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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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data from HSDB

Data source

Reference
Reference Type:
other: Authoritative database
Title:
Reproductive and developmental toxicity study of test material was performed in rats
Author:
HSDB
Year:
2018
Bibliographic source:
U.S. National Library of Medicine National Institutes of Health, Health & Human Services; 2018

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: OECD 421
Principles of method if other than guideline:
Reproductive and developmental toxicity study of test material was performed on rats.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (IUPAC name): 1,3,3 trimethyl 2 oxabicyclo[2,2,2]octane
- Common name: Eucalyptol
- Molecular formula: C10H18O
- Molecular weight: 154.2512 g/mol
- Smiles notation: C[C@@]12CC[C@@H](CC1)C(C)(C)O2
- InChl: 1S/C10H18O/c1-9(2)8-4-6-10(3,11-9)7-5-8/h8H,4-7H2,1-3H3/t8-,10+
- Substance type: Organic
- Physical State: Liquid

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Han (TM): RCCHan(TM): WIST
Details on test animals and environmental conditions:
No data available

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Arachis oil BP
Details on exposure:
Details on exposure
PREPARATION OF DOSING SOLUTIONS: test material soluble in Arachis oil BP.
DIET PREPARATION
- Rate of preparation of diet (frequency):Fresh diets were made and distributed weekly
- Mixing appropriate amounts with (Type of food )
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): Arachis oil BP
- Concentration in vehicle: 0, 30, 300 and 600mg/kg bw/day
- Amount of vehicle (if gavage):
- Lot/batch no. (if required): No data available
- Purity: No data available
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: [artificial insemination / purchased timed pregnant / cohoused]
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation:
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: [no / yes (explain)]
- Verification of same strain and source of both sexes: [yes / no (explain)]
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy
- Any other deviations from standard protocol:
Duration of treatment / exposure:
11 week ( (including a two week pre-pairing phase, pairing, gestation and early lactation for females)
Frequency of treatment:
Daily
Duration of test:
11 weeks
Doses / concentrations
Remarks:
0, 30,300,600 mg/kg bw/day
No. of animals per sex per dose:
Total:80
0 mg/kg bw/day: 10 male and 10 female
30mg/kg bw/day: 10 male and 10 female
300mg/kg bw/day: 10 male and 10 female
600mg/kg bw/day: 10 male and 10 female
Control animals:
yes, concurrent vehicle
Details on study design:
No data available

Examinations

Maternal examinations:
Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes

DETAILED CLINICAL OBSERVATIONS: Yes

Time schedule:

BODY WEIGHT: Yes
Time schedule for examinations: .
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): yes
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other:
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations:No data
- Skeletal examinations: No data
- Head examinations: No data
Statistics:
No data available
Indices:
No data available
Historical control data:
No data available

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
Assessment of surface righting ability on Day 1; offspring clinical signs did not indicate any effect of maternal treatment
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
Description (incidence and severity):
At 600 mg/kg bw/day initial offspring body weight was similar to control but weight gain to Day 4 was statistically significantly lower than control. Mean offspring body weights, litter weight and weight gains to Day 4 of age were unaffected by maternal treatment at 30 and 300 mg/kg bw/day.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Maternal developmental toxicity

Number of abortions:
not specified
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:
not specified
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Gestation length was considered to be unaffected by treatment at 30, 300 and 600 mg/kg bw/day.
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
not specified
Other effects:
not specified

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
600 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
clinical signs
body weight and weight gain
gross pathology
Remarks on result:
other: No developmental toxic effects observed

Maternal abnormalities

Abnormalities:
not specified
Localisation:
not specified

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
At 600 mg/kg bw/day initial offspring body weight was similar to control but weight gain to Day 4 was statistically significantly lower than control. Mean offspring body weights, litter weight and weight gains to Day 4 of age were unaffected by maternal treatment at 30 and 300 mg/kg bw/day.

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Reduction in number of live offspring:
not specified
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Description (incidence and severity):
Macroscopic necropsy findings did not indicate any effect of treatment at 30, 300 and 600 mg/kg bw/day.
Skeletal malformations:
not specified
Visceral malformations:
not specified
Other effects:
not specified

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
600 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
reduction in number of live offspring
changes in litter size and weights
external malformations
Remarks on result:
other: No developmental toxic effects was observed

Fetal abnormalities

Abnormalities:
not specified
Localisation:
other: not specified

Overall developmental toxicity

Developmental effects observed:
not specified
Treatment related:
not specified
Relation to maternal toxicity:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to 600mg/kg/day, When male and female rats were treated with test material orally for 11weeks.
Executive summary:

The reproductive and developmental toxicity study of test material was performed on male and femaleWistar Han (TM): RCCHan(TM): WIST strain rats. The test material was dissolved in Arachis oil BP and administered in dose concentration 0, 30,300,600mg/kg bw /day via oral gavage for up to eleven weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females).Each treatment group contain 10 male and 10 female rats while a control group of ten males and ten females was dosed with vehicle alone (Arachis oil BP). Clinical signs, bodyweight change, dietary intake and water consumption were monitored during the study. Pairing of animals within each dose group was undertaken on a one male: one female basis within each treatment group on Day 5 of the study, with females subsequently being allowed to litter and rear their offspring to Day 5 of lactation. An additional pairing for high dose females that failed to achieve pregnancy was performed to fully assess mating performance and fertility. During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size and offspring weights and assessment of surface righting reflex. Adult males were terminated on Day 52 of the study following the completion of the second pairing at 600 mg/kg bw/day. Females and offspring were terminated on day 5 post partum. Any female which did not produce a pregnancy (unless allocated to a further mating phase) was terminated on or after Day 25 post coitum. All animals were subjected to a gross necropsy examination and histopathological evaluation of reproductive tissues was performed. Additional male organ weight and detailed histopathological examination of the testes were performed to more fully assess male fertility.

 

There were no unscheduled deaths in the study.Transient post-dosing salivation was observed from Day 7 at 600 mg/kg bw/day and Day 13 at 300 mg/kg bw/day. This sign was observed regularly throughout the treatment period with all animals being affected at both dosages, although the incidence of thisfinding was greatest at the high dosage. Transient post dosing salivation was also observed at 30 mg/kg bw/day for two females on Day 2 and one male on Day 50 of this study.At 600 mg/kg bw/day body weight gain of males was statistically significantly lower than control during thefirst week of treatment. Subsequent body weight gains were considered to reflect normal biological variation, but overall gain at termination remained lower than control.

Bodyweight gain of males at 30 and 300 mg/kg bw/day and for females at all dosages, throughout the pre-pairing, gestation and lactation phases of the study, were considered to have been unaffected by treatment. Food consumption for both sexes was considered to have been unaffected by treatment throughout the study, and including gestation and lactation phases for females, at 30, 300 and 600 mg/kg bw/day. Food efficiency: At 600 mg/kg bw/day food conversation efficiency for males was lower than control during week 1; subsequent food utilisation was similar to control. Food conversation efficiency of males at 30 and 300 mg/kg bw/day and for females at all dosages, throughout the pre-pairing, gestation and lactation phases of the study, were considered to have been unaffected by the treatment. Male reproductive organ weights were unaffected by treatment at 30, 300 and 600 mg/kg bw/day and did not indicate any effect on fertility. Histopathological examinations did not indicate any effect of treatment at 600 mg/kg bw/day and these examinations, including detailed assessment of the spermatogenetic cycle for the testes did not indicate any effect on male fertility. Pre-coital interval and mating evidence at the times of conception did not indicate any adverse effect of treatment on mating performance at 30, 300 and 600 mg/kg bw/day. Fertility: At 600 mg/kg bw/day, only seven females delivered a litter following the initial pairing but subsequent re-mating and additional assessment of male organ weight and detailed testicular histopathology did not indicate any treatment related effect on fertility for either sex. There was also no effect of treatment on fertility at 30 and 300 mg/kg bw/day. Gestation length was considered to be unaffected by treatment at 30, 300 and 600 mg/kg bw/day. Litter responses: Offspring litter size, sex ratio and viability: There was no effect of maternal treatment on corpora lutea and implantations counts, pre- and postimplantation loss, number of offspring born, sex ratio or subsequent survival to Day 4 of age at 30, 300 and 600 mg/kg bw/day. Assessment of surface righting ability on Day 1; offspring clinical signs and necropsyfindings and did not indicate any effect of maternal treatment. Assessment of surface righting ability on Day 1; offspring clinical signs and necropsyfindings and did not indicate any effect of maternal treatment.Macroscopic necropsyfindings did not indicate any effect of treatment at 30, 300 and 600 mg/kgbw/day. HenceNo Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to 600mg/kg/day,When male and femalerats were treated with test material orally for 11weeks.