Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
05 Jul - 15 May 1997
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Administration of test article only during organogenesis.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997
Report date:
1997

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
adopted in 1981
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
adopted in 2001
Deviations:
yes
Remarks:
only organogenesis covered
Qualifier:
according to guideline
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
only organogenesis covered
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Fatty acids, C16-18, esters with ethylene glycol
EC Number:
292-932-1
EC Name:
Fatty acids, C16-18, esters with ethylene glycol
Cas Number:
91031-31-1
Molecular formula:
C18H36O3, C20H40O3, C34H66O2, C36H70O4, C38H74O2

Test animals

Species:
rat
Strain:
other: Sprague-Dawley, CD
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles Rover, Sulzfeld, Germany
- Age at study initiation: 8 weeks
- Weight at study initiation: 198 g
- Housing: animals were housed individually in Makrolon M3 cages with standard softwood bedding.
- Diet: pelleted Altromin Maintenance Diet 1324, Lot No. 170994/1340 (Altromin GmbH, Lage, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-24
- Humidity (%): 47-82
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5% sodium carboxymethylcellulose and 0.25% Cremophor in aqua dest.
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test article was prepared daily before administration.
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
- Impregnation procedure: purchased timed pregnant
- They were received at the testing facility on Day 0 of gestation.
Duration of treatment / exposure:
Day 6-15 of gestation
Frequency of treatment:
daily, 7 days/week
Duration of test:
Day 20 of gestation
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
900 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
24 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: dose levels were based on the results of toxicological examinations (no further information, Henkel Report TBD 710070).

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily (working days) for mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least twice daily (working days) for signs of reaction to treatment and/or symptoms of illness

BODY WEIGHT: Yes
- Time schedule for examinations: on Day 0, 6, 16 and 20 post coitum

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation Day 20
- Organs examined: Gross macroscopic examination of all maternal organs with emphasis on the uterus, uterine contents, and position of foetuses in the uterus.
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
- Visceral examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Statistics:
If the variables could be assumed to follow a normal distribution, the Dunnett-test, based on a pooled variance, was applied for the comparison between the treated groups and the control group. The Steel-test was applied when the data could not be assumed to follow a normal distribution. Fisher’s Exact test for 2x2 tables was applied if the variables could be dichotomized without loss of information (Bonferroni-Holm-corrected).

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
No compound-related symptoms were observed in the treatment groups in comparison to the control group.
Mortality:
no mortality observed
Description (incidence):
No mortalities occurred during the study period.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weight, body weight gains and corrected body weight were within expected ranges.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
At scheduled necropsy no macroscopic changes were noted in the dams of the treatment groups.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Description (incidence and severity):
Mean foetal placental and uterus weights were not affected by treatment.

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Description (incidence and severity):
Only one dead foetus was observed in the mid- and one dead fetus in the high-dose group from 345 and 306 live foetuses, respectively.
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
no effects observed

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 900 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
The mean weight of live male and female foetuses in the mid-dose group was significantly increased The weights of live foetuses of the other treatment groups exhibited no significant differences on a litter and individual basis e.g. mean weight in comparison to the control group.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Foetal sex ratio was comparable in all groups.
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
No treatment-related foetal abnormalities were found at necropsy.
Skeletal malformations:
no effects observed
Description (incidence and severity):
The examined foetuses showed no treatment-related malformations. The figures of skeletal ossifications and variations showed no treatment-related deviations.
Visceral malformations:
no effects observed
Description (incidence and severity):
The figures of visceral variations in the test groups were considered to be similar to the control group.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 900 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

Table 1. Results of study.

Parameter

Group 1

0 mg/kg bw

Group 2

100 mg/kg bw

Group 3

300 mg/kg bw

Group 4

900 mg/kg bw

Number of corpora lutea [total/number of dams ± SD]

16.7 ± 1.9

17.1 ± 2.0

16.7 ± 1.9

16.5 ± 1.4

Implantations [total/number of dams ± SD]

15.3 ± 2.2

15.4 ± 2.7

14.9 ± 2.3

14.8 ± 1.5

Pre-implantation loss

34

39

44

38

Post-implantation loss

15

18

13

20

Embryonic death [total]

15

18

12

19

Embryonic resorptions [total/number of dams ± SD]

0.6 ± 1.1

0.7 ± 1.1

0.5 ± 0.7

0.7 ± 0.9

Foetal resorptions [total/number of dams ± SD]

0.0 ± 0.2

0.0 ± 0.2

0.0 ± 0.0

0.1 ± 0.4

Live foetuses

336

337

345

306

Dead foetuses

0

0

1

1

Malformed foetuses [total/number of dams ± SD]

0.0 ± 0.2

0.0 ± 0.0

0.0 ± 0.0

0.0 ± 0.2

Sex of foetuses (%males : % females)

47.3 : 52.7

51.6 : 48.4

50.3 : 49.4

52.1 : 47.6

Weights of live foetuses (mean ± SD)

Males

Females

 

 

4.3 ± 0.9

4.0 ± 0.8

 

 

4.2 ± 0.8

4.0 ± 0.7

 

 

5.0 ± 0.9*

4.6 ± 0.8*

 

 

4.5 ± 0.7

4.3 ± 0.7

Weights of placenta (mean ± SD)

0.6 ± 0.1

0.6 ± 0.1

0.6 ± 0.1

0.6 ± 0.1

Weights of uteri (mean ± SD)

88.7 ± 14.9

89.3 ± 19.2

97.9 ± 18.9

90.9 ± 11.7

*: Dunnett-test based on pooled variance, significant at level 5%

Table 2. Skeletal examination of foetuses (stage of development).

 

Parameter (%)

Group 1

0 mg/kg bw

Group 2

100 mg/kg bw

Group 3

300 mg/kg bw

Group 4

900 mg/kg bw

Foetal skeleton

No abnormal findings

4.0

9.8

16.1##

10.0

Skull bones, single incompletely ossified

4.5

11.6#

10.0

5.0

Sternebrae

incompletely ossified

abnormally ossified

 

66.5

24.4

 

84.4##

17.9

 

51.1##

9.4##

 

66.3

17.5

Coccygeal vertebrae, 4 and more ossified

 

32.4

 

22.5

 

56.1##

 

47.5#

Pelvis, pubis: incompletely ossified

6.2

0.6#

0.6##

1.3

#/##: Fishers exact test (two-sided) significant at level 5% (#) or 1% (##), Bonferroni-Holm-corrected

Applicant's summary and conclusion