decisions based on structure-activity relationships (SAR), to fill data gaps without generating additional test data.

Specific details on test material used for the study:

The profiling and categorization was carried out on O=C(OCCCC)CCCCCCCC(=O)OCCCC (C17H32O4), CCCCCCCCC(=O)CCCCCCCCC(=O)OCCCC (C22H42O3), O(CC(COC(=O)CCCCCCCC)OC(=O)CCCCCCCC)C(=O)CCC (C25H46O5), OCC(COC(=O)CCCCCCCC(=O)OCCCC)OC(=O)CCCCCCCC(=O)OCCCC (C29H52O9), O(C(=O)CCCCCCCC(=O)OCCCC)CC(COC(=O)CCCCCCCC(=O)OCCCC)OC(=O)CCCCCCCC(=O)OCCCC (C42H74O12)

Conclusions:

The target substance does not have alerts for reproductive and development toxicity.

Reference 6

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

2004

Reliability:

2 (reliable with restrictions)

Justification for type of information:

The source and the target substances share structural similarities with common functional groups, esters, and side chains varying in their lenght. Moreover, the side chains are chemically simple structures which have no structural alerts for toxicity and which are closely related to substances of known low toxicity.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

> 2 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

clinical signs

food consumption and compound intake

Remarks on result:

not determinable due to absence of adverse toxic effects

Dose descriptor:

other: NOAEL/Local

Effect level:

ca. 200 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

dermal irritation

Remarks on result:

other: Maternal toxicity: Local irritation at the application site. No systemic effects

Dose descriptor:

NOAEL

Effect level:

> 2 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

fetal/pup body weight changes

changes in litter size and weights

external malformations

Remarks on result:

not determinable due to absence of adverse toxic effects

Abnormalities:

no effects observed

Developmental effects observed:

no

Reference 7

Endpoint:

developmental toxicity

Remarks:

Study on a second species in consideration of the registration tonnage

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

In consideration of the outcomes of the available studies according to OECD 422 (on the substance with CAS 126-57-8) and to OECD 414 on rat (on the substance with CAS 11138-60-6), of the results of the Qsar evaluations reported in the section 7.8.2 and 7.8.3 and of the results of all other available tox studies, a second study according to OECD 414 on a different species is not considered necessary

Species:

rabbit

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

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

A prenatal developmental toxicity study was carried out on read-across substance 2-ethylhexyl stearate according to OECD guideline 414 (Aulmann, 2000). The test substance was administered to mated female Sprague-Dawley rats by oral gavage at doses of 0, 100, 300 and 1000 mg/kg bw/d from day 6 to day 15 of gestation. On day 20 post coitum, the females were sacrificed and the foetuses were removed following caesarean section. Investigations included clinical and post-mortem examinations of the dams, examination of uterine content and reproductive parameters, foetal soft tissue and skeletal development.

No maternal toxicity was observed in any of the dose groups. All examined reproduction parameters were comparable with the animals of the control group. No treatment-related malformations were detected during the visceral and skeletal examinations. The following NOAELs were therefore determined:

- Maternal toxicity NOAEL: 1000 mg/kg bw/d

- Embryo and foetotoxicity NOAEL: 1000 mg/kg bw/d

- Teratogenicity NOAEL: 1000 mg/kg bw/d

 

This study further substantiates that it can be reasonably assumed that FAV-ES will not exert distinct effects of reproductive toxicity.

Justification for classification or non-classification

Based on the results of the reprotox testing performed on the read-across substances, FAV-ES should not be classified for reproductive toxicity faccording to the criteria described in EU Regulation No. 1272/2008 on the Classification, Labelling and Packaging of Substances and Mixtures (CLP). Likewise, classification for reproductive toxicity is not required under the conditions described in Directive 67/548/EEC (Dangerous Substances Directive).