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Toxicological information

Developmental toxicity / teratogenicity

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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

Conclusions:
CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008.