Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

46.4 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

5

Dose descriptor starting point:

NOAEL

Value:

188 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

232 mg/m³

Explanation for the modification of the dose descriptor starting point:

Oral chronic repeated dose toxicity study available ( NOAEL 188 mg/kg; Bioassay of dl-menthol for possible carcinogenicity (103 weeks feeding study).

Corrected human NOAEC = 232 mg/m³ (188 x 1/0,38 x7/5 x50/100 x 6.7/10)

A correction has to be made for workers because of their exposure only being 5 days a week instead of 7 days a week, which is a factor 7/5.

Bioavailability: animal experiment (oral) = 50% (default oral)

Bioavailability human route = 100% (default inhalation)

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

Justification:

Default value ECHA

AF for interspecies differences (allometric scaling):

1

Justification:

Default value ECHA

AF for other interspecies differences:

1

Justification:

* In male rats a NOAEL was 375 mg/kg bw and in female rats the NOAEL is 188 mg/kg bw. In male and female mice a NOAEL of 667 mg/kg bw was found. Therefore an additional interspecies AF is not required as the NOAEL of the most susceptible species and gender is used.

AF for intraspecies differences:

5

Justification:

Default value ECHA

AF for the quality of the whole database:

1

Justification:

Default value ECHA

AF for remaining uncertainties:

1

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

13.15 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

20

Dose descriptor starting point:

NOAEL

Value:

188 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

263 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Oral chronic repeated dose toxicity study available ( NOAEL 188 mg/kg; Bioassay of dl-menthol for possible carcinogenicity (103 weeks feeding study).

Corrected human NOAEC = 263 mg/kg (188 x 7/5)

A correction has to be made for workers because of their exposure only being 5 days a week instead of 7 days a week, which is a factor 7/5.

Bioavailability: animal experiment (oral) = 50% (default oral)

Bioavailability human route = 50% (default dermal)

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

Justification:

Default value ECHA

AF for interspecies differences (allometric scaling):

4

Justification:

Default value ECHA

AF for other interspecies differences:

1

Justification:

* In male rats a NOAEL was 375 mg/kg bw and in female rats the NOAEL is 188 mg/kg bw. In male and female mice a NOAEL of 667 mg/kg bw was found. Therefore an additional interspecies AF is not required as the NOAEL of the most susceptible species and gender is used.

AF for intraspecies differences:

5

Justification:

Default value ECHA

AF for the quality of the whole database:

1

Justification:

Default value ECHA

AF for remaining uncertainties:

1

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

low hazard (no threshold derived)

Menthols (CAS 89-78-1, 1490-04-6, 15356-60-2, 2216-51-5)

DNELs

Repeated dose toxicity

Basis for delineation of the DNEL:

Study: Bioassay of d,l-menthol for possible carcinogenicity

administration period:

males and females,

103 weeks feeding study

rat: 0 (control), 3750, 7500 ppm

ca. 0, 188, 375 mg/kg bw/d

– males + females

Effects, NOAEL

NOAEL = 188 mg/kg bw/day (female rats)

NOAEL = 375 mg/kg bw/day (male rats)

effects:

The mean body weights of male and female rats were slightly reduced at all dose levels. No statistical analysis has been performed on body weights. Estimated maximal body weight differences between control and high dose groups were < 10 % in male rats and male and female mice and < 14 % in female rats. In low dosed female rats body weights were reduced by maximal 10 %. In male rats chronic inflammation of the kidney was found with greater frequency in dosed males than in control males (controls: 29/49; low-dose: 41/50; high-dose 41/50). These findings were regarded as of questionable relevance by the authors, since such lesions are often found in aged male Fischer rats

Reference

National Cancer Institute Carcinogenesis

Technical Report Series No. 98 (1979)

U.S Department of Health, Education, and Welfare

Public Health service

National Institute of Health

1.) Long-term toxicity – systemic effects (workers)

Long-term oral or dermal route-systemic effects (worker) using default extrapolation factors:

NOEL (rat) from a chronic toxicity study: 188 mg/kg bw/day

A correction has to be made for workers because of their exposure only being 5 days a week instead of 7 days a week, which is a factor 7/5.

Corrected human NOAL = 263 mg/kg (188 x 7/5)

Penetration oral compared to dermal (both assumed 50 %) 1

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 1*

For intraspecies differences in workers: 5

For extrapolation of exposure duration: 1

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 20

Worker DNEL long-term for oral or dermal route-systemic: 13.15 mg/kg bw/day (263 / 20)

* In male rats a NOAEL was 375 mg/kg bw and in female rats the NOAEL is 188 mg/kg bw. In male and female mice a NOAEL of 667 mg/kg bw was found. Therefore an additional interspecies AF is not required as the NOAEL of the most susceptible species and gender is used.

Long-term inhalation route-systemic effects (worker):

NOEL (rat) from a chronic toxicity study: 188 mg/kg bw/day

A correction has to be made for workers because of their exposure only being 5 days a week instead of 7 days a week, which is a factor 7/5.

Bioavailability: animal experiment (oral) = 50% (default oral)

Bioavailability human route = 100% (default inhalation)

Correction of the starting point according TGD Figure R.8-3:

Corrected inhalatory NOEC = Oral NOEL(188) x 1/0,38 x7/5 x50/100 x 6.7/10)

=> NOAEC worker = 232 mg/m³

For interspecies differences rat vs. human: 1 (according TGD Table

R.8-4. already covered by correction of starting point)

For remaining interspecies differences: 1*

For intraspecies differences in workers: 5

For extrapolation of exposure duration: 1

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 5

Worker DNEL long-term for inhalation exposure: 46.4 mg/m³

* In male rats a NOAEL was 375 mg/kg bw and in female rats the NOAEL is 188 mg/kg bw. In male and female mice a NOAEL of 667 mg/kg bw was found. Therefore an additional interspecies AF is not required as the NOAEL of the most susceptible species and gender is used.

2.) Short-term toxicity – systemic effects (workers)

LD50(dermal) > 5000 mg/kg bw (Not classified); LC50(inhalation) ca. 5289 mg/m³ (Not classified)

Therefore:

Worker DNELshort-term for oral or dermal route-systemic: No hazard identified

Worker DNEL short-term for inhalation exposure: No hazard identified

Conclusion (systemic effects):

Worker DNEL long-term for oral or dermal route-systemic: 13.15 mg/kg bw/day

Worker DNEL long-term for inhalation exposure: 46.4 mg/m³

Worker DNELshort-term for oral or dermal route-systemic: No hazard identified

Worker DNEL short-term for inhalation exposure: No hazard identified

3.) Reproductive Toxicity – systemic effects (workers)

In the EOGRTS study according OECD 443, the NOAEL for systemic toxicity in the F0 and F1 adult animals was concluded to be the intermediate dose of 419-499 mg/kg/day for males and 455-594 mg/kg/day for females, based upon the impaired body weight gain at the high dose level.

Based on the results obtained in this study it was concluded that the No-Observed-Effect-Level (NOEL) for reproductive performance of the F0 and F1 Cohort 1B animals was the intermediate dose of 419-499 mg/kg/day for males and 455-594 mg/kg/day for females due to lower litter size observed in both generations at the high dose level, a level which was associated with reduced food consumption and body weight gain in the parental animals of both generations.

The NOEL for the F1 and F2 offspring up to weaning was concluded to be the intermediate dose of 512-611 mg/kg/day due to reduced pre-weaning growth in both generations.

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).

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.

Teratogenicity studies with L-menthol were conducted in rats, mice, hamsters and rabbits (FDA,1973). In all four developmental toxicity studies, maternally toxic dose levels were not used. The dose levels were, however, sufficiently high to allow an initial assessment of this endpoint:

2.18, 10.15, 47.05 and 218.0 mg/kg bw/d were administered by gavage to Wistar rats from gestation day 6 to 15. There was no effect on maternal and fetal survival and the number of abnormalities in soft or skeletal tissues observed did not differ from sham treated control. No clinical signs of maternal toxicity were observed. Therefore the NOEL derived for maternal and fetal toxicity and teratogenicity in rats can be determined as 218.0 mg/kg bw/d.

Doses of 1.85, 8.59, 39.9 and 185.0 mg/kg bw/d were administered to CD-1 mice from gestation day 6 to 15. No effect on maternal and fetal survival and no dose-related increase in the number of abnormalities in soft or skeletal tissues were observed. No clinical signs of maternal toxicity were observed. The NOEL derived for maternal and fetal toxicity and teratogenicity was 185.0 mg/kg bw/d.

Rabbits were administered menthol from gestation day 6 to 18 in following doses: 4.25, 19.75, 91.7 and 425.0 mg/kg bw/d. Few of the rabbits died or aborted before day 29 (4.25/2 out of 13 animals, 19.75/3 out of 12 animals, 91.7/1 out of 11 animals, 425.0/4 out of 14 animals), however, these effects were not dose related and are not considered to be a consequence of test substance administration. Also in rabbits no effect on maternal and fetal survival and no dose-related increases in the number of abnormalities in soft or skeletal tissues were observed. No clinical signs of maternal toxicity were observed. The NOEL derived for maternal and fetal toxicity and teratogenicity was therefore 425.0 mg/kg bw/d.

No adverse effects on reproductive organs were found in the repeated dose study (carcinogenicity study). This indicates that fertility is not influenced in doses up to 375 mg/kg bw/d.

The NOEL derived for maternal and fetal toxicity and teratogenicity in rats was 185.0 mg/kg bw/d. In rabbits the derived NOAEL derived for maternal and fetal toxicity and teratogenicity was 425 mg/kg bw/day.

As the NOEL for reproductive/developmental toxicity is higher than the NOAEL for repeated dose toxicity (188 mg/kg bw/day), the derivation of a separate DNEL for reproductive/ developmental toxicity is not necessary, because the DNEL for repeated dose toxicity covers both endpoints.

4. Long-term and short-term dermal or inhalation route - local effects (worker)

In rabbits, menthol is irritating to the skin (OECD TG 404), and slightly irritating to the eyes (OECD TG 405).

Classification: Skin Irrit.2 (C > 25%)

Classification: Eye Irrit.2 (C > 25%)

Therefore the allocation to the low hazard band justified (ECHA guidance document)

5. Sensitization

Menthol is not sensitising to the skin of guinea pigs.

References:

• NCI (1979) National Cancer Institute: Bioassay of D/L-menthol for possible carcinogenicity.

Technical Report Series No. 98, Bethesda, Maryland: 1 - 112

• FDA (1973) Teratologic evaluation of FDA 71-57 (menthol natural, brazilian) Prepared for:

Washington, D.C., U.S. Food and Drug Administration , PB-223 815 // June, 1973, 1-55

• Haarmann and Reimer GmbH (1989) Assessment of the eye irritant effect of HR 89/131136 in

rabbits. Prepared for: 3450 Holzminden , Lab. No. 11877, 1 - 9

• Haarmann and Reimer GmbH (1989) Assessment of the eye irritant effect of HR 89/620006 in

rabbits. Prepared for: 3450 Holzminden , Lab. No. 11872, 1 - 9

• Haarmann and Reimer GmbH (1991) HR90/000102 Buehler sensitization test in guinea pigs , IRIInveresk Research International Limited, prepared for: Haarmann and Reimer GmbH, Holzminden, 6870 05/07/91, 1 - 20

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.17 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor starting point:

NOAEL

Value:

188 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

81.74 mg/m³

Explanation for the modification of the dose descriptor starting point:

Oral chronic repeated dose toxicity study available ( NOAEL 188 mg/kg; Bioassay of dl-menthol for possible carcinogenicity (103 weeks feeding study).

Corrected human NOAEC = 81.74 mg/m³ (188 x 1/1,15 x 50/100)

Bioavailability: animal experiment (oral) = 50% (default oral)

Bioavailability human route = 100% (default inhalation)

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

Justification:

Default value ECHA

AF for interspecies differences (allometric scaling):

1

Justification:

Default value ECHA

AF for other interspecies differences:

1

Justification:

* In male rats a NOAEL was 375 mg/kg bw and in female rats the NOAEL is 188 mg/kg bw. In male and female mice a NOAEL of 667 mg/kg bw was found. Therefore an additional interspecies AF is not required as the NOAEL of the most susceptible species and gender is used.

AF for intraspecies differences:

10

Justification:

Default value ECHA

AF for the quality of the whole database:

1

Justification:

Default value ECHA

AF for remaining uncertainties:

1

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.7 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

40

Dose descriptor starting point:

NOAEL

Value:

188 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Oral chronic repeated dose toxicity study available ( NOAEL 188 mg/kg; Bioassay of dl-menthol for possible carcinogenicity (103 weeks feeding study).

AF for dose response relationship:

1

Justification:

Default value ECHA

AF for differences in duration of exposure:

1

Justification:

Default value ECHA

AF for interspecies differences (allometric scaling):

4

Justification:

Default value ECHA

AF for other interspecies differences:

1

Justification:

* In male rats a NOAEL was 375 mg/kg bw and in female rats the NOAEL is 188 mg/kg bw. In male and female mice a NOAEL of 667 mg/kg bw was found. Therefore an additional interspecies AF is not required as the NOAEL of the most susceptible species and gender is used.

AF for intraspecies differences:

10

Justification:

Default value ECHA

AF for the quality of the whole database:

1

Justification:

Default value ECHA

AF for remaining uncertainties:

1

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.7 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

40

Dose descriptor starting point:

NOAEL

Value:

188 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Oral chronic repeated dose toxicity study available ( NOAEL 188 mg/kg; Bioassay of dl-menthol for possible carcinogenicity (103 weeks feeding study).

AF for dose response relationship:

1

Justification:

Default value ECHA

AF for differences in duration of exposure:

1

Justification:

Default value ECHA

AF for interspecies differences (allometric scaling):

4

Justification:

Default value ECHA

AF for other interspecies differences:

1

Justification:

* In male rats a NOAEL was 375 mg/kg bw and in female rats the NOAEL is 188 mg/kg bw. In male and female mice a NOAEL of 667 mg/kg bw was found. Therefore an additional interspecies AF is not required as the NOAEL of the most susceptible species and gender is used.

AF for intraspecies differences:

10

Justification:

Default value ECHA

AF for the quality of the whole database:

1

Justification:

Default value ECHA

AF for remaining uncertainties:

1

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

low hazard (no threshold derived)

Menthols (CAS 89-78-1, 1490-04-6, 15356-60-2, 2216-51-5)

DNELs (general population)

Repeated dose toxicity

Basis for delineation of the DNEL:

Study: Bioassay of d,l-menthol for possible carcinogenicity

administration period:

males and females,

103 weeks feeding study

rat: 0 (control), 3750, 7500 ppm

ca. 0, 188, 375 mg/kg bw/d

– males + females

Effects, NOAEL

NOAEL = 188 mg/kg bw/day (female rats)

NOAEL = 375 mg/kg bw/day (male rats)

effects:

The mean body weights of male and female rats were slightly reduced at all dose levels. No statistical analysis has been performed on body weights. Estimated maximal body weight differences between control and high dose groups were < 10 % in male rats and male and female mice and < 14 % in female rats. In low dosed female rats body weights were reduced by maximal 10 %. In male rats chronic inflammation of the kidney was found with greater frequency in dosed males than in control males (controls: 29/49; low-dose: 41/50; high-dose 41/50). These findings were regarded as of questionable relevance by the authors, since such lesions are often found in aged male Fischer rats

Reference

National Cancer Institute Carcinogenesis

Technical Report Series No. 98 (1979)

U.S Department of Health, Education, and Welfare

Public Health service

National Institute of Health

1.) Long-term toxicity – systemic effects (general population)

Long-term oral or dermal route-systemic effects (general population) using default extrapolation factors:

NOEL (rat) from a chronic toxicity study: 188 mg/kg bw/day

Penetration oral compared to dermal (both assumed 50%) 1

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 1*

For intraspecies differences in general population: 10

For extrapolation of exposure duration: 1

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 40

Worker DNEL long-term for oral or dermal route-systemic: 4.7 mg/kg bw/day

* In male rats a NOAEL was 375 mg/kg bw and in female rats the NOAEL is 188 mg/kg bw. In male and female mice a NOAEL of 667 mg/kg bw was found. Therefore an additional interspecies AF is not required as the NOAEL of the most susceptible species and gender is used.

Long-term inhalation route-systemic effects (general population):

NOEL (rat) from a chronic toxicity study: 188 mg/kg bw/day

Correction of the starting point according TGD Figure R.8-3:

Corrected inhalatory NOEC = Oral NOEL (188 mg/kg) x 1/1.15 m³/kg x 50/100

=> NOEC general population = 81.74 mg/m³

For interspecies differences rat vs. human: 1 (according TGD Table

R.8-4. already covered by correction of starting point)

For remaining interspecies differences: 1*

For intraspecies differences general population: 10

For extrapolation of exposure duration: 1

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 10

general population DNEL long-term for inhalation exposure: 8.17 mg/m³

* In male rats a NOAEL was 375 mg/kg bw and in female rats the NOAEL is 188 mg/kg bw. In male and female mice a NOAEL of 667 mg/kg bw was found. Therefore an additional interspecies AF is not required as the NOAEL of the most susceptible species and gender is used.

2.) Short-term toxicity – systemic effects (general population)

LD50(dermal) > 5000 mg/kg bw (Not classified); LC50(inhalation) ca. 5289 mg/m³ (Not classified)

Therefore:

Worker DNELshort-term for oral or dermal route-systemic: No hazard identified

Worker DNEL short-term for inhalation exposure: No hazard identified

Conclusion (systemic effects):

General population DNEL long-term for oral or dermal route-systemic: 4.7 mg/kg bw/day

General population long-term for inhalation exposure: 8.17 mg/m³

General population DNELshort-term for oral or dermal route-systemic: No hazard identified

General population DNELshort-term for inhalation exposure: No hazard identified

3.) Reproductive Toxicity – systemic effects (general population)