Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
66.28 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor starting point:
NOAEL
DNEL value:
188 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
331.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

Corrected inhalatory NOEC = Oral NOEL (188 mg/kg) x 1/0.38 m³/kg x 6.7 m³/10m³ x 1.0

=> NOAEC worker = 331.4 mg/m³

AF for dose response relationship:
1
AF for differences in duration of exposure:
1
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
1
Justification:
see 'Additional information - Workers'
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
66.28 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
DNEL extrapolated from long term DNEL
Dose descriptor starting point:
NOAEL
DNEL value:
188 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
331.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

Corrected inhalatory NOEC = Oral NOEL (188 mg/kg) x 1/0.38 m³/kg x 6.7 m³/10m³ x 1.0

=> NOAEC worker = 331.4 mg/m³

Short term DNEL = Long Term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/m³
DNEL related information
DNEL derivation method:
other: see 'Additional information - Workers'
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/m³
DNEL related information
DNEL derivation method:
other: see 'Additional information - Workers'

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
20
Dose descriptor starting point:
NOAEL
DNEL value:
188 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
1
Justification:
see 'Additional information - Workers'
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
20
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

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

Penetration oral compared to dermal (both assumed 100%) 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: 9.4 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 (worker):

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 1/0.38 m³/kg x 6.7 m³/10m³ x 1.0

=> NOAEC worker = 331.4 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: 66.28 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)

Short term DNEL = Long Term DNEL

Therefore:

Worker DNELshort-term for oral or dermal route-systemic: 9.4 mg/kg bw

Worker DNEL short-term for inhalation exposure: 66.28 mg/m³

Conclusion (systemic effects):

Worker DNEL long-term for oral or dermal route-systemic: 9.4 mg/kg bw/day

Worker DNEL long-term for inhalation exposure: 66.28 mg/m³

Worker DNELshort-term for oral or dermal route-systemic: 9.4 mg/kg bw

Worker DNEL short-term for inhalation exposure: 66.28 mg/m³

3.) Reproductive Toxicity – systemic effects (workers)

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.

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)

Menthol, tested according to OECD Guideline 404, is irritating to the skin if applied undiluted

Menthol, tested according to OECD Guideline 405, is slightly irritating to the eye.

5. Sensitization

Menthol is not sensitising to the skin of guinea pigs.

5. 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).

Based on the irritating effects the systemic DNEL not applies to local effects. There are no studies available to define a threshold for local toxicity after dermal application and inhalation. Consequently, for local effects the derivation of a long- and short-term DNEL for dermal toxicity is not possible due to the irritating effects of menthol.

DNEL (long-term, local) for inhalation

In the REACH TGD the DNEL calculation for compounds without fully valid long term inhalation study is usually based on oral studies. This extrapolation covers the systemic effects of the compound. For non-irritating compounds it can be assumed that the potential local effects will be covered by the derived systemic DNEL. For compounds with irritating or corrosive properties the derived systemic DNEL might not cover potential local effects.

A toxicological TF within the German VCI discussed the derivation of DNEL for local irritating compound with a limited database. The experts developed upper boundary values for irritating and/or corrosive compounds based on available data. In particular the expert TF evaluated the German MAK-values published in the TRGS900 in 2009. For irritating compounds labelled with R36 or R38 but without relevant inhalation toxicity data available the TF developed a generic upper boundary value of 10 mg/m3; for compounds with corrosive properties (R34 or R35) a respective value of 1 mg/m3 is developed.

For menthol an odour threshold value of 0,026 ppm (ca. 0.162 mg/m³) was determined.

Since for menthol a classification with R38 is justified and for the odour threshold value of ca. 0.162 mg/m³ was determined, as an upper boundary value of 1 mg/m³ is proposed as a long-term inhalation DNEL for local effects.

6) Short-term toxicity – local effects (workers)

For local effects the derivation of a dermal short-term DNEL is not appropriate due to the irritating effects of menthol. We propose to take the above mentioned long-term inhalation DNEL value also for short-term exposure.

Conclusion (systemic and local effects):

Route of exposure DNEL; local effect DNEL; systemic effect

Oral (long term)              -                            9.4 mg/kg

Oral (short term)             -                            9.4 mg/kg

Dermal (long term) No threshold;

Eye Irrit.2; C > 25% (H319)                       9.4 mg/kg

Dermal (short term) No threshold;               9.4 mg/kg

Eye Irrit.2; C > 25% (H319)

Inhalation (long term) 1 mg/m³                     66.2 mg/m³

Inhalation (short term) 1 mg/m³                   66.2 mg/m³

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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
16.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor starting point:
NOAEL
DNEL value:
188 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
163.47 mg/m³
Explanation for the modification of the dose descriptor starting point:

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 1.0

=> NOEC general population = 163,47 mg/m³

AF for dose response relationship:
1
AF for differences in duration of exposure:
1
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
1
Justification:
see 'Additional information - General Population'
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
16.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
DNEL extrapolated from long term DNEL
Dose descriptor starting point:
NOAEL
DNEL value:
188 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
163.47 mg/m³
Explanation for the modification of the dose descriptor starting point:

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 1.0

=> NOEC general population = 163,47 mg/m³

Short term DNEL = Long Term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/m³
DNEL related information
DNEL derivation method:
other: see 'Additional information - General Population'
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/m³
DNEL related information
DNEL derivation method:
other: see 'Additional information - General Population'

General Population - Hazard via dermal route

Systemic effects

Long term exposure
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 related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
40
Dose descriptor starting point:
NOAEL
DNEL value:
188 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
1
Justification:
see 'Additional information - General Population'
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
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 related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
40
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

General Population - Hazard via oral route

Systemic effects

Long term exposure
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 related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
40
Dose descriptor starting point:
NOAEL
DNEL value:
188 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
1
Justification:
see 'Additional information - General Population'
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
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 related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
40
DNEL extrapolated from long term DNEL
Dose descriptor starting point:
NOAEL
DNEL value:
188 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Short term DNEL = Long Term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

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 100%) 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 1.0

=> NOEC general population = 163,47 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: 16.3 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)

Short term DNEL = Long Term DNEL

Therefore:

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

General population DNELshort-term for inhalation exposure: 16.3 mg/m³

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: 16.3 mg/m³

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

General population DNELshort-term for inhalation exposure: 16.3 mg/m³

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

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.

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 (general population)

Menthol, tested according to OECD Guideline 404, is irritating to the skin if applied undiluted

Menthol, tested according to OECD Guideline 405, is slightly irritating to the eye.

5. Sensitization

Menthol is not sensitizing to the skin of guinea pigs.

6. Long-term and short-term dermal or inhalation route - local effects (general population)

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

Based on the irritating effects the systemic DNEL not applies to local effects. There are no studies available to define a threshold for local toxicity after dermal application and inhalation. Consequently, for local effects the derivation of a long- and short-term DNEL for dermal toxicity is not possible due to the irritating effects of menthol.

DNEL (long-term, local) for inhalation

In the REACH TGD the DNEL calculation for compounds without fully valid long term inhalation study is usually based on oral studies. This extrapolation covers the systemic effects of the compound. For non-irritating compounds it can be assumed that the potential local effects will be covered by the derived systemic DNEL. For compounds with irritating or corrosive properties the derived systemic DNEL might not cover potential local effects.

A toxicological TF within the German VCI discussed the derivation of DNEL for local irritating compound with a limited database. The experts developed upper boundary values for irritating and/or corrosive compounds based on available data. In particular the expert TF evaluated the German MAK-values published in the TRGS900 in 2009. For irritating compounds labelled with R36 or R38 but without relevant inhalation toxicity data available the TF developed a generic upper boundary value of 10 mg/m3; for compounds with corrosive properties (R34 or R35) a respective value of 1 mg/m3 is developed.

For menthol an odour threshold value of 0,026 ppm (ca. 0.162 mg/m³) was determined.

Since for menthol a classification with R38 is justified and for the odour threshold value of ca. 0.162 mg/m³ was determined, as an upper boundary value of 1 mg/m³ is proposed as a long-term inhalation DNEL for local effects for worker.

Concerning the higher intraspecies difference for the general population (AF = 10) in respect to worker (AF = 5) by a factor of 2

as an upper boundary value of 0.5 mg/m³ for the general population is proposed as a long-term inhalation DNEL for local effects.

7) Short-term toxicity – local effects (general population)

For local effects the derivation of a dermal short-term DNEL is not appropriate due to the irritating effects of menthol. We propose to take the above mentioned long-term inhalation DNEL value also for short-term exposure.

Conclusion (systemic and local effects):

Route of exposure DNEL; local effect DNEL; systemic effect

Oral (long term)                     -                       4.7 mg/kg

Oral (short term)                   -                        4.7 mg/kg

Dermal (long term) No threshold;

Eye Irrit.2; C > 25%                                      4.7 mg/kg

Dermal (short term) No threshold;

Eye Irrit.2; C > 25%                                    4.7 mg/kg

Inhalation (long term) 0.5 mg/m³ 16.3 mg/m³

Inhalation (short term) 0.5 mg/m³ 16.3 mg/m³

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: Haarmann and Reimer GmbH,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: Haarmann and Reimer GmbH,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