Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

OECD 416, GLP compliant: the NOAEL for fertility was determined to be ≥ 90 mg/kg bw/day.

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Details on species / strain selection:
Wistar Crl : (WI) BR
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Dosing of the F0 generation with 0, 3,10, and 30 mg/kg bw/day started 10 weeks prior to mating.
Dosing of the F1 generation with 0, 10, 30 and 90 mg/kg/day mg/kg bw/day started when the animals were 3-5 weeks old. Pups were not treated during the weaning period. 10 weeks prior to mating animals were dosed.
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
F0, F1
Dose / conc.:
3 mg/kg bw/day (nominal)
Remarks:
F0
Dose / conc.:
10 mg/kg bw/day (nominal)
Remarks:
F0, F1
Dose / conc.:
30 mg/kg bw/day (nominal)
Remarks:
F0, F1
Dose / conc.:
90 mg/kg bw/day (nominal)
Remarks:
F1
No. of animals per sex per dose:
F1: 25
Control animals:
yes, concurrent vehicle
Positive control:
no positive control performed
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION
- Time schedule for examinations: weekly

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

Oestrous cyclicity (parental animals):
Oestrus cycle was examined in P and F1.
The ovaries and uterus were examined prior to fixation and the number of corpora lutea and implantation sites recorded.
Sperm parameters (parental animals):
Parameters examined in P and F1 male parental generations.
Sperm motility, sperm morphology, enumeration of homogenisation-resistant spermatids, and cauda epididymal sperm reserves.
Litter observations:
STANDARDISATION OF LITTERS.
On day 4 after birth all litters of more than 8 pups were culled to approximately 4 males and 4 females.

PARAMETERS EXAMINED
The following parameters were examined in F1, F2 pups:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities.
Weights of live pups were recorded at day 1, 4, 7, 14 and 21.

ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: not performed

ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: Not performed
Postmortem examinations (parental animals):
SACRIFICE
F0 Females from both generations were killed at day 21 post partum. F0 males were killed as soon as possible after successful mating while F1 males were only killed after successful delivery of the dams.

GROSS NECROPSY
All parental animals were subject to a necropsy and some tissues weighed adrenals, brain, epididymides, kidneys, liver, ovaries, pituitary, prostate, seminal vesicles, spleen, testes, thyroid, uterus with oviducts and cervix.
All pups not selected for mating were taken for necropsy at day 21 post partum or shortly thereafter; organ weights were recorded for brain, spleen and thymus.

HISTOPATHOLOGY / ORGAN WEIGHTS
adrenals, brain, coagulating glands, epididymides, identification marks, kidneys, liver, ovaries, pituitary, prostate, seminal vesicles, spleen, testes, thyroid, uterus with oviducts and cervix, vagina were preserved for histological examination.
Postmortem examinations (offspring):
GROSS NECROPSY
- yes only macroscopic pathology was performed on the F1 and F2 pups.

Reproductive indices:
Parameters: Mating, fertility index, conception rate, gestation index, duration of gestation, percentage live offspring by sex, percentage of post-natal loss, percentage of breeding loss, percentage live at weaning by sex, viability index, weaning index.
Offspring viability indices:
Litters were examined for number of live and dead pups.
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
F0: 2 males and 1 female (0 mg/kg bw/day), 1 female (3 mg/kg bw/day), 1 female (10 mg/kg bw/day), 1 females (30 mg/kg bw/day).
Animals were found dead or killed in extremis due to bad health or delivery difficulties. The deaths are not considered to be treatment-related.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Females of the 30 mg/kg bw/day group showed small but significant decreases in body weight gain during lactation on days 4, 7 and 14, and body weight loss on day 4 during lactation.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Females of the 30 mg/kg bw/day group showed a significant decrease in food consumption from day 1-4 during lactation.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not specified
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathology of the male kidneys showed changes typical of 2u -globulin nephropathy at all doses. No other histopathological changes were reported and no similar changes were observed in females.
Histopathological findings: neoplastic:
no effects observed
Other effects:
not examined
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
>= 30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no treatment related adverse effects on fertility were observed
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
organ weights and organ / body weight ratios
Remarks on result:
other:
Remarks:
Male toxicity
Dose descriptor:
NOAEL
Effect level:
>= 30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No substance related adverse effects observed
Remarks on result:
other:
Remarks:
Female toxicity
Key result
Critical effects observed:
no
Lowest effective dose / conc.:
30 mg/kg bw/day (nominal)
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
no
Relevant for humans:
not specified
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
0 mg/kg bw/day: 1 female
10 mg/kg bw/day: 1 female
30 mg/kg bw/day: 2 females
90 mg/kg bw/day: 1 female
Animals were found dead or killed in extremis due to bad health or delivery difficulties. The deaths are not considered to be treatment-related.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Females of the 90 mg/kg bw/day group had in increased body weight and body weight gain.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
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:
effects observed, treatment-related
Description (incidence and severity):
30 mg/kg bw/day: Increased relative liver weight and absolute and relative increased kidney weights in the male rats.
90 mg/kg bw/day:Increased relative liver weight and absolute and relative increased kidney weights in the male rats.
Effects were dose related.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathology of the male kidneys showed changes typical of 2u -globulin nephropathy at all doses. No differences were seen in females and no other histopathological changes were reported.
Histopathological findings: neoplastic:
no effects observed
Other effects:
not examined
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
>= 90 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No substance related effects on fertility
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
organ weights and organ / body weight ratios
Remarks on result:
other:
Remarks:
male toxicity
Dose descriptor:
NOAEL
Effect level:
>= 90 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No treatment related effects observed.
Remarks on result:
other:
Remarks:
female toxicity
Key result
Critical effects observed:
no
Lowest effective dose / conc.:
30 mg/kg bw/day (nominal)
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Key result
Critical effects observed:
no
Lowest effective dose / conc.:
30 mg/kg bw/day (nominal)
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
not specified
Description (incidence and severity):
Survival index: no toxicological relevant effects found.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Other effects:
not examined
Behaviour (functional findings):
no effects observed
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed on the pups.
Key result
Critical effects observed:
no
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
not specified
Description (incidence and severity):
Survival index: no toxicological relevant effects found.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Other effects:
not examined
Behaviour (functional findings):
no effects observed
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
>= 90 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects on fertility were observed
Key result
Reproductive effects observed:
no

Summary table of the 2 generation study. Cited from: CLH report, 2012 (version 3) Submitted by: National Institute for Public Health and the Environment (RIVM).

 

 

Dose (mg/kg bw/day)

0

 

3

 

10

 

30

 

90

 

 

Sex

m

f

m

f

m

f

m

f

m

f

F0 animals

Mortality (A)

2

1

 

1

 

1

 

1

 

 

 

Clinical signs

no toxicologically relevant effect

 

 

 

Body weight (gain)(B)

 

 

 

 

 

 

 

ds

 

 

 

Food consumption (C)

 

 

 

 

 

 

 

ds

 

 

 

Mating, fertility, gestation

no toxicologically relevant effect

 

 

 

Oestrus cycle

no toxicologically relevant effect

 

 

 

Sperm parameters

no toxicologically relevant effect

 

 

 

Organ weights

-kidney

-thyroid

 

 

 

 

 

 

 

Is (a)

 

 

 

Is (r )

 

 

 

 

Pathology

no toxicologically relevant effect

 

 

 

macroscopy

no toxicologically relevant effect

 

 

 

Microscopy (D)

no toxicologically relevant effect

 

 

F1 pups

Litter size

no toxicologically relevant effect

 

 

 

Survival index

no toxicologically relevant effect

 

 

 

Sex ratio

no toxicologically relevant effect

 

 

 

Body weight

no toxicologically relevant effect

 

 

 

Organ weight

no toxicologically relevant effect

 

 

 

Pathology

 

 

 

 

macroscopy

no toxicologically relevant effect

 

 

 

Microscopy(weanlings)

Not performed

 

 

F1 animals

Mortality (A)

 

1

 

 

 

1

 

2

 

1

 

Clinical signs

 

 

 

no toxicologically relevant effect

 

Body weight E

 

 

 

no toxicologically relevant effect

 

Food consumption

 

 

 

no toxicologically relevant effect

 

Mating, fertility, gestation

 

 

 

no toxicologically relevant effect

 

Oestrus cycle

 

 

 

no toxicologically relevant effect

 

Sperm parameters

 

 

 

no toxicologically relevant effect

dr

dr

Organs weights

-kidney

-liver

 

 

 

 

 

 

 

 

Is (r )

Is(ar)

 

 

 

Is (r )

Is(ar)

 

 

Pathology

 

 

 

 

 

-macroscopy

 

 

 

no toxicologically relevant effect

 

-microscopy

 

 

 

no toxicologically relevant effect

F2 pups

Litter size

 

 

 

no toxicologically relevant effect

 

Survival index

 

 

 

no toxicologically relevant effect

 

Sex ratio

 

 

 

no toxicologically relevant effect

 

Body weight

 

 

 

no toxicologically relevant effect

 

pathology

 

 

 

 

 

-macroscopy

 

 

 

no toxicologically relevant effect

 

-microscopy

 

 

 

Not performed

dr = dose related; i = increased; d = decreased; is = increased significantly; ds = decreased significantly, a= absolute, r=relative

 

A. Animals were found dead or killed in extremis due to bad health or delivery difficulties. The deaths are not considered to be treatment-related.

B. Females of the 30 mg/kg bw/day group showed small but significant decreases in body weight gain during lactation on days 4, 7 and 14, and body weight loss on day 4 during lactation.

C. Females of the 30 mg/kg bw/day group showed a significant decrease in food consumption from day 1-4 during lactation.

D. Males of all treated groups showed histopathological changes in the kidney consistent with accumulation of α2u-globulin.

E. Females of the 90 mg/kg bw/day group had in increased body weight and body weight gain. The study authors considers this finding not toxicologically relevant. The present reviewers endorse this view

Conclusions:
Under the conditions of the test no adverse effects on fertility were observed. Therefore the NOAEL for fertility ≥ 90 mg/kg bw/day
Executive summary:

An OECD 416 study was performed in compliance with GLP. In this 2 generation study, 25 Wistar rats were exposed by oral gavage to 0, 3, 10, and 30 mg/kg bw d-carvone (F0). Dosing of the F0 generation started 10 weeks prior to mating. Dosing of the F1 generation with 0, 10, 30 and 90 mg/kg/day mg/kg bw/day started after weaning when the animals were 3-5 weeks old. Parental animals were subject to necropsy and tissues were weighted (adrenals, brain, epididymides, kidneys, liver, ovaries, pituitary, prostate, seminal vesicles, spleen, testes, thyroid, uterus with oviducts and cervix). Histological examination was performed on adrenals, brain, coagulating glands, epididymides, identification marks, kidneys, liver, ovaries, pituitary, prostate, seminal vesicles, spleen, testes, thyroid, uterus with oviducts and cervix, and vagina. The oestrus cycle was examined in the females and sperm parameters were examined in the males. Mortality, weight and sex were recorded for the pups. Furthermore, physical or behavioural abnormalities were recorded. Macroscopic examinations after necropsy was performed on the pups. The following reproductive indices were determined: mating, fertility index, conception rate, gestation index, duration of gestation, percentage live offspring by sex, percentage of post-natal loss, percentage of breeding loss, percentage live at weaning by sex, viability index, weaning index. Under the conditions of the test no adverse effects on fertility were observed. Therefore, the NOAEL for fertility ≥ 90 mg/kg bw/day.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
90 mg/kg bw/day
Species:
rat
Quality of whole database:
An OECD 416, GLP compliant study was performed.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

An OECD 416 study was performed in compliance with GLP. In this 2 generation study, 25 Wistar rats were exposed by oral gavage to 0, 3, 10, and 30 mg/kg bw d-carvone (F0). Dosing of the F0 generation started 10 weeks prior to mating. Dosing of the F1 generation with 0, 10, 30 and 90 mg/kg/day mg/kg bw/day started after weaning when the animals were 3-5 weeks old. Parental animals were subject to necropsy and tissues were weighted (adrenals, brain, epididymides, kidneys, liver, ovaries, pituitary, prostate, seminal vesicles, spleen, testes, thyroid, uterus with oviducts and cervix). Histological examination was performed on adrenals, brain, coagulating glands, epididymides, identification marks, kidneys, liver, ovaries, pituitary, prostate, seminal vesicles, spleen, testes, thyroid, uterus with oviducts and cervix, and vagina. The oestrus cycle was examined in the females and sperm parameters were examined in the males. Mortality, weight and sex were recorded for the pups. Furthermore, physical or behavioural abnormalities were recorded. Macroscopic examinations after necropsy was performed on the pups. The following reproductive indices were determined: mating, fertility index, conception rate, gestation index, duration of gestation, percentage live offspring by sex, percentage of post-natal loss, percentage of breeding loss, percentage live at weaning by sex, viability index, weaning index. Under the conditions of the test no adverse effects on fertility were observed. Therefore, the NOAEL for fertility ≥ 90 mg/kg bw/day.

Effects on developmental toxicity

Description of key information

OECD 414: NOAEL was determined to be ≥ 200 mg/kg bw/day for maternal and developmental toxicity.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
not specified
Remarks:
Data obtained from a review article and no details regarding GLP were available.
Limit test:
no
Species:
rat
Strain:
not specified
Route of administration:
not specified
Vehicle:
not specified
Duration of treatment / exposure:
Gestational day 6 to 20
Duration of test:
until gestational day 21
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
20 mg/kg bw/day (nominal)
Dose / conc.:
70 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
Control animals:
yes, concurrent vehicle
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes

WATER CONSUMPTION AND COMPOUND INTAKE: No

POST-MORTEM EXAMINATIONS: Yes

OTHER: acetylcholinesterase activity in the brain was determined
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: No data
- Number of late resorptions: No data
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: not specified
- Other: acetylcholinesterase activity in the brain was determined
Clinical signs:
no effects observed
Description (incidence and severity):
no toxicologically relevant effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One animal in the 70 mg/kg bw/day group showed an early delivery on GD 19 and was killed.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Body weight gain was statistically significantly reduced on GD 9 and 12 in the 70 mg/kg bw/day dose group and on GD 9, 12 and 15 in the 200 mg/kg bw/day dose group. The effects were small and are not toxicologically relevant.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Food consumption in the 200 mg/kg bw/day dose group was decreased from days 6-12 post coitum. Food consumption of the 70 mg/kg bw/day dose group was decreased from GD6-9. The reductions were small and not toxicologically relevant.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not specified
Description (incidence and severity):
acetylcholinesterase activity was determined in the plasma collected on gestation day 21. No conclusions could be drawn regarding the effect of d-carvone on the AChE activity.
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):
No toxicologically relevant effects observed with macroscopic research.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No toxicologically relevant effects observed with macroscopic research.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
no toxicologically relevant effects observed with microscopic research.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
no toxicologically relevant effects observed with microscopic research.
Other effects:
not specified
Description (incidence and severity):
acetylcholinesterase activity was determined in the brain. No conclusions could be drawn regarding the effect of d-carvone on the AChE activity.
Number of abortions:
effects observed, non-treatment-related
Description (incidence and severity):
One animal in the 70 mg/kg bw/day dose group showed an early delivery on GD 19 and was killed.
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
No toxicologically relevant effects observed regarding pre-implantation loss.
In the 200 mg/kg bw/day dose group a significant increase in post implantation loss and number of dead foetuses was observed. This was due to one litter consisting of ten dead foetuses.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
In the 200 mg/kg bw/day dose group: one litter consisting of ten dead foetuses.
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
not specified
Description (incidence and severity):
Acetylcholinesterase activity was determined in the brain. No conclusions could be drawn regarding the effect of d-carvone on the AChE activity.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 200 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: No treatment related adverse effects observed.
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
effects observed, non-treatment-related
Description (incidence and severity):
In the 200 mg/kg bw/day dose group: one litter consisting of ten dead foetuses
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
not specified
Description (incidence and severity):
acetylcholinesterase activity was determined in the brain. No conclusions could be drawn regarding the effect of d-carvone on the AChE activity.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No treatment related effects observed
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no

Summary table of the developmental toxicity study. Cited from: CLH report, 2012 (version 3) Submitted by: National Institute for Public Health and the Environment (RIVM).

 

Dose (mg/kg bw/day)

0

20

70

200

Maternal effects

Mortality*

 

 

1

 

 

Clinical signs

no toxicologically relevant effect

 

Pregnant animals

no toxicologically relevant effect

 

Abortions*

 

 

1

 

 

Corpus lutea

no toxicologically relevant effect

 

Body weight gain**

no toxicologically relevant effect

 

Food consumption***

 

 

 

 

 

Pathology

 

 

 

 

 

-macroscopy

no toxicologically relevant effect

 

-microscopy

no toxicologically relevant effect

Litter response

Live fetuses

no toxicologically relevant effect

 

Fetal weight

no toxicologically relevant effect

 

Pre implantation loss

no toxicologically relevant effect

 

Post implantation loss****

no toxicologically relevant effect

 

Sex ratio

no toxicologically relevant effect

Fetus examination

No. of foetuses

no toxicologically relevant effect

 

No. of abnormal foetuses

no toxicologically relevant effect

 

No. of dead fetuses****

no toxicologically relevant effect

 

Malformations

 

 

 

 

 

External observations and

visceral deviations

no toxicologically relevant effect

 

Skeletal deviations

no toxicologically relevant effect

* One animal in the mid-dose group showed an early delivery on GD 19 and was killed.

** Body weight gain was statistically significantly reduced on GD 9 and 12 in the mid-dose group and on GD 9, 12 and 15 in the high-dose group. However, the effects were small and are not considered toxicologically relevant

*** Food consumption in the highest-dose group was decreased from days 6-12 post coitum. Food consumption of the mid-dose group was decreased from GD6-9. However, the reductions were small and not considered toxicologically relevant.

**** In the highest dose group a significant increase in post implantation loss and number of dead foetuses was observed. This was due to one litter consisting of ten dead foetuses. The study authors consider this a chance finding. The present reviewers endorse this view.

Conclusions:
Under the conditions of the test the NOAEL was determined to be ≥ 200 mg/kg bw/day for maternal and developmental toxicity.
Executive summary:

A OECD 414 study was performed with rats. The animals were dose with 0, 20, 70, and 200 mg/kg bw/day d-carvone during gestational day 6 to 20. The dams were examined for mortality, clinical sigs, pregnancy, abortions, corpus lutea, body weight gain, food consumption, and pathology (macro and microscopy). Litter response was determined by monitoring the live fetuses, fetal weight, pre-implantation loss, post implantation loss, and sex ratio. Fetal examination included no. of fetuses, no of abnormal fetuses, no. of dead fetuses, malformations, external observations and visceral deviation, and skeletal deviations. No treatment related adverse effects were observed in the dams and the fetuses. Under the conditions of the test the NOAEL was determined to be ≥ 200 mg/kg bw/day for maternal and developmental toxicity.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Species:
rat
Quality of whole database:
An OECD 414 study is available.
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

A OECD 414 study was performed with rats. The animals were dose with 0, 20, 70, and 200 mg/kg bw/day d-carvone during gestational day 6 to 20. The dams were examined for mortality, clinical sigs, pregnancy, abortions, corpus lutea, body weight gain, food consumption, and pathology (macro and microscopy). Litter response was determined by monitoring the live fetuses, fetal weight, pre-implantation loss, post implantation loss, and sex ratio. Fetal examination included no. of fetuses, no of abnormal fetuses, no. of dead fetuses, malformations, external observations and visceral deviation, and skeletal deviations. No treatment related adverse effects were observed in the dams and the fetuses. Under the conditions of the test the NOAEL was determined to be ≥ 200 mg/kg bw/day for maternal and developmental toxicity.

Justification for classification or non-classification

The substance is not classified for reproductive or developemental toxicity, according to Regulation 1272/2008/EC (CLP).