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

Toxicity to reproduction

Administrative data

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

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

two-generation reproductive toxicity

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

See attached justification

Reason / purpose for cross-reference:

read-across source

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

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

Key result

Critical effects observed:

no

Lowest effective dose / conc.:

30 mg/kg bw/day (nominal)

System:

hepatobiliary

Organ:

liver

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.

Data source

Reference

Reference Type:

review article or handbook

Title:

Unnamed

Year:

2012

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

(S)-2-methyl-5-(1-methylvinyl)cyclohex-2-en-1-one

EC Number:

218-827-2

EC Name:

(S)-2-methyl-5-(1-methylvinyl)cyclohex-2-en-1-one

Cas Number:

2244-16-8

Molecular formula:

C10H14O

IUPAC Name:

(S)-2-methyl-5-(1-methylvinyl)cyclohex-2-en-1-one

Test material form:

liquid

Test animals

Species:

rat

Strain:

Wistar

Details on species / strain selection:

Wistar Crl : (WI) BR

Sex:

male/female

Administration / exposure

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.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

F0, F1

Doses / concentrations 2

Dose / conc.:

3 mg/kg bw/day (nominal)

Remarks:

F0

Doses / concentrations 3

Dose / conc.:

10 mg/kg bw/day (nominal)

Remarks:

F0, F1

Doses / concentrations 4

Dose / conc.:

30 mg/kg bw/day (nominal)

Remarks:

F0, F1

Doses / concentrations 5

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

Examinations

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.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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 / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Effect levels (P0)

1

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

2

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

3

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

Target system / organ toxicity (P0)

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

Results: P1 (second parental generation)

General toxicity (P1)

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 / performance (P1)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Effect levels (P1)

1

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

2

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

3

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

Target system / organ toxicity (P1)

1

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

2

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

Results: F1 generation

General toxicity (F1)

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

Developmental neurotoxicity (F1)

Behaviour (functional findings):

no effects observed

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not examined

Effect levels (F1)

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.

Target system / organ toxicity (F1)

Key result

Critical effects observed:

no

Results: F2 generation

General toxicity (F2)

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

Developmental neurotoxicity (F2)

Behaviour (functional findings):

no effects observed

Developmental immunotoxicity (F2)

Developmental immunotoxicity:

not examined

Effect levels (F2)

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

Overall reproductive toxicity

Key result

Reproductive effects observed:

no

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.