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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
August - October 1992
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation

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
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
May 12, 1981
Qualifier:
according to guideline
Guideline:
other: Off. J. Europ. Commun. L 133, May 30, 1988; 87/302/EEC
Qualifier:
according to guideline
Guideline:
other: Off. J. Europ. Commun. L 180, March 01, 1991; 91/325/EEC
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

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, mixed diesters with octanoic acid and propylene glycol

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, Wiga GmbH, D-97633 Sulzfeld
- Age at study initiation: 8-10 weeks
- Weight at study initiation: mean 216 g
- Fasting period before study: no
- Housing: One animal in Makrolon Type M3 cage (Ebeco) with standard softwood bedding (ARWI-Center, 0-45307 Essen).
- Diet: Pelleted Altromin Maintenance Diet 1324, lot No. 090792/0826 (Fa. Altromin GmbH, 0-32770 Lage) ad libitum
- Water: Community Tap Water from Düsseldorf ad libitum (analysed monthly for use as drinking water)
- Acclimation period: 5 days under laboratory conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 10 - 24 °C
- Humidity (%): 41 - 65 %
- Air changes (per hr): 10 - 15 air changes per hour
- Photoperiod (hrs dark / hrs light): lux units 20 - 430, 12 hours artificial fluorescent light /12 hours dark

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Remarks:
DAB 10
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Arachidis oil, DAB 10, was used as vehicle for the test substance. The test article was prepared daily before administration. No details on the preparation are available.
Analytical verification of doses or concentrations:
no
Details on mating procedure:
The females were mated at the supplier with an accurate day of mating. They were received at the testing facility on day 0 of gestation.
Duration of treatment / exposure:
The test substance was administered once daily in the morning from day 6 p.c. to day 15 p.c. (10 applications).
Frequency of treatment:
Once daily.
Duration of test:
20 days
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
group 2
Dose / conc.:
300 mg/kg bw/day (nominal)
Remarks:
group 3
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
group 4
No. of animals per sex per dose:
at least 24 females
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily (working days)

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least twice daily (working days)

BODY WEIGHT: Yes
- Time schedule for examinations: on day 0, 6, 16 and 20

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Details: Gross macroscopic examination of all maternal organs with emphasis on the uterus, uterine contents, position of fetuses in the uterus and number of corpora lutea was performed and the data recorded. Number and distribution of intrauterine implantations were classified as live or dead fetuses, late intrauterine deaths (resorptions), early intrauterine (resorption sites).
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Details: Gross macroscopic examination of all maternal organs with emphasis on the uterus, uterine contents, position of fetuses in the uterus and number of corpora lutea was performed and the data recorded. Number and distribution of intrauterine implantations were classified as live or dead fetuses, late intrauterine deaths (resorptions), early intrauterine (resorption sites).
Fetal examinations:
The fetuses were removed from the uterus. Intrauterine deaths were classified on the basis of the presence (late) or absence (early) of fetal or decidual tissue in addition to placental tissue. The live fetuses were sexed, weighed individually including placentae, examined for gross external abnormalities and allocated to one of the following procedures:
1) Half of the fetuses from each litter was non-individually fixed in Bouin's solution in order to examine viscera and brain by Wilson's slicing technique. After examination the sections were not preserved. All abnormalities were recorded.
2) The remaining fetuses from each litter were fixed non-individually in ethanol for the following staining with alizarin red (Shandon Varistain 24-T). The skeletons were examined and preserved in pure glycerine in plastic containers. All abnormalities were recorded.
The uteri (including content) of all females were weighed at necropsy on day 20 p.c. to enable the calculation of the corrected body weight gain.
Statistics:
The following statistical methods were used: 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).
Historical control data:
Not available.

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 death occurred in the dams of the vehicle control group and in the test groups.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weight profiles of the pregnant females were essentially similar in all groups. Mean corrected body weight gain of the treatment groups compared favourably with the control values.
Food efficiency:
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:
no effects observed
Description (incidence and severity):
At scheduled necropsy no macroscopic changes were noted in the dams of the groups.
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
Abortions of test groups in range of control group.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Pre- and post implantation loss of test groups in range of control group.
Pre-implantation loss (% of corp. lutea): group 1: 15.5, group 2: 13.9, group 3: 12.6, group 4: 13.7
Post-implantation loss (% of impl. sites): group 1: 5.3, group 2: 3.7, group 3: 3.7, group 4: 4.0
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
Total litter losses of test groups in range of control group.
Embryonic death: group 1: 12, group 2: 12, group 3: 12, group 4: 14
Early or late resorptions:
no effects observed
Description (incidence and severity):
Resorptions of test groups in range of control group.
Embryonic resorption: group 1: 9, group 2: 9, group 3: 12, group 4: 10
Fetal resorption: group 1: 3, group 2: 3, group 3: 0, group 4: 4
Dead fetuses:
no effects observed
Description (incidence and severity):
Number of dead fetuses of test groups in range of control group.
Dead fetuses: group 1: 6, group 2: 0, group 3: 0, group 4: 0
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
not examined

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEC
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: no adverse effects observed

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
The weights of live fetuses exibited no significant differences on a litter and individuel basis e.g. mean weight between the control group and the treatment groups.
Reduction in number of live offspring:
not examined
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The sex ratio of the fetuses was not effected by the treatment with the test substance.
Males: group 1: 159, group 2: 160, group 3: 164, group 4: 170
Females: group 1: 160, group 2: 156, group 3: 151, group 4: 163
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
Litter size and weights of test groups in range of control group.
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No macroscopical findings were noted et external examination of fetuses which were considered to be an effect of the treatment with the test article. In the group 1 (6 death fetuses) were recorded. In all 6 fetuses of the dam no. 15 were noted malformations as hydrocephalus, exencephalus, agenesis of the mandibula and maxilla, in three out of them exophthalmus and in one fetus additionally spina bifida. One fetus was noted in the group 2 (dam no. 35) with hydrocephalus. These singular findings are normal observations in the animal strain used.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Retardations:
Group 1: 168 examined fetuses: skull bones incomplete ossified (12 fetuses out of 23 dams) skull bones non ossified (6 fetuses out of 23 dams)
Group 2: 166 examined fetuses: skull bones incomplete ossified, significant decrease at level 1% (1 fetus out of 23 dams)
Group 3: 165 examined fetuses: no significant findings
Group 4: 173 examined fetuses: skull bones incomplete ossified, significant decrease at level 1% (1 fetus out of 23 dams); skull bones non ossified, significant decrease at level 5% (0 fetus out of 23 dams)
The findings were considered to be incidental because in the control group 12 fetuses showed "skull bones incomplete ossified" and 6 fetuses "skull bones non ossified" out of 23 dams. These retardation offectes were not accompanied by weight retardation of the treatment groups.
Variations:
Group 1 - 4: no variations
Malformations:
Group 1: 6 fetuses exencephaly, 3 fetuses of them in addition exophthalmus, agenesis of the mandibula and maxilla 1 fetus agenesis of the mandibula
Group 2: 1 fetus exencephaly
Group 3: no findings
Group 4: no findings
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The findings were as follows:
Group 1: 157 examined fetuses: 17 hydronephrosis 2 ureter dilatation 3 ureter waved 1 thorax -blood coagulum [artifact]
Group 2: 150 examined fetuses: 26 hydronephrosis 6 ureter dilatation 8 ureter waved
Group 3: 150 examined fetuses: 21 hydronephrosis 7 ureter dilatation 7 ureter waved 1 runt, organs normal 1 hydrocephalus internus
Group 4: 160 examined fetuses: 31 hydronephrosis 6 ureter dilatation 16 ureter waved
The visceral examination of the preserved fetuses did not reveal any treatment related abnormalities.
Other effects:
effects observed, non-treatment-related

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEC
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
The test item does not reveal any embryotoxic or teratogenic potential at dose levels up to 1000 mg/kg body weight/day in an OECD 414 test.
Executive summary:

The effect of the test item on embryonic and fetal development in pregnant CD-rats was assessed in a test according to OECD guideline 414. The test item was tested at dose levels of 0 (group 1), 100 (group 2), 300 (group 3) and 1000 (group 4) mg/kg bw/day. Each group consisted of 24 female rats. The test item was administered orally by gavage once daily from day 6 to day 15 of gestation. A standard dose volume of 5 mL/kg body weight was used. Control animals were dosed with the vehicle alone (arachidis oil, DAB 10) over the period described. Clinical condition and reaction to treatment were recorded at least once daily. Body weights were reported for day 0, 6, 16 and 20 of gestation. All surviving females were sacrificed on day 20 of gestation and the fetuses were removed by caesarean section. At necropsy the females were examined macroscopically and live fetuses were weighed, sexed and examined for visceral and skeletal abnormalities. The dams tolerated the applied dose levels of up to 1000 mg/kg bw/day test item without lethality. No compound-related symptoms were observed in all treatment groups. Maternal body weight gain was not affected by treatment. No treatment-related abnormalities were found at necropsy of the females. Apart from the group1 (6 dead fetuses) all females had viable fetuses. Pre- and post-implantation losses, embryonic death, mean numbers of resorptions and total fetuses were not affected by treatment. Mean final placental and uterus weights were not affected by treatment. Fetal sex ratio was comparable in all groups. No treatment-related fetal abnormalities were found at necropsy. There were no treatment-related effects in reproduction. The examined fetuses showed no treatment-related malformations. The figures of skeletal variations in test and control groups were similar. The figures of skeletal ossifications showed some deviations in the group 2 and 4 which were noted as no treatment-related effects and considered to be within the normal range. The observations of visceral variations in test and control groups were similar. The results showed that repeated oral administration (day 6 -day 15 post coitum) of the test item to pregnant rats caused no symptoms of cumulative toxicity up to a dose level of 1000 mg/kg body weight/day. According to this study the test item is not cumulative toxic to pregnant rats and does not reveal any embryotoxic or teratogenic potential at dose levels up to 1000 mg/kg bw/day.