Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

There are no fertility studies with menthol or its isomers available. An extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension) in rats, oral feed is proposed.

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Groups of 50 rats of each sex were administrated dl-menthol at one of the following doses, either 3750 or 7500 ppm (= ca. 188 or 375 mg/kg bw/d) for 103 weeks. At the end all animals were killed and necropsied; gross and microscopic examination of: all major organs, including reproductive organs; in male rats prostate, testes, epididymis, scrotum; in female rats mammary gland, vagina, uterus, uterus/endometrium, ovary/panovarian, and ovary.

Histopathological examinations of the reproduction organs of rats showed no changes in the repeated dose toxicity studies with D/L-menthol and also in carcinogenicity studies with D/L-menthol. Hence there is no indication of a potential of D/L-menthol to interfere adversely with reproduction.

In the analogue study in mice also no indication of a potential of D/L-menthol to interfere adversely with reproduction was found.


Short description of key information:
A carcinogenicity study with histopathological examination of male and female reproduction organs in rats and mice was performed

Effects on developmental toxicity

Description of key information

The administration of up to 218 mg/kg (body weight) of the test material to pregnant rats for 10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.

The administration of up to 405 mg/kg (body weight) of the test material to pregnant hamsters for 5 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.

The administration of up to 185 mg/kg (body weight) of the test material to pregnant mice for 10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.

The administration of up to 425 mg/kg (body weight) of the test material to pregnant rabbits for 13 consecutive days had no clearly
discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well documented and scientifically acceptable
Reason / purpose:
read-across: supporting information
Principles of method if other than guideline:
Virgin adult female albino rats (Wistar derived stock) were individually housed in mesh bottom cages in temperature and humidity-controlled
quarters with free access to food and fresh tap water.
They were mated with young adult males, and observation of the vaginal sperm plug was considered Day 0 of gestation. Beginning on Day 6
and continuing daily through Day 15 of gestation, the females were dosed with the indicated dosage s by oral intubations. The controls
were sham treated with the vehicle at a level equivalent to the group receiving the highest test dose.
Body weights were recorded on Days 0, 6, 11, 15, and 20 of gestation. All animals were observed daily for appearance and behavior
with particular attention to food consumption and weight, in order to rule out any abnormalities which may have occurred as a
result of anorexic effects in the pregnant female animal.
On Day 20 all dams were subjected to Caesarean section under surgical anesthesia and the numbers of implantation sites, resorption
sites, and live and dead fetuses were recorded. The body weights of the live pups were also recorded. The urogenital tract of each dam
was examined in detail for anatomical normality.
All fetuses were examined grossly for the presence of external congenital abnormalities. One-third of the fetuses of each litter
underwent detailed visceral examinations employing l0 x magnification. The remaining two-thirds were cleared in potassium hydroxide (KOH),
stained with alizarin red S dye and examined for skeletal defects.
GLP compliance:
not specified
Specific details on test material used for the study:
Menthol natural, brazilian (FDA 71-57).
Menthol natural, brazilian (FDA 71-57) is L-menthol (CAS 2216-51-5). L-menthol is a constituent of menthol racemic (CAS 89-78-1).
Species:
rat
Strain:
Wistar
Route of administration:
oral: gavage
Vehicle:
not specified
Details on mating procedure:
They were mated with young adult males, and observation of the vaginal sperm plug was considered Day 0 of gestation
Duration of treatment / exposure:
Beginning on Day 6 and continuing daily through Day 15 of gestation, the females were dosed with the indicated dosage s by oral intubations. The controls were sham treated with the vehicle at a level equivalent to the group receiving the highest test dose.
On Day 20 all dams were subjectcd to Cacsarean section under surgical anesthesia
Frequency of treatment:
daily
Duration of test:
20 days
No. of animals per sex per dose:
22-23 animals/dose
Control animals:
other: sham treated with corn oil
Details on study design:
Sex: female
Dose descriptor:
NOEL
Effect level:
218 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks on result:
other: no efects observed at the highest applied dose
Abnormalities:
no effects observed
Dose descriptor:
NOAEL
Effect level:
218 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: no effects observed at the highest applied dose
Abnormalities:
no effects observed
Developmental effects observed:
no

All dose groups: no clearly discernible effect on nidation or on maternal or fetal survival; the number of abnormalities seen in either soft or skeletal tissues not differing from the number occuring  spontaneously in the controls.

Reproduction data:

Group:

Dose (mg/kg):

 Sham  2.18  10.15  47.05  218.0

Pregnancies

Total. No.

Died or aborted (before day 20)

To term (on day 20)

25

0

25

22

0

22

23

0

23 

23

0

23 

22

0

22 

Live Litters

Total No.*

 

25

 

22

 

23

23

22

Implant sites

total No.

Average/dam*

241 

9.64

256

11.6

266

11.6

275

12.0

250

11.4

Resorptions

Total No.*

Dams with 1 or more sites resorbed

Dams with all sites resorbed

Per cent partial resorptions

Per cent complete resorptions

5

4

-

16 .0

8

3

-

13.6

-

-

-

-

2

2

-

8.70

4

4

-

18.2

Live Fetuses

Total No..

Average/dam*

Sex ratio (M//F)

236

9.44

0.79 

248

11.3

1.07 

 

266

11.6

0.72

273

11.9

0.82

246

11.2

0.85

Dead Fetuses

Total*

Dans with 1 or more dead

Dams with all dead

Per cent partial dead

Per cent all dead

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

 Average Fetus Weight, g

 3.82

 3.82

 3.82

 3.85

 3.88

* Includes only those dams examined at term.

Summary of skeletal findings*

Findings

Dose (mg/kg) 

Sham

2.18

10.15

 

47.05

218.0

 Live Fetuses Examined

(at term)

 167/25

 175/22

 183/23

 190/23

 173/22

Sternebrae

Incomplete oss.

Scrambled

Bipartite

Fused

Extra

Missing

Other

80/22

1/1

14/6

92/20

11/8

93/22

2/2

17/5

 

101/19

11/4

 

92/19

1/1

 

Ribs

Incomplete oss.

Fused/split

Wavy

Less than 12

More than 13

Other

 

25/10

3/3

 

33/13

5/3

 

1/1

19/10

2/2

 

21/10

2/2

 

16/8

3/3

Vertebrae

Incomplete oss.

Scrambled

Fused

Extra ctrs. oss.

Scoliosis

Tail defects

Other

 9/5

11/6

12/7

 

 14/7

 10/7

Skull

Incomplete closure

Missing

Craniostosis

Other

 41/16

 46/15

 63/16

 67/20

 49/17

Extremities

Incomplete oss.

Missing

Extra

 

1/1

 

 

 

 

Miscellaneous

Hyoid; missing

Hyoid; reduced

 

18/13

13/10

18/8

25/1

 

27/12

16/10

22/13

20/10

 

15/9

19/7

* Numerator = Number of fetuses affected; Denominator = Number of litters

Summary of Soft Tissue Abnormalities

 Group  Material

 Dose level

mg/kg

 Dam

 Number of

pubs

 Description
 254  FDA 71 -57  10.15

K 4044

K 4053

1

1

Petechiae

Anophthalmia

 255

  FDA 71 -57

40.05 

K 4064

K 4066

K 4072

K 4075

K 4084

1

1

1

1

Hydrocephalus: lobster claw

Anophthalmia

Anophthalmia

Gastroschisis

Gastroschisis

Executive summary:

The administration of up to 218 mg/kg (body weight) of the test material to pregnant rats for 10 consecutive days had no clearly descernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the

test groups did not differ from the number occurring spontaneously in the sham-treated controls.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well documented and scientifically acceptable
Reason / purpose:
read-across: supporting information
Principles of method if other than guideline:
Virgin, adult, Dutch-belted female rabbits were individually housed in mesh bottom cages in temperature and humidity-controlled quarters with free access to food and fresh tap water. On Day 0, each doe was given an injection of 0.4 ml of human chorionic gonadotropin (400 IU) via the marginal ear vein. Three hours later, each doe was inseminated artificially with 0.3 ml of diluted semen from a proven donor buck using approximately 20 x 10E6 motile sperm according to the procedure described by Vogin et al (Pharmacologist 11,282 (1969)). Beginning on Day 6 and continuing daily through Day 18 the females were dosed with the indicated dosages by oral intubation.
The controls were sham treated with the vehicle at a level equivalent to the group receiving the highest test dose.
Body weights ware recorded on Days 0, 6, 12, 18, and 29 of gestation. All animals were observed dailly for appearance and behavior, with particular attention to food consumption and body weight in order to rule out any abnormalities which may have occurred as a result of anorexic effects in the pregnant female animal.
On Day 29 all does were subjected to Caesarean section under surgical anesthesia, and the numbers of corpora lutea, implantation sites, resorption sites and live and dead fetuses were recorded. Body weights of the live pups were also recorded. The urogenital tract of each animal was examined in detail for normality. In addition all fetuses underwent a detailed gross examination for the presence of external congenital abnormalities. The live fetuses of each litter were then placed in an incubator for 24 hours for the evaluation of neonatal survival. All surviving pups were sacrificed, and all pups examined for visceral abnormalities (by dissection). All fetuses were then cleared in potassium hydroxide (KOH), stained with alizarin red S dye and examined for skeletal defects.
GLP compliance:
not specified
Specific details on test material used for the study:
Menthol natural, brazilian (FDA 71-57).
Menthol natural, brazilian (FDA 71-57) is L-menthol (CAS 2216-51-5). L-menthol is a constituent of menthol racemic (CAS 89-78-1).
Species:
rabbit
Strain:
Dutch
Route of administration:
oral: gavage
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
On Day 0, each doe was given an injection of 0.4 ml of human chorionic gonadotropin (400 IU) via the marginal ear vein. Three hours later, each doe was inseminated artificially with 0.3 ml of diluted semen from a proven donor buck using approximately 20 x 10E6 motile sperm according to the procedure dcccribed by Vogin et al (Pharmacologist 11, 282 (1969)).
Duration of treatment / exposure:
Beginning on Day 6 and continuing daily through Day 18 the females were dosed with the indicated dosages by oral intubation.
The controls were sham treated with the vehicle at a level equivalent to the group receiving the highest test dose.
Body weights ware recorded on Days 0, 6, 12, 18, and 29 of gestation.
On Day 29 all does were subjected to Caesarean section under surgical anesthesia
Frequency of treatment:
daily
Duration of test:
29 days
No. of animals per sex per dose:
15 - 19 animals/dose
Control animals:
other: sham treated with corn oil
Details on study design:
Sex: female
Dose descriptor:
NOEL
Effect level:
425 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks on result:
other: no effects observed at the highest applied dose
Abnormalities:
no effects observed
Dose descriptor:
NOAEL
Effect level:
425 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: no effects observed at the highest applied dose
Abnormalities:
no effects observed
Developmental effects observed:
no

All dose groups: no clearly discernible effect on nidation or on maternal or fetal survival; the number of abnormalities seen in either soft or skeletal tissues not differing from the number occuring spontaneously in the controls.

Reproduction data:

Group:

Dose (mg/kg):

 Sham  4.25  19.75  91 .7  425.0

Pregnancies

Total. No.

Died or aborted (before day 29)

To term (on day 29)

12

1

11

13

2

11

12

3

9

11

1

10 

14

4

10

Corpora Lutea

Total No.

Average/dam mated

Live litters

Total No.*

Implant sites

Total No.

Average/dam*

161

12.4

11

71 

6.45

216

14.4

10

73

6.64

165

11.8

9

64

7.11

140

12.7

10

65

6.50

213

15.2

9

72

7.20

Resorptions

Total No.*

Dams with 1 or more sites resorbed

Dams with all sites resorbed

Per cent partial resorptions

Per cent complete resorptions

10

5

-

45.5

1

1

-

9.09

5

5

-

55.6

4

4

-

40.0

11

3

1

30.0

10.0 

Live Fetuses

Total No..

Average/dam*

Sex ratio (M//F)

61

5.55

0.85 

70

6.36

1.12 

 

59

6.56

1.68

61

6.10

0.97

61

6.10

0.97

Dead Fetuses

Total*

Dans with 1 or more dead

Dams with all dead

Per cent partial dead

Per cent all dead

-

-

-

-

2

1

1

9.09

9.09

-

-

-

-

-

-

-

-

-

-

-

-

-

 Average Fetus Weight, g

 35.3

 33.5

 38.7

 36.8

 38.5

* Includes only those dams examined at term.

Summary of skeletal findings*

Findings

Dose (mg/kg) 

Sham

4.25

19.75

 

97.1

425.0

 Live Fetuses Examined

(at term)

 61/11

 70/10

 59/9

 61/10

 60/9

Sternebrae

Incomplete oss.

Scrambled

Bipartite

Fused

Extra

Missing

Other

3/2

2/1

1/1

1/1

1/1

3/2

1/1

1/1

1/1

2/1

2/1

 

1/1

1/1

 

3/3

1/1

 2/2

Ribs

Incomplete oss.

Fused/split

Wavy

Less than 12

More than 13

Other

 

 

1/1

Vertebrae

Incomplete oss.

Scrambled

Fused

Extra ctrs. oss.

Scoliosis

Tail defects

Other

 

1/1

 

 

1/1

 

1/1

2/2

1/1

Skull

Incomplete closure

Missing

Craniostosis

Other

 

 

 

 

 1/1

Extremities

Incomplete oss.

Missing

Extra

 

 

 

 

 

* Numerator = Number of fetuses affected; Denominator = Number of litters

Summary of Soft Tissue Abnormalities

 Group  Material

 Dose level

mg/kg

 Dam

 Number of

pubs

 Description
 251  Sham  0.0

S 6421

S 6424

2

1

Anopia

Umbilical hernia

 253

  FDA 71 -57

4.25 

K 6012

Umbilical hernia

 255

  FDA 71 -57

 91.7

 K 6047

 1

Medial rotation of hind limbs

 256

 FDA 71 -57

 425.0

 K 6072

 1

 Club foot; hydrocephaly

Executive summary:

The administration of up to 425 mg/kg (body weight) of the test material to pregnant rabbits for 13 consecutive days had no clearly

discernible effect on nidation or on maternal or fetal survival. The number of abnorrnalities seen in either soft or skeletal tissues of the

test groups did not differ from the number occurring spontaneously in the sham-treated controls.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
218 mg/kg bw/day
Species:
rat
Quality of whole database:
Scientifically acceptable and well documented.
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

Development toxicity/teratogenicity studies on rats, rabbits, mice and hamsters revealed no evidence of teratogenic effects of menthol.

Toxicity to reproduction: other studies

Description of key information

There are no fertility studies with menthol or its isomers available.  Examinations of reproductive organs in repeated dose studies can however be used to evaluate adverse effects on reproductive organs. These studies are reported in IUCLID sections 7.5 (repeated dose toxicity) and 7.7 (carcinogenicity).

In a feeding carcinogenicity study with D/L-menthol in mice and rats (103 weeks), no changes in reproductive organs (testes, prostate, uterus, ovaries, mammary gland and adrenals) were observed in histopathological examinations at any of the doses administered (up to about 375 mg/kg bw/d in rats and 667 mg/kg bw/d in mice) (NCI, 1979).

Conclusion: There is no evidence indicating a potential of D/L-menthol to interfere adversely with reproduction. Histopathological examinations of the reproduction organs of rats and mice showed no changes in repeated dose toxicity studies with D/L-menthol and also in carcinogenicity studies with D/L-menthol (OECD SIDS for methols, UNEP publication 2003).  

Recent literature (Mangelsdorf et al 2003, Ulbrich & Palmer 1995, Dent 2007, Sanbuissho et al. 2009) concluded that in rodents histopathological examinations in repeated dose toxicity studies of reproductive tissues are of high value and high sensitivity for evaluation of reproductive toxicity in males and females. Data evaluation of 117 substances or substance classes by Ulbrich & Palmer (1995)  revealed that  histopathology and organ weight analysis provide the best general purpose means of detecting substances with potential to affect male fertility, particularly those related to effects on spermatogenesis. The data evaluation by Mangelsdorf et al (2003) revealed that the most sensitive endpoint for detecting adverse effects of chemicals on male reproduction is the histopathology of the testis. Sanbuissho et al (2009) revealed that comprehensive histopathological examination of the female reproduction organs is a good tool to assess female reproduction function.  Pathological findings of ovarian toxicity (decreases in follicles, increases in atretic follicles, increases in currently formed corpora lutea, etc.) reflected the female fertility parameter (irregular estrous cycle, pre-implantation loss). The data analysis by Dent (2007) revealed that subchronic toxicity studies are suitable to predict effects on rodent fertility.  - Mangelsdorf. et al., 2003: Some aspects relating to the evaluation of the effects of chemicals on male fertility. Regulatory toxicology and Pharmacology 36, 69-98 - Ulbrich & Palmer, 1995: Detection of effects on male reproduction – a literature survey. J Am. College of Toxicology 14, 293-327 - Janer et al., 2007: A retrospective analysis of the added value of the rat two-generation reproductive toxicity study versus the rat subchronic toxicity study. Reproductive Toxicology 24, 103-113 - Dent, 2007: Strength and limitations of using repeated-dose toxicity studies to predict effects on fertility. Regulatory Toxicology and Pharmacology 48, 241-258 - Sanbuissho et al., 2009: Collaborative work on evaluation of ovarian toxicity by repeated-dose and fertility studies in female rats. J Tox. Sci. 34: Special Issue SP1-SP22 - Piersma et al., 2011: Combined retrospective analysis of 498 rat multi-generation reproductive toxicity studies: on the impact of parameters related to F1 mating and F2 offspring. Reproductive Toxicology 31, 392-401.  

Link to relevant study records

Referenceopen allclose all

Endpoint:
toxicity to reproduction: other studies
Remarks:
other: carcinogenicity study with histopathologic examiniation of male and female reproduction organs
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other:
Principles of method if other than guideline:
A bioassay of dl-menthol for possible carcinogenicity was conducted by administrating the test chemical in feed to Fisher 344 rats.
Groups of 50 rats of each sex were administrated dl-menthol at one of the following doses, either 3750 or 7500 ppm for 103 weeks, then observed for 1 or 2 additional weeks. Matched controls consisted of 50 untreated rats of each sex. All surviving rats were killed at 105 weeks.
At the end all animals were killed and necropsied; gross and microscopic examination of: all major organs, including reproductive organs; in male rats prostate,testes, epididymis, scrotum; in female rats mammary gland, vagina, uterus, uterus/endometrium, ovary/panovarian, ovary.
GLP compliance:
not specified
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 2 batches test:
Lot No. 4-HTP-6
Lot No. Nl 1-26-74-2054

Identity confirmed
Batch 1:
2 impurites:
0.3 %
1.3 %
Batch 2:
0.2 % Impurity
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
corn oil
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
daily
Dose / conc.:
3 570 ppm
Remarks:
ca. 188 mg/kg bw/d
Dose / conc.:
7 500 ppm
Remarks:
ca. 375 mg/kg bw/d
No. of animals per sex per dose:
50 rats of either sex/dose
Control animals:
other: untreated diet containing 2 % corn oil
Dose descriptor:
NOAEL
Effect level:
ca. 375 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: 375 mg/kg bw/d was the highest applied dose
Conclusions:
Histopathological examinations of the reproduction organs of rats and mice showed no changes in repeated dose toxicity studies with D/L-menthol and also in carcinogenicity studies with D/Lmenthol.
Hence there is no indication of a potential of D/L-menthol to interfere adversely with reproduction.
Executive summary:

Groups of 50 rats of each sex were administrated dl-menthol at one of the following doses, either 3750 or 7500 ppm for 103 weeks, then observed for 1 or 2 additional weeks. Matched controls consisted of 50 untreated rats of each sex. All surviving rats were killed at 105 weeks. Body weights and clinical signs were recorded and pathological and histopathological examinations conducted. At the end all animals were killed and necropsied; gross and microscopic examination of: all major organs, including reproductive organs; in male rats prostate,testes, epididymis, scrotum; in female rats mammary gland, vagina, uterus, uterus/endometrium, ovary/panovarian, ovary.

Histopathological examinations of the reproduction organs of rats showed no changes in the repeated dose toxicity studies with D/L-menthol and also in carcinogenicity studies with D/Lmenthol. Hence there is no indication of a potential of D/L-menthol to interfere adversely with reproduction.

Endpoint:
toxicity to reproduction: other studies
Remarks:
other: carcinogenicity study with histopathologic examiniation of male and female reproduction organs
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other:
Principles of method if other than guideline:
A bioassay of dl-menthol for possible carcinogenicity was conducted by administrating the test chemical in feed to B6C3F1 mice.
Groups of 50 mice of each sex were administrated dl-menthol at one of the following doses, either 3750 or 7500 ppm for 103 weeks, then observed for 1 or 2 additional weeks. Matched controls consisted of 50 untreated mice of each sex. All surviving mice were killed at 104 weeks.
At the end all animals were killed and necropsied; gross and microscopic examination of: all major organs, including reproductive organs; in male mice penis, prepuce, preputial gland, prostate, epididymis; in female mice uterus, uterus/endometrium, ovary.
GLP compliance:
not specified
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 2 batches test:
Lot No. 4-HTP-6
Lot No. Nl 1-26-74-2054

Identity confirmed
Batch 1:
2 impurites:
0.3 %
1.3 %
Batch 2:
0.2 % Impurity
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
corn oil
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
103 w
Frequency of treatment:
daily
Dose / conc.:
2 000 ppm
Remarks:
ca. 334 mg/kg bw/d
Dose / conc.:
4 000 ppm
Remarks:
ca. 667 mg/kg bw/d
No. of animals per sex per dose:
50 mice of each sex per dose
Control animals:
other: untreated diet containing 2 % corn oil
Dose descriptor:
NOAEL
Effect level:
ca. 667 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: 667 mg/kg bw/d was the highest applied dose
Conclusions:
Histopathological examinations of the reproduction organs of rats and mice showed no changes in repeated dose toxicity studies with D/L-menthol and also in carcinogenicity studies with D/Lmenthol.
Hence there is no indication of a potential of D/L-menthol to interfere adversely with reproduction.
Executive summary:

Groups of 50 mice of each sex were administrated dl-menthol at one of the following doses, either 3750 or 7500 ppm (= ca. 334 or 667 mg/kg bw/d) for 103 weeks, then observed for 1 or 2 additional weeks. Matched controls consisted of 50 untreated mice of each sex. All surviving mice were killed at 104 weeks. At the end all animals were killed and necropsied; gross and microscopic examination of: all major organs, including reproductive organs; in male mice penis, prepuce, preputial gland, prostate, epididymis; in female mice uterus, uterus/endometrium, ovary.

Histopathological examinations of the reproduction organs of mice showed no changes in the repeated dose toxicity studies with D/L-menthol and also in carcinogenicity studies with D/Lmenthol. Hence there is no indication of a potential of D/L-menthol to interfere adversely with reproduction.

Additional information

no data

Justification for classification or non-classification

From the available data a classification according to CLP classification criteria (Regulation (EC) No 1272/2008) is not justified