Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP-Guideline study, tested with the source substance Decanoic acid, mixed diesters with octanoic acid and propylene glycol (CAS 68583-51-7). According to the ECHA guidance document “Practical guide 6: How to report read-across and categories (March 2010)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report Date:
1994

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
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], Decanoic acids, mixed diesters with octanoic acid and propylenglycol
- Physical state: colourless liquid
- Analytical purity: 100%
- Lot/batch No.: 259
- Expiration date of the lot/batch: 27 Jan 1993
- Stability under test conditions: stable in arachidis oil, DAB 10
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
other: Sprague-Dawley, CD
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga, Sulzfeld, Germany
- Age at study initiation: 8-10 weeks
- Weight at study initiation: mean 216 g
- Housing: individual in Makrolon cages
- Diet: pelleted Altromin Maintenance Diet 1324 (Lot No. 090792/0826), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 41-65
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12 (lux values 20-430)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Dosing solutions were prepared daily by dissolving of the test material in arachidis oil yielding a final concentration of 20-200 mg/mL.

VEHICLE
- Concentration in vehicle: 2, 6, and 20% (w/v)
- Amount of vehicle (if gavage): 5 mL/kg bw
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: the females were mated at the supplier with an accurate day of mating. The animals were reveived 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:
10 days
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 300 and 1000 mg/kg bw/day
Basis:
other: nominal dose
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 (Potokar, 1988).

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily
- Cage side observations which were included: clinical signs

BODY WEIGHT: Yes
- Time schedule for examinations: Day 0, 6, 16 and 20 of gestation

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: all maternal organs, with emphasis on 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]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
- Head examinations: Yes: [half per litter]
Statistics:
In case of 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 Stell-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 variable 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:
During the study:
- no maternal mortality occurred,
- no compound-related symptoms were observed,
- body weight profiles were similar in all groups,
- no compound-related differences between the mean reproduction data of the test groups in comparison to the control group occurred,
- and no macroscopic changes were noted.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes. Remark: No adverse or treatment-related effects

Details on embryotoxic / teratogenic effects:
The body weights of live foetus/weights of placenta and uterus exhibited no significant differences between treatment and control groups. The sex ratio was not affected by treatment (see Tables 1, 2 and 3 under ‘Any other information on results incl. tables’).

External Examination:
Only in the control group, 6 dead foetuses of dam no. 15 were observed. All 6 foetuses had malformations as hydrocephalus, exencephaly, agenesis of the mandibula and maxilla, in 3/6 exophthalmus and in 1/6 spina bifida, as well. In group 2 (100 mg/kg bw) one foetus with hydrocephalus was noted.

Visceral Examination:
In the control group 157 foetuses were examined with 17/157 showing hydronephrosis, 2/157 ureter dilatation, 3/157 ureter waved and 1/157 thorax blood coagulum. In the dose group 100 mg/kg bw, 26/150 examined foetuses had hydronephrosis, 6/150 ureter dilatation and 8/150 ureter waved. In the dose group 300 mg/kg bw, 21/150 examined foetuses had hydronephrosis, 7/150 ureter dilatation and 7/150 ureter waved. One runt was observed with normal organs and 1 foetus with hydrocephalus internus. In dose group 1000 mg/kg bw, 31/150 examined foetuses had hydronephrosis, 6/150 ureter dilatation and 16/150 ureter waved. According to the author the observed abnormalities were not treatment-related.

Skeletal Examination:
The observation revealed in the control group 12/168 foetuses with incomplete ossified skull bones and 6/168 with non ossified skull bones. In the first treatment group only 1/166 examined foetuses showed incomplete ossified skull bones and there were no findings in group 3 (300 mg/kg bw). In dose group 1000 mg/kg bw, 1/173 foetuses had incomplete ossified skull bones. The findings were considered to be identical in all groups and therefore not treatment-related.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table 1. Maternal effects

Parameter

Group 1

0 mg/kg bw

Group 2

100 mg/kg bw

Group 3

300 mg/kg bw

Group 4

1000 mg/kg bw

Number of dams examined

24

24

24

24

Clinical findings

No clinical signs were observed during the study period in all groups.

Mortality of dams [%]

No death occurred in the dams of all groups.

Body weight gain [g]

Day 6-20

131.9

128.0

131.2

137.8

Uterus weight (mean) [g]

84.9

82.1

86.0

86.8

Pregnancies [%]

96

96

92

96

 

Table 2. Litter response (Caesarean section data)

Parameter

Group 1

0 mg/kg bw

Group 2

100 mg/kg bw

Group 3

300 mg/kg bw

Group 4

1000 mg/kg bw

Corpora lutea [total number]

399

381

374

402

Corpora lutea

[total/ no of dams with implantations ± SD]

17.3 ± 2.1

16.6 ± 1.6

17.0 ±2.5

17.5 ±2.2

Implantations[total number]

337

328

327

347

Implantations[total/number of dams ± SD]

14.7 ± 2.3

14.3 ± 2.6

14.9 ± 2.7

15.1 ± 2.5

Total number of live foetuses

319

316

315

333

Total number of dead foetuses

6

0

0

0

Pre-implantation loss

[total/no. of dams with implantations]

2.7

2.3

2.1

2.4

Post-implantation loss

[total/no. of dams with implantations]

0.8

0.5

0.5

0.6

Foetal sex ration[% male/female]

48.9/49.2

50.6/49.4

52.1/47.9

51.1/48.9

Foetus weight(mean) [g]

4.0

4.1

4.0

4.0

Placenta weight(mean) [g]

0.6

0.6

0.6

0.6

Total number of litters

23

23

22

23

Table 3: Examination of the foetuses

Parameter

Group 1

0 mg/kg bw

Group 2

100 mg/kg bw

Group 3

300 mg/kg bw

Group 4

1000 mg/kg bw

Number of foetuses per group

325

316

315

333

Total number of foetuses with malformations

6

1

0

0

% of foetuses with malformations

1.8

0.3

0

0

Applicant's summary and conclusion

Conclusions:
The test substance had no effect on intrauterine development.
CLP: not classified
DSD: not classified