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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
05 Jul - 28 Jul 1994
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study with acceptable restrictions. 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:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
only organogenesis covered
Qualifier:
according to
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
only organogenesis covered
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): trade name given
- Chemical denomination: Fatty acids, C16-18; ester with ethylenglycol
- Physical state: white powder
- Analytical purity: 100%
- Lot/batch No.: 152/4
- Expiration date of the lot/batch: May 1995
- Storage condition of test material: at room temperature, dark

Test animals

Species:
rat
Strain:
other: Sprague-Dawley, CD
Details on test animals 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 / concentrations
Remarks:
Doses / Concentrations:
100, 300 and 900 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
24 P 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

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No mortalities occurred during the study period. No compound-related symptoms were observed in the treatment groups in comparison to the control group. Body weight, body weight gains and corrected body weight were within expected ranges. No compound related differences were noted between the mean reproduction data of the test groups in comparison to the control group. At scheduled necropsy no macroscopic changes were noted in the dams of the treatment groups.

Effect levels (maternal animals)

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

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No substance-related symptoms were observed in the treatment groups. Pre-implantation loss, post-implantation loss, mean number of resorptions, embryonic deaths and total foetuses were not affected by treatment. Only one dead foetus was observed in the middle- and one dead foetus in the high-dose group from 345 and 306 live foetuses, respectively. Mean foetal placental and uterus weights were not affected by treatment. Foetal sex ratio was comparable in all groups. No treatment-related foetal abnormalities were found at necropsy. The examined foetuses showed no treatment-related malformations. The figures of visceral variations in the test groups were considered to be similar to the control group.
The mean weight of live male and female foetuses in the mid-dose group was significantly increased (see Table 1 under "Any other information on results incl. tables"). 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.
The figures of skeletal ossifications and variations showed no treatment-related deviations, significant evidences between treated groups and the control group are listed in Table 2 under "Any other information on results incl. tables". The statistically significant differences concerning increased or decreased figures of various findings were considered to be incidental. Furthermore, no dose-relationship in any finding was observed.

Effect levels (fetuses)

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

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

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

Fetal resorptions [total/number of dams ± SD]

0.0 ± 0.2

0.0 ± 0.2

0.0 ± 0.0

0.1 ± 0.4

Live fetuses

336

337

345

306

Dead fetuses

0

0

1

1

Malformed fetuses [total/number of dams ± SD]

0.0 ± 0.2

0.0 ± 0.0

0.0 ± 0.0

0.0 ± 0.2

Sex of fetuses (%males : % females)

47.3 : 52.7

51.6 : 48.4

50.3 : 49.4

52.1 : 47.6

Weights of live fetuses (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 fetuses (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

Fetal 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:
The test substance had no effect on intrauterine development.