Octanoic acid, 1,1'-(1,3-propanediyl) ester

Developmental toxicity / teratogenicity

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. 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 guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.31 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Decanoic acid, mixed diesters with octanoic acid and propylene glycol

EC Number:

271-516-3

EC Name:

Decanoic acid, mixed diesters with octanoic acid and propylene glycol

Cas Number:

68583-51-7

Molecular formula:

C21H44O6

IUPAC Name:

decanoic acid; octanoic acid; propane-1,2-diol

Details on test material:

- Name of test material (as cited in study report): [trade name], Decanoic acid, 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 or test system 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

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)

1

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

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.

Effect levels (fetuses)

Remarks on result:

other: See description above

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