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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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998
Report date:
1998

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese MAFF Guidelines ‘Teratogenicity Study’
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: 88/302/EEC
Deviations:
no
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Reference substance name:
3-(3,5-Dichlorophenyl)-2-oxo-1-oxaspiro[4.5]dec-3-en-4-yl 2,2-dimethylbutanoate
Cas Number:
148477-71-8
Molecular formula:
C21H24Cl2O4
IUPAC Name:
3-(3,5-Dichlorophenyl)-2-oxo-1-oxaspiro[4.5]dec-3-en-4-yl 2,2-dimethylbutanoate

Test animals

Species:
rabbit
Strain:
Himalayan
Details on test animals or test system and environmental conditions:
22 (23 in the 300 mg/kg bw/d group) female Himalayan rabbits.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5% aqueous suspension
Details on exposure:
22 (23 in the 300 mg/kg bw/d group) female Himalayan rabbits each were treated daily, orally by gavage, with spirodiclofen formulated in a suspension of 0.5% carboxymethylcellulose in demineralized water, from gestation day 6 to 28 at doses of 0, 100, 300 or 1000 mg/kg bw/d.
Duration of treatment / exposure:
Treated daily with test material concentrations from day 6 to 28 post coitum.
Frequency of treatment:
Daily
Duration of test:
29-day
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
22 (23 in the 300 mg/kg group) female Himalayan rabbits.
Details on study design:
22 (23 in the 300 mg/kg group) female Himalayan rabbits each were treated daily, orally by gavage, with Spirodiclofen, formulated in a suspension of 0.5% carboxymethylcellulose in demineralized water, from day 6 to 28 post coitum in doses of 0, 100, 300 or 1000 mg/kg bw per day. On day 29 of gestation the fetuses were delivered by cesarean section.

The doses were based on the results of a pilot study in which doses of 0, 100, 300, and 1000 mg/kg bw Spirodiclofen were tested. In this study one of the two pregnant females of the 1000 mg/kg group revealed marked transient body weight loss after start of treatment (133 g from day 6 to 7 post coitum). Maternal toxicity could not be excluded at the 1000 mg/kg level while there was no indication of developmental toxicity at this dose level.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least daily

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: The body weight of the females was determined on day 0 p.c. and daily from day 6 to day 29 p.c. Corrected body weight gain was determined by subtracting the uterus weight on day 29 p.c. from the body weight gain from day 0 to 29 p.c.

FOOD CONSUMPTION: Yes
- Time schedule for examinations: The feed intakes of the animals were determined from the difference in weight between the feed offered and the feed not consumed for the following days of gestation: days 0-6, 6-9, 9-12, 12-15, 15-18, 18-21,21 - 24, 24 - 27 and 27 - 29 p.c.

WATER CONSUMPTION: Yes
- Time schedule for examinations: Water intake was assessed by visual estimation of the quantities left over.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes / No / No data
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:
The fetuses were eviscerated according to the modified Staples technique, including a transverse section through the brain in about 50% of the fetuses. After evaluation of the fetuses the viscera were discarded.

- Occurrence of findings of the skeletal system including the cartilaginous part in the fetuses (processing and evaluation were performed after cesarean section) Staining of the cartilage of fetuses (including about 50 % of the skulls) was performed by using Alcian blue. Afterwards the fetuses were cleared with diluted potassium hydroxide solution and were stained with alizarin red S according to the modified Dawson technique.

- occurrence of visceral findings in the fetal skull: evaluation of about 50% of the fetal skulls according to the modified Wilson technique; processing and evaluation were performed after cesarean section)
Statistics:
Females with uterine anomaly or without implantation sites as well as females which aborted or died were not taken into account for calculation of mean values. Differences between the control and treated groups were considered significant when p<0.05. Statistical significance was tested using the following methods:
a. ANOVA and Dunnett's test for
- feed intakes
- body weights and body weight gains and corrected body weight gains
- uterus weights
- number of corpora lutea per female
- number of implantations per female
- number of live fetuses per female and as percentage of implantations per female
- placental weights
- fetal weights

b. CHI-squared test (with Yates' correction according to Yates) for:
- fertility rate
- gestation rate
- number of fetuses or litters with malformations or with external or visceral deviations

c. 2 by N CHI-squared test; in case of significant differences Fisher's exact test with Bonferroni correction for
- number of implantations per group
- number of preimplantation losses per group
- number of post-implantation losses, early resorptions, late resorptions or dead fetuses per group
- number of live fetuses per group in percent of implantations
- number of male or female fetuses or fetuses with indeterminable sex per group
- number of fetuses or litters with skeletal findings

d. Kruskall-Wallis test; in case of significant differences Dunn's test for
- number of pre-implantation losses per female
- number of post-implantation losses, early resorptions, late resorptions or dead fetuses per female
- number of male or female fetuses or fetuses with indeterminable sex per female

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
an increased incidence of alopecia occurred at the
1000 mg/kg level, for which a treatment related effect cannot be excluded.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The body weight gain was transiently decreased after start of treatment at dose levels of 300
mg/kg and above. Overall body weight gain during the treatment and gestation period as well as corrected body
weight gain were also decreased at the 1000 mg/kg bw level.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The feed intakes and correspondingly the amounts of feces were transiently decreased at >300 mg/kg bw.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
The feed intakes and correspondingly the amounts of feces were transiently decreased at >300 mg/kg bw.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine 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):
Necropsy of the females on day 29 post coitum did not
reveal treatment-related findings at levels up to and including 1000 mg/kg bw.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
effects observed, treatment-related
Description (incidence and severity):
One female of the 1000 mg/kg bw group aborted on day 20 post coitum after it had shown
distinct systemic effects before (cold ears, nearly no feed intake and severe body weight loss after start of treatment as well as distinct liver lobulation at necropsy).
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
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
One female of the 1000 mg/kg bw group aborted on day 20 post coitum after it had shown distinct systemic effects before (cold ears, nearly no feed intake and severe body weight loss after start of treatment as well as distinct liver lobulation at necropsy). Furthermore, an increased incidence of alopecia occurred at the 1000 mg/kg level, for which a treatment related effect cannot be excluded. None of the females died due to treatment. The feed intakes and correspondingly the amounts of feces were transiently decreased at >300 mg/kg bw.
Decreased water consumption with subsequently decreased, concentrated and discolored urination occurred at the 1000 mg/kg bw level. The body weight gain was transiently decreased after start of treatment at dose levels of 300 mg/kg and above. Overall body weight gain during the treatment and gestation period as well as corrected body weight gain were also decreased at the 1000 mg/kg bw level. Necropsy of the females on day 29 post coitum did not reveal treatment-related findings at levels up to and including 1000 mg/kg bw.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake
number of abortions

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Anogenital distance of all rodent fetuses:
not examined
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Details on embryotoxic / teratogenic effects:
Regarding the intrauterine development, the gestation rate was marginally decreased by one abortion at 1000 mg/kg bw. It cannot be excluded that this was a consequence of maternal toxicity. The remaining parameters of intrauterine development (external appearance and weight of placentas, the postimplantation loss in the females with viable fetuses on day 29 post coitum and correspondingly the number of fetuses, fetal sex distribution and fetal weight, fetal morphology including stage of ossification) were not affected by treatment at levels up to and including 1000 mg/kg bw. An effect on the incidence of malformations was not evident.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)

Applicant's summary and conclusion

Conclusions:
A maternal NOAEL of 100 mg/kg bw/d was determined for this study based on abortion and clinical signs (at 1000 mg/kg bw/d), reduced body weight gain and food consumption (at 300 mg/kg bw/d).  A developmental NOAEL of 1000 mg/kg bw/d can be determined in the absence of any effects of treatment
Executive summary:

In this pre-natal developmental toxicity study, groups of 22 or 23 mated female Himalayan rabbits were treated daily, orally by gavage, with spirodiclofen in 0.5% carboxymethylcellulose from gestation day 6 to 28 at dose levels of 0, 100, 300 or 1000 mg/kg bw/d.  On gestation day 29, the fetuses were delivered by caesarean section.  Investigations were performed on general tolerance by the females as well as on its effect on intrauterine development.  One female of the 1000 mg/kg bw/d aborted on gestation day 20 after it had shown distinct systemic effects before (cold ears, nearly no feed intakes and severe body weight loss after start of treatment as well as distinct liver lobulation at necropsy).  Furthermore, an increased incidence of alopecia occurred at the 1000 mg/kg bw/d for which a treatment related effect cannot be excluded.  None of the females died due to treatment.  The feed intakes and correspondingly the amounts of faeces were transiently decreased at dose levels of 300 and 1000 mg/kg bw/d. Decreased water consumption and decreased, concentrated and discolored urination occurred in rabbits at 1000 mg/kg bw/d.  Body weight gain was transiently decreased after start of treatment at levels of 300 and 1000 mg/kg bw/d. Overall body weight gain during the treatment and gestation period as well as corrected body weight gain were also decreased at 1000 mg/kg bw/d.  Necropsy of females on gestation day 29 did not reveal treatment related findings at dose levels up to and including 1000 mg/kg bw/d. With respect to intrauterine development the gestation rate was marginally decreased by one abortion at 1000 mg/kg bw/d for which a treatment-related effect as consequence of maternal toxicity cannot be excluded.  The remaining parameters of intrauterine development (external appearance and weight of placentas, the postimplantation loss in the females with viable fetuses on gestation day and correspondingly the number of fetuses, fetal sex distribution  and fetal weight, fetal morphology including stage of ossification) were not affected by treatment at levels up to and including 1000 mg/kg bw/d. A maternal NOAEL of 100 mg/kg bw/d was determined for this study based on abortion and clinical signs (at 1000 mg/kg bw/d), reduced body weight gain and food consumption (at 300 mg/kg bw/d).  A developmental NOAEL of 1000 mg/kg bw/d can be determined in the absence of any effects of treatment.