3-hydroxypropyl octanoate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

A screening study for reproductive/ developmental toxicity study does not need to be conducted since data on pre-natal developmental toxicity in the rat are available with two structural analogue substances.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because a pre-natal developmental toxicity study is available

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

Test data on two read across substances revealed no embryotoxic or teratogenic potential at dose levels up to 900 mg/kg bw/day after repeated oral administration (day 6 – 15) in studies according to OECD 414.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

05 - 27.07.1994

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

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

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 weeks
- Weight at study initiation: mean 198 g
- Fasting period before study: no
- Housing: One animal / Makrolon Type M3 cage (Ebeco, 0-44579 Castrop-Rauxel) with standard softwood bedding (ARWI-Center, 0-45307 Essen).
- Diet: Pelleted Altromin Maintenance Diet 1324, lot No. 170994/1340 (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): 19 - 24 °C
- Humidity (%): 47 - 82 %
- Air changes (per hr): 10 - 15 air changes per hour
- Photoperiod (hrs dark / hrs light): lux units 40 - 500, 12 hours artificial fluorescent light /12 hours dark

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
0.5 % sodium carboxymethylcellulose + 0.25 % Cremophor in aqua desto (CMCC) was used as vehicle for the test substance. The test article was prepared daily before administration. The concentrations of the test substance in CMCC, based on the results of analysis of the dry weight, are as foliows:
1 % (100 mg/kg) = 1.1 %
3 % (300 mg/kg) = 3.3 %
10 % (900 mg/kg) = 9.6 %

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The formulation of the test article was analysed once for achieved concentration by "Henkel TTA-Analytical Centre". No details are available.

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

Dose / conc.:

100 mg/kg bw/day (nominal)

Remarks:

group 2

Dose / conc.:

300 mg/kg bw/day (nominal)

Remarks:

group 3

Dose / conc.:

900 mg/kg bw/day (nominal)

Remarks:

group 4

No. of animals per sex per dose:

at least 24 females

Control animals:

yes, concurrent vehicle

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.

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 similar in all groups. Mean corrected body weight gain (corrected for uterus weight) 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

Number of abortions:

no effects observed

Description (incidence and severity):

Abortions of test groups in range of control group.
group 1: 15, group 2: 18, group 3: 12, group 4: 19

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: 8.8, group 2: 9.9, group 3: 10.9, group 4: 10.4
Post-implantation loss (% of impl. sites): group 1: 4.3, group 2: 5.1, group 3: 3.6, group 4: 6.1

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: 15, group 2: 18, group 3: 12, group 4: 19

Early or late resorptions:

no effects observed

Description (incidence and severity):

Resorptions of test groups in range of control group.
Embryonic resorption: group 1: 14, group 2: 17, group 3: 12, group 4: 16
Fetal resorption: group 1: 1, group 2: 1, group 3: 0, group 4: 3

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: 0, group 2: 0, group 3: 1, group 4: 1

Changes in pregnancy duration:

not examined

Changes in number of pregnant:

not examined

Key result

Dose descriptor:

NOAEC

Effect level:

900 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: no adverse effects observed

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

The mean weight of live male and female fetuses of the group 3 were significantly increased. The weights of live fetuses of the group 2 and 4 exibited 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:

not examined

Changes in sex ratio:

no effects observed

Description (incidence and severity):

Sex ratio of test groups in range of control group.
Males: group 1: 159, group 2: 174, group 3: 174, group 4: 160
Females: group 1: 177, group 2: 163, group 3: 171, group 4: 146

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 at external examination of fetuses which were considered to be an effect of the treatment with the test article. The following abnormal spontaneous findings were ascertained during external examination:
One fetus with a missing tail (see skeletal examination) (female 23, group 1).
One dead fetus approx. on day 13 (no signs of malformation) (female 52, group 3).
One dead fetus approx. on day 16 with hydrops/hydrocephalus (female 75, group 4).
One fetus with beginning hydrops fetalis (see visceral examination: runt, cleft palate) (female 81, group 4)

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Following abnormal spontaneous findings were noted:
One fetus with acaudia (coccygeal vertebrae non ossified, sacral vertebrae 2 - 5 non ossified) (female no. 23, group 1).
One fetus with incompletely ossified palate (female no. 25, group 2).
Two fetuses with thickened and nodular ribs, shortened intervertebral spaces in the thoracic region and curved clavicles (female no. 59, group 3).

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

The findings were as follows:
Group I, 160 examined fetuses: 10 (6.3 %) hydronephrosis; 8 (5.0 %) ureter dilatation; 5 (3.1 %) ureter waved
Group 2, 164 examined fetuses: 19 (11.6 %) hydronephrosis; 10 (6.1 %) ureter dilatation; 7 (4.3 %) ureter waved
Group 3, 165 examined fetuses: 15 (9.1 %) hydronephrosis; 8 (4.8 %) ureter dilatation; 1 (0.6 %) ureter waved; 1 ( 0.6 %) esophagus dilatation
Group 4, 146 examined fetuses: 28 (19.2 %) hydronephrosis; 13 (8.9 %) ureter dilatation; 7 (4.8 %) ureter waved; 1 (0.7 %) hematoma submandibular region; 1 (0.7 %) runt, cleft palate
The visceral examination of the preserved fetuses did not reveal any treatment related abnormalities.

Other effects:

effects observed, non-treatment-related

Description (incidence and severity):

A generally retarded ossification was found in:
One fetus (female no. 17, group 1).
Two fetuses (female no. 82, group 4).

Key result

Dose descriptor:

NOAEL

Effect level:

900 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Conclusions:

The test item does not reveal any embryotoxic or teratogenic potential at dose levels up to 900 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 900 (group 4) mg/kg bw/day. 24 female rats per group at the study start (pregnant rats: Group 1: 23; group 2: 23; group 3: 24; group 4: 22). The test item was administered orally by gavage once daily from day 6 to day 15 of gestation (10 applications). A standard dose volume of 10 mL/kg body weight was used adjusted to the body weight of day 6 post coitum (p.c.). Control animals were dosed with the vehicle alone (0.5 % sodium carboxymethylcellulose + 0.25 % Cremophor in aqua dest. - CMCC) over the period described. Clinical condition and reaction to treatment were recorded at least once daily. Body weights were reported for days 0, 6, 16 and 20 of gestation. All surviving females were sacrificed on day 20 of gestation and removed by caesarean section. At necropsy the females and live fetuses were weighed, sexed and examined for skeletal abnormalities. The dams tolerated the applied dose levels up to 900 mg/kg bw/day test item without lethality. No substance-related symptoms were observed in the treatment groups 2 - 4 in comparison to the control group 1. Maternal body weight gain was not affected by treatment. No treatment-related abnormalities were found at necropsy of the females. All females had viable fetuses. Pre-implantation loss, post-implantation loss, mean numbers of resorptions, embryonic deaths and total fetuses were not affected by treatment. Mean fetal 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 the reproduction data. The examined fetuses showed no treatment-related malformations. The figures of visceral variations in the test groups were considered to be similar to the control group. The figures of skeletal ossifications and variations showed no treatment-related deviations. The results of this study showed that repeated oral administration (day 6 p.c. to day 15 p.c.) of the test item to pregnant rats caused no symptoms of cumulative toxicity up to 900 mg/kg body weight/day. According to the study described, the test item does not reveal any embryotoxic or teratogenic potential at dose levels up to 900 mg/kg body weight/day.

Reference 2

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

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

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

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

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

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.

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

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

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: no adverse effects observed

Key result

Abnormalities:

no effects observed

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

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

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

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.

Reference 3

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

Please refer to Chapter 13.

Reason / purpose for cross-reference:

read-across source

Species:

rat

Key result

Dose descriptor:

NOAEL

Effect level:

900 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: no adverse effects observed

Key result

Abnormalities:

no effects observed

Key result

Dose descriptor:

NOAEC

Effect level:

900 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Reference 4

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

Please refer to Chapter 13.

Reason / purpose for cross-reference:

read-across source

Species:

rat

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: no adverse effects observed

Key result

Abnormalities:

no effects observed

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

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

No data on the test item is available. With the read-across substances the following results were obtained (please refer to section 13 for justification of read-across):

The effect of the read across substance CAS 68583-51-7 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 (group1), 100 (group 2), 300 (group3) and 1000 (group 4) mg/kg body weight,  24 female rats per group. 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, DAB10) over the period described. Clinical observations 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 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 group1 (6 dead fetuses) all females had viable fetuses. Pre- and post-implantation loss, embryonic deaths, mean numbers of resorptions and total fetuses were not affected by treatment. Mean fatal 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 the reproduction data. The examined fetuses showed no treatment-related malformations. Skeletal variations in both the test groups and the control group were considered to be similar. Skeletal ossifications showed some deviations in the group 2 and 4 which were considered to be not treatment-related and to be within the normal range. Visceral variations in both test groups and the control group were considered to be 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 toxic to pregnant rats and does not induce embryotoxic or teratogenic potential at dose levels up to 1000 mg/kg body weight/day.

 

The effect of the read across substance CAS 91031-31-1 on embryo 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 900 (group 4) mg/kg body weight. Each group consisted at least of 24 female rats at the start of the study (pregnant rats: Group 1: 23; group 2: 23; group 3: 24; group 4: 22). The test item was administered orally by gavage once daily from day 6 to day 15 of gestation (10 applications). A standard dose volume of 10 mL/kg body weight was used adjusted to the body weight of day 6 post coitum (p.c.). Control animals were dosed with the vehicle alone (0.5 %. sodium carboxymethylcellulose + 0.25 %. Cremophor in aqua dest. - CMCC) 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 removed by caesarean section. At necropsy the females macroscopically and live fetuses were weighed, sexed and examined skeletal abnormalities. The dams tolerated the applied dose levels up to 900 mg/kg test item without lethality. No substance-related symptoms were observed in the treatment groups 2 – 4 compared to control group 1. Maternal body weight gain was not affected by treatment. No treatment-related abnormalities were found at necropsy of the females. All females had viable fetuses. The rates of pre-implantation loss, post-implantation loss, mean numbers of resorptions, embryonic deaths and total fetuses were not affected by treatment. Mean fetal 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 the reproduction data. The examined fetuses showed no treatment-related malformations. The figures of visceral variations in the test groups were considered to be similar to the control group. The figures of skeletal ossification and variation showed no treatment-related deviations. The results of this study showed that repeated oral administration (day 6 p.c. to day 15 p.c.) of the test item to pregnant rats caused no symptoms of cumulative toxicity up to 900 mg/kg body weight/day. According to the study described, the test item does not reveal any embryotoxic or teratogenic potential at dose levels up to 900 mg/kg body weight/day.

Furthermore in the ECHA disseminated Dossiers of the target substance-metabolites 1,3-Propanediol (CAS 504-63-2) and Octanoic acid (CAS 124-07-2) it is also concluded that these substances do not possess teratogenic properties.

 

Justification for classification or non-classification

The available test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data on toxicity to reproduction, the test item does not require classification for toxicity to reproduction according to Regulation (EC) No 1272/2008 (CLP), as amended for the fifteenth time in Regulation (EU) No 2020/1182.