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EC number: 908-917-6 | CAS number: -
Developmental toxicity / teratogenicity
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:
- 1 997
- 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
- 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
Constituent 1
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
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