Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No data on reproductive toxicity / effects on fertility for the target substance are needed because reliable information on pre-natal developmental toxicity studies for adequate source substances are available. However, based on the results of available sub-chronic repeated dose toxicity studies investigating parameters of reproductive toxicity for adequate source substances and on toxicokinetic considerations, no adverse effects on reproductive organs and tissues are expected for the target substance.

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
Additional information

No data on reproductive toxicity / effects on fertility for the target substance are needed because reliable information on pre-natal developmental toxicity studies for adequate source substances are available. Moreover, data taken from repeated dose toxicity studies are available including sub-chronic studies for the analogue substances Fatty acids, C5-9, tetraesters with pentaerythritol (CAS No. 67762-53-2) and Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS No. 146289-36-3). The studies indicate no potential for reproductive effects.

In a 13-week oral repeated-dose toxicity study performed comparable to OECD Guideline 408 with Pentaerythritol ester of pentanoic acids and isononanoic acid in rats (CAS No. 146289-36-3) reproductive organs were examined as well (Emery, 1998). Groups of 10 male and female Wistar rats each were exposed to the substance by gavage at 100, 300 and 1000 mg/kg bw for 90 consecutive days. Overall, there were no adverse effects found after oral application of the test substance for 90 days. With special regard to the reproductive organs (ovaries, epididymides, prostate, testes and uterus), the examination of organ weights as well as gross necropsy and histopathology revealed no substance-related findings. Based on the absence of effects up to the highest dose tested, the 90-day oral systemic NOAEL was found to exceed 1000 mg/kg bw/day.

A 90-day dermal toxicity study with Fatty acids, C5-9, tetraesters with pentaerythritol (CAS No. 67762-53-2) was performed comparable to OECD Guideline 411 (Exxon, 1988).Groups of 10 male and female Sprague-Dawley rats each were once daily (5 days/week) exposed to the substance (purity not specified) at concentrations of 800 and 2000 mg/kg bw for 90 days (65 applications in total). Application to the skin was done open without coverage. Reproductive endpoints examined were sperm morphology and weights of reproductive organs. Overall, there were no adverse effects found after dermal application of the test substance for 90 days. Examination of reproductive organs (ovaries, epididymides, prostate and seminal vesicles, testes, uterus and vagina) revealed no substance-related findings. Additionally, cauda epididymal sperm of the control and high dose groups, examined at the end of the treatment period, did not show changes in morphology. Based on the absence of effects concerning weight of reproductive organs and sperm morphology up to the highest dose tested, the 90-day dermal systemic NOAEL was found to exceed 2000 mg/kg bw/day for the test substance in Sprague-Dawley rats.

A 90-day subchronic inhalation toxicity study was performed with Fatty acids, C5-9, tetraesters with pentaerythritol (CAS No. 67762-53-2) comparable to OECD guideline 413 in Sprague-Dawley rats (Exxon, 1992). 15 males and 15 females per group were whole body exposed to the test substance for 6 hours/day, 5 days/week at concentrations of 0.05, 0.15 and 0.5 mg/L air. The respective controls inhaled clean air under the same conditions. Reproductive parameters examined included reproductive organs and testicular spermatid count as well as epididymal sperm count and morphology. No changes in reproductive organs or effects on sperm count and morphology could be detected in the high dose group compared to the control animals. The NOAEC for systemic effects was therefore found to exceed 0.5 mg/L air.

Conclusion on reproductive toxicity / effects on fertility

Based on the results of available sub-chronic studies investigating parameters of reproductive toxicity for adequate source substances and on toxicokinetic considerations, no adverse effects on reproductive organs and tissues are expected for the target substance Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid.

Effects on developmental toxicity

Description of key information

Oral: OECD 414, rat, NOAEL developmental ≥ 1000 mg/kg bw/day

Oral: OECD 414, rat, NOAEL systemic ≥ 1000 mg/kg bw/day

Read-across from structural analogue source substance Fatty acids, C8-10 mixed esters with dipenaterythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS No. 189200-42-8)

Dermal: similar to OECD 414, rat, LOAEL developmental = 800 mg/kg bw/day

Dermal: similar to OECD 414, rat, NOAEL systemic = 2000 mg/kg bw/day

Read-across from structural analogue source substance Fatty acids, C5-9, tetraesters with pentaerythritol (CAS No. 67762-53-2)

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restricitions (Lack of data on test substance).
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
- lack of data on test substance
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Crl:CD BR VAF/Plus
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Stone Ridge, NY, USA
- Age at study initiation: approximately 9 - 10 weeks
- Weight at study initiation: 200 - 274 g (female)
- Housing: The animals were housed in suspended stainless steel and wire mesh cages with absorbent paper below the cages. The females were housed separately during the study period except during mating.
- Diet: Purina Certified Rodent Chow No. 5002, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 13 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.0 - 24.4
- Humidity (%): 40 - 70
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES:
From: 03 Oct 1994
To: 08 Nov 1994
Route of administration:
oral: gavage
Vehicle:
other: polyethylene glycol (PEG 400)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The undiluted test substance was thoroughly mixed in vehicle prior to dispensing. The dosing solutions were prepared weekly.

VEHICLE
- Lot/batch no. (if required): 122H1109
- Physical state: colorless liquid
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis for homogenity of the test substance dilutions were performed on the lowest and the highest concentrations expected during the course of the study. The relative standard deviation ranged from 0.72 to 3.19%. Concentrations were analysed in the first and the third dosing mixture preparation. The analytical results for all test solutions were within 7% of the nominal concentrations for weeks 1 and 3.
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1/1
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy
After confirmation of pregnancy, each mated female was returned to its cage and new females were placed into the males' cages until a required number of pregnant females was obtained.
Duration of treatment / exposure:
gestation days (GD) 6 - 15
Frequency of treatment:
daily, 7 d/week
Duration of test:
21 d (GD 0 - 21)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
25 females per dose, 50 males in total
Control animals:
yes, concurrent vehicle
Details on study design:
- Rationale for animal assignment: Mated females were assigned to dose groups in the order of mating. Accordingly, the first confirmed mated female was assigned to Group 1, the next to Group 2 and so on until all mated animals for a given day were assigned to dose groups. On subsequent days, the next group in sequence was filled by the first confirmed mated female on that day and so on. Assignments were made until all groups were filled with confirmed mated females.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily during the treatment period and once daily at all other times during the study period

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to selection and daily during gestation

BODY WEIGHT: Yes
- Time schedule for examinations: prior to selection and on GD 0, 6, 9, 12, 15, 18 and 21

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

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on GD 21
- all females were examined by gross necropsy
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Statistics:
Bartlett's Test was performed to determine if the dose groups had equal variance (1% level of significance). If equal, the testing was done using parametric methods, otherwise nonparametric techniques were used. Parametric procedures: a standard one way ANOVA (F distribution) was used. If significant differences among the means were indicated, Dunnett's Test was used to determine which treatment groups differed significantly from control. In addition to the ANOVA, a standard regression analysis for linear response in the dose groups was performed that also tested for linear lack of fit in the model. Nonparametric procedures: the test of equality of means was performed using the Kruskal-Wallis Test. If significant differences among the means were indicated, Dunn's Summed Rank Test was used to determine which treatment groups differed significantly from the control. In addition, Jonckheere's Test for monotonic trend in the dose response was performed. All tests were conducted at the 5% and 1% level of significance.
Fetal weight was analyzed by a standard nested analysis of covariance (fetuses nested within dams and dams nested within doses and litter size (both sexes combined)). If differences in groups were identified, the Least Significant Difference technique was used to determine which groups differed from the control group. Male and female fetuses were tested separately (the covariate was combined sexes in each analysis). Fetal malformation and variation incidence data were analyzed for statistical significance as follows: a standard chi-square analysis was performed to determine if the proportions of incidences differ between the groups tested. If any one cell had an expected value less than 5, this step was not reported. Next, each treatment group was compared to the control group using a 2x2 Fisher Exact Test. Thirdly, Armitage's test for linear trend in the dosage groups was performed. All tests were reported at the 5% or 1% level of significance.
Indices:
Preimplantation loss = (no. of Corpora Lutea - no. of Implantation Sites) / no. of Corpora Lutea * 100

Postimplantation loss = (no. of Implantation Sites - no. of live foetuses) / no. of Implantation Sites * 100
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
Mortality:
No treatment-related mortality occurred. On GD 7, one female of the 500 mg/kg bw/d group was found dead. At necropsy, discolored and consolidated lungs were the only findings. The death of this female was probably a result of an accidental gavage error.

Clinical signs:
No treatment-related clinical signs were observed during the study period. The most frequently observation was soft stool, that occurred in treated and control animals and was therefore considered as a response to the vehicle rather than to the test substance. Other findings were scabs, little sign of stool, rales and alopecia in one or more groups. One female of the high dose group had a subcutis mass in the cervical area on GD 21. In summary, these clinical findings were considered to be incidental and unrelated to treatment with the test substance.

Body weight:
Treatment with the test substance had no statistically significant effect on mean body weight and mean body weight change at any interval.

Food consumption:
There were no statistically significant differences in mean food consumption between treated and control animals at any interval.

Post-mortem examinations:
There were no necropsy findings that were considered to be treatment-related. One high dose female had a subcutaneous mass in the cervical area and one control and one high dose female had dilated renal pelvis. In summary, these necropsy findings were considered to be incidental and unrelated to treatment.
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: NOAEL is corresponding to the highest dose tested
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Fetal body weight:
There were no statistically significant differences between treated and control mean fetal body weights of either sex (see Table 1).

Implantation data:
There were no statistically significant differences in the mean live fetuses, mean live male or female fetuses, mean resorptions, mean implantation sites, mean corpora lutea, mean total dead fetuses, mean fetuses per implantation sites, mean dead fetuses per implantation sites, mean resorptions per implantation sites, % pre-implantation loss, % post-implantation loss, mean malformed fetuses, mean fetuses with variations, or mean affected (resorptions + dead + malformed fetuses per litter) fetuses between treated and control groups. (see Table 1)

Fetal observations:
No biologically or statistically significant differences in total or individual variations or malformations were observed between the litters of test substance groups and control group (see Table 2). In the control, 100, 500 and 1000 mg/kg bw/d group, 5, 2, 6 and 1 fetuses, respectively, were stunted.
External observations regarded as malformations were found in one fetus of the 100 mg/kg bw/d group (agnathia, astomia, low set ears, anophthalmia) and single findings of cleft palate, syndactyly and kinked tail in three foetuses of separate litters of the 500 mg/kg bw/d group. External variations were not observed in any group.
Visceral observations regarded as malformations were limited to single occurrences of anophthalmia in one foetus each of the low and mid dose group, cleft palate and dilated brain ventricles in the 100 mg/kg bw/d group and two occurrences of folded retina in the control group. Visceral variations included a single or low incidence of dilated renal pelves, distended ureters and/or convoluted ureter.
Skeletal observations regarded as malformations were limited to multiple skull bones malformed in one foetus of the 100 mg/kg bw/d group, short pubis in one foetus of the 1000 mg/kg bw/d group and one less presacral vertebrae in one foetus of the control, two foetuses in the low dose and one foetus in the high dose groups. Skeletal variations were observed throughout the groups and consisted primarily of hypoplastic, misshapen or unossified stemebrae, hypoplastic skull bones or pubis and rudimentary or misshapen ribs.
In summary and without a clear pattern of response, all malformations were considered incidental and not to be treatment-related. Statistically significant differences in incidences of variations were limited to a decrease in hypoplastic skull bones of the mid dose group and a decrease in unossified stemebrae of the high dose group compared with controls. All variations were of no biological importance.

Skeletal ossification:
There were no statistically significant differences in mean ossification sites between treated and control groups.
Dose descriptor:
NOAEL
Remarks:
developmental
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: NOAEL corresponds to highest dose tested
Abnormalities:
no effects observed
Developmental effects observed:
no

Table 1: Litter data and fetal body weight

 

 

Control

dose groups [mg/kg bw/day]

 

100

500

1000

No. of dams/litters examined

25

21

23

25

Mean no. of Corpora Lutea

16.8

16.8

17.7

16.8

± 2.28

± 2.50

± 3.50

± 1.82

n=25

n=20

n=23

n=25

Mean no. of Implantation Sites

15.76

15.9

16.09

15.52

± 2.24

± 2.62

± 2.25

± 2.49

n=25

n=21

n=23

n=25

Mean no. of resorptions

0.88

0.81

0.91

0.56

± 1.05

± 1.29

± 1.12

± 0.82

n=25

n=21

n=23

n=25

Pre-implantation loss [%]

5.7

6.7

8

7.7

± 8.1

± 8.2

± 8.2

± 12.9

n=25

n=20

n=23

n=25

Post-implantation loss per litter [%]

5.4

4.9

6

4.4

± 6.4

± 7.7

± 7.3

± 6.4

n=25

n=21

n=23

n=25

Mean no. of live fetuses

14.88

15.1

15.13

14.88

± 2.19

± 2.64

± 2.46

± 2.64

n=25

n=21

n=23

n=25

Mean no. of dead fetuses

0

0

0.04

0.08

 

 

± 0.21

± 0.28

n=25

n=21

n=23

n=25

Mean no. of female fetuses

7.72

7.48

8.04

7.8

± 2.28

± 3.11

± 2.29

± 1.78

n=25

n=21

n=23

n=25

Mean no. of male fetuses

7.16

7.62

7.09

7.08

± 1.93

± 2.25

± 2.09

± 2.58

n=25

n=21

n=23

n=25

Mean body weight (female fetuses) (g)

5.04

5.05

5.06

5.2

± 0.44

± 0.32

± 0.46

± 0.37

n=188

n=157

n=185

n=195

Mean body weight (male fetuses) (g)

5.33

5.27

5.39

5.44

± 0.52

± 0.39

± 0.38

± 0.38

n=175

n=160

n=163

n=177

Table 2: Fetal variations and malformations

 

 

Control

dose groups [mg/kg bw/day]

 

100

500

1000

No. of fetuses with external variations

0

0

0

0

n=372

n=317

n=347

n=358

No. of fetuses with external malformations

0

1

3

0

n=372

n=317

n=347

n=358

No. of fetuses with visceral or head variations

0

0

1

2

n=187

n=161

n=173

n=186/187*

No. of fetuses with visceral or head malformations

2

2

1

0

n=187

n=161

n=173

n=186/187*

No. of fetuses with skeletal variations

45

39

29

35

n=185

n=156

n=176

n=185

No. of fetuses with skeletal malformations

1

3

0

2

n=185

n=156

n=176

n=185

  

*186 visceral examinations performed, 187 head examinations performed

Conclusions:
The test substance was not considered embryotoxic under the conditions of this study. Accordingly, the maternal and developmental NOAELs were established at 1000 mg/kg bw/d under the conditions of this study. The results indicate that test substance was not a selective developmental toxicant and was not embryotoxic or teratogenic under the conditions of this study.
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions (15 dams per group instead of 20, administration on day 0-19 of gestation, limited details on study design)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
(only 15 presumed pregnant females per group, exposure on day 0-19 of gestation, only 2 dose levels, nonstandard dermal exposure, limited details on exposure)
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, N.Y.
- Age at study initiation: approx. 9 weeks
- Mean weight at study initiation: 248 g
- Diet: Purina Certified Rodent Chow #5002 (Meal), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 22
- Humidity (%): 40 - 60
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
dermal
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Type of wrap if used: open exposure, no wrap
- Time intervals for shavings or clipplings: no data on frequency; clipped, intact skin
- Site: dorsal
Controls: The rats of the control group were clipped and collared. The intact dorsal skin of each rat was stroked with the tip of a syringe, but no test material was applied.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): The amount of the test material applied with a syringe was calculated based on the body weight of the animals and the density of the test substance.

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes. To minimize ingestion of the test material, the rats were fitted with cardboard Elizabethan-style collars.
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused: M/F ratio per cage: 1/1
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
gestation days 0 - 19
Frequency of treatment:
daily
Duration of test:
The animals were sacrificed on day 20 of gestation.
Dose / conc.:
800 mg/kg bw/day (nominal)
Dose / conc.:
2 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
15 presumed-pregnant females
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: based on results of a 13-week dermal study previously conducted with the same material
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily
- Cage side observations checked: signs of pathosis, abortion, premature delivery, and death

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: day 0, 3, 6, 10, 13, 16, and 20 of gestation

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
- Time schedule for calculation: days 0-3, 3-6, 6-10, 10-13, 13-16, and 16-20

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

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: The thoracic and abdominal cavities were exposed and all organs were examined grossly for evidence of pathosis.

OTHER:
- Clinical chemistry: alanine aminotransferase (ALT), albumin, albumin/globulin ration, alkaline phosphatase (ALP), aspartate aminotransferase (AST), bilirubin, calcium, chloride, cholesterol, creatinine, globuline, glucose, iron, lactate dehydrogenase (LDH), phosphorus, potassium, sodium, sorbitol dehydrogenase (SDH), total protein, triglycerides, urea nitrogen, and uric acid
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Number of live and dead fetuses: Yes
- Other: The ovaries of non-pregnant females were grossly examined and then discarded.
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No
Statistics:
- Analysis of variances and group comparison using Fisher's Exact or Dunnett's test (maternal biophase and cesarean section data, and fetal data)
- ANOVA and Fisher's Exact test (fetal skeletal data)
- Fisher's Exact test (fetal visceral data)
- SAS procdures, Student-Newman-Keul's multiple comparison test (clinical chemistry data)
P < 0.05
Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: slight local effects

Details on maternal toxic effects:
- General observations: neck lesions, red nasal exudate, and chromodacryorrhea in all groups (considered not to be test substance-related as these signs are common in animals that are collared)
- Local effects: mild dermal irritation including erythema and flaking of the skin in the treatment groups
- Body weight: similar to controls in both treatment groups
- Body weight gain: similar to controls in both treatment groups
- Uterine and net body weights: similar to controls in both treatment groups
- Food consumption: similar to control in both treatment groups; only difference (statistically significant) in high dose group on day 13-16: 31.5 g vs. 29.5 g (corresponding control data)
- Necropsy: no remarkable findings were observed
- Fetal status and uterine position: no parameter evaluated appeared to be adversly affected
- Clinical chemistry: no differences between treated and non-treated rats were observed
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: no adverse effects observed; slight local dermal irritation
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
- Fetal body measurements: Mean fetal body weights and crown-rump lengths, parameters of body growth and development were normal compared to controls.
- Fetal examination: No malformations or variations were observeed. Bruises were observed on the skin of 4 fetuses from the control group and 2 fetuses form the 800 mg/kg bw/day group (considered to be incidental). One fetus from one dam exposed to 800 mg/kg bw/day was pale in colour. No other remarkable findings were observed during external examination.
- Malformations (lumbar and sacral vertebrae, tail, sternebrae, and ribs) were observed. The incidence was low and there was no apparent dose-response relationship, these effects were considered to be not treatment-related. Comparable incidences of variant skeletal development were observed in both cotnrol and trated fetuses.
- Visceral examinations: A statistically significant (high dose) increase in the number of fetuses with levocardia was observed. The response appeared to be dose-related
Levocardia:
Litters: control: 0 (0%); 800 mg/kg bw/day: 2 (14.3%); 2000 mg/kg bw/day: 7 (50%); 14 litters per group examined
Fetuses: control: 0 (0%); 800 mg/kg bw/day: 3 (3.2%); 2000 mg/kg bw/day: 7 (10.1%); 94, 93, and 99 fetuses examined, respectively
Microphthalmia, anophtalmia and "apparent" hydronephrosis were also observed. Variant visceral development was observed in control and treated fetuses.
Dose descriptor:
NOAEL
Remarks:
developmental
Effect level:
< 800 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
visceral malformations
Dose descriptor:
LOAEL
Remarks:
developmental
Effect level:
800 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
visceral malformations
Abnormalities:
effects observed, treatment-related
Localisation:
visceral/soft tissue: cardiovascular
Description (incidence and severity):
increased number of fetuses with levocardia
Developmental effects observed:
yes
Lowest effective dose / conc.:
800 mg/kg bw/day (nominal)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects in the absence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
no

Levocardia was the only parameter affected in fetuses of dams treated with the test substance during gestation. In other studies, levocardia was observed in control fetuses, too. However, the effect of the test substance on heart development should be focused on in further studies as well as the impact, this effect has on postnatal survival.

Conclusions:
In a developmental toxicity study, pregnant rats were dermally exposed to the test substance. No adverse effects were observed in any maternal or reproductive parameter nor on external and skeletal development of fetuses. Levocardia was observed in 3.2% and 10.1% of the fetuses exposed in utero to 800 and 2000 mg/kg bw /day, respectively. Thus, the developmental NOAEL was determined to be < 800 mg/kg bw.
Executive summary:

In this particular study, soft tissue examinations revealed an increased number of fetuses with “levocardia” but the internal anatomy of the heart was normal and no accompanying heart or other malformations in the thoracic cavity were detected. It is important to note that the term levocardia as used in the study report describes the placement of the heart in the extreme left hemithorax without any reversal of organs or any other malformations.

Since levocardia was observed in both treated groups (800 and 2000 mg/kg bw/day) the NOAEL for embryo-/fetotoxicity and teratogenicity in rats for fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) was found to be < 800 mg/kg bw/day and the LOAEL = 800 mg/kg bw/day. To evaluate the toxicological significance of this finding it needs to be noted that all other maternal as well as fetal parameters investigated were unaffected. Maternal parameters (food consumption, body weight gain) monitored throughout gestation (days 0 - 19) were not adversely affected. Serum chemistry values for control and exposed animals were comparable for all components tested, test substance and controls. Reproductive parameters (number of implants, resorptions, or viable fetuses) were not adversely affected by the test substance at either of the dose levels tested. Mean fetal body weights and crown-rump distances were similar in all of the experimental groups. No evidence of teratogenicity (abnormal development) – other than levocardia – was observed during examination of fetuses from pregnant dams. Moreover, levocardia is occasionally observed in vehicle control fetuses (Smith et al. 1988, Teratogenic effects of trichloroacetonitrile in the Long-Evans rat. Teratology. Aug;38(2):113-20.) and in control fetuses of other tests conducted in the test laboratory at that time.

It is therefore concluded that the effect observed has no toxicological relevance for humans.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The available information comprises an adequate and reliable (Klimisch score 2) study from a source substance with similar structure and intrinsic properties. Read-across is justified based on common precursors and hydrolysis products and consistent trends in environmental fate, ecotoxicological and toxicological profile. The selected study is thus sufficient to fulfil the standard information requirements set out in Annexes VIII - X, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
800 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The available information comprises an adequate and reliable (Klimisch score 2) study from a source substance with similar structure and intrinsic properties. Read-across is justified based on common precursors and hydrolysis products and consistent trends in environmental fate, ecotoxicological and toxicological profile. The selected study is thus sufficient to fulfil the standard information requirements set out in Annexes VIII - X, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.
Additional information

Justification for grouping of substances and read-across

The analogue approach comprises aliphatic esters of poly-functional alcohols containing four to six reactive hydroxyl groups and one to six fatty acid chains. The read-across analogue approach contains mono constituent, multi-constituent and UVCB substances with fatty acid carbon chain lengths ranging from C5 - C20, which are mainly saturated but also mono unsaturated C16 and C18, polyunsaturated C18 and branched C5, C7 and C9, building mono-, di-, tri-, and tetra esters with the polyol. The available data allow for an accurate hazard and risk assessment of the target substance and the source substances and the read-across concept is applied for the assessment of environmental fate and environmental and human health hazards. Thus, where applicable, environmental and human health effects are predicted from adequate and reliable data for source substances within the read-across analogue approach by interpolation to the target substances in accordance with Annex XI, Item 1.5, of Regulation (EC) No. 1907/2006 (REACH). In particular, for each specific endpoint the source substance or substances structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source substance and target substances are the basis of read-across.

A detailed justification for the read-across applied is provided in the technical dossier (see IUCLID Section 7.1 and 13) and within Chapter 5.1 of the CSR.

Developmental toxicity

There are two reliable studies available for structural analogue source substances investigating pre-natal developmental toxicity. While administration of the test substance in the first study was by oral gavage, the dermal route of exposure was utilized in the second study.

The developmental toxicity of Fatty acids C8-10, mixed esters with dipentaerythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS No. 189200-42-8) was investigated according to OECD Guideline 414 (prenatal developmental toxicity study) and under GLP conditions (ExxonMobil, 1995h). 50 male Sprague-Dawley rats were mated with females to achieve groups of 25 pregnant Sprague-Dawley rats which then received daily oral gavage doses of the test substance at concentrations of 100, 500 and 1000 mg/kg bw/day during gestational days 6 to 15. Control animals received the vehicle polyethylene glycol (PEG 400) only. On day 21 of gestation the animals were euthanized and examined for maternal and fetal parameters. There were no adverse effects found for all parameters examined in maternal animals. Based on the number of implantations, number of total litter losses by resorption, mortality, clinical signs, body weight, gross pathology and organ weights of maternal animals the NOAEL for maternal systemic toxicity was found to be 1000 mg/kg bw/day. Examination of fetus litter size and weights, offspring viability (number alive and number dead), sex ratio, grossly visible abnormalities, external, head, soft tissue and skeletal abnormalities showed only incidental malformations in two high dose females. The NOAEL for embryo-/fetotoxicity and teratogenicity in rats of the test substance was therefore found to be 1000 mg/kg bw/day.

In another developmental toxicity study Fatty acids, C5-9, tetraesters with pentaerythritol (CAS No. 67762-53-2) was investigated comparable to OECD Guideline 414 (prenatal developmental toxicity study) (Exxon, 1988b). Groups of 15 presumed pregnant female Sprague-Dawley rats received daily dermal doses of the test substance at concentrations of 800 and 2000 mg/kg bw/day during gestational days 0 to 19. Control animals remained untreated. On day 20 of gestation the animals were euthanized and examined for maternal and fetal parameters. There were no adverse effects found for all parameters examined in maternal animals. Based on the number of implantations, number of total litter losses by resorption, mortality, clinical signs, body weight, gross pathology and organ weights of maternal animals the NOAEL for maternal systemic toxicity was found to be 2000 mg/kg bw/day. Examination of fetus litter size and weights, offspring viability (number alive and number dead), sex ratio, grossly visible abnormalities, external, head, soft tissue and skeletal abnormalities revealed no differences to controls and thus no indication for teratogenic effects. Soft tissue examination revealed an increased number of fetuses with “levocardia” but the internal anatomy of the heart was normal and no accompanying heart or other malformations in the thoracic cavity were detected. It is important to note that the term levocardia as used in the study report describes the placement of the heart in the extreme left hemithorax without any reversal of organs or any other malformations or adverse effects. It is therefore concluded that the effect observed has no toxicological relevance for humans. However, since levocardia was observed in both treated groups, the NOAEL for embryo- / fetotoxicity and teratogenicity in rats for Fatty acids, C5-9, tetraesters with pentaerythritol under the experimental conditions of the study was determined to be < 800 mg/kg bw/day and the LOAEL = 800 mg/kg bw/day.

Conclusion on developmental toxicity

The available data on developmental toxicity from adequate source substances do not indicate any significant toxicological adverse effects on maternal and embryonal toxicity. Although in one of the two studies referred to “levocardia” in rats after dermal exposure was detected, it could be demonstrated that this effect has no toxicological relevance for humans as the effect described the positioning of the heart in the extreme left hemithorax without any further adverse implications and malformations. Therefore, based on the available data and following the analogue approach, no hazard for reproduction (development) was identified for the target substance Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid and the NOAEL values for systemic and developmental toxicity of ≥ 1000 mg/kg bw/day are considered for hazard and risk assessment.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 (REACH) information on intrinsic properties of substances may be generated by means other than tests, e.g. using information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI states that “substances whose physico-chemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the read-across concept is applied to the target substance Fatty acids lanolin, di-, tri- and tetraesters with pentaerythritol and rape fatty acid, data gaps can be filled by interpolation from representative structural analogue source substances to avoid unnecessary animal testing.

The read-across concept is also used to derive the classification of the target substance taking the properties of the source substances into account. Based on the read-across concept, all available data on reproductive and developmental toxicity do not meet the classification criteria according to Regulation (EC) No. 1272/2008 (CLP) as there either were no effects or effects observed were not considered relevant for humans. Data are therefore conclusive but not sufficient for classification.