Essential oil of Spearmint obtained from the aerial part of Mentha spicata and/or Mentha cardiaca (Lamiaceae) obtained by distillation

Endpoint summary

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 for cross-reference:

reference to same study

Qualifier:

according to guideline

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 for cross-reference:

reference to same study

Qualifier:

according to guideline

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 developmental toxicity, according to Regulation 1272/2008/EC (CLP).