Menthol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

Menthols Category Justification OECD SIDS UNEP Publications

Type of information:

other: Menthols Category Justification OECD SIDS UNEP Publications

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: OECD SIDS Initial Assessment Report dated 2003

Data source

Reference

Reference Type:

review article or handbook

Title:

Menthols Category Justification OECD SIDS UNEP Publications

Author:

OECD SIDS

Year:

2003

Bibliographic source:

OECD SIDS for Menthols UNEP Publications

Materials and methods

Objective of study:

other: Menthols Category Justification OECD SIDS UNEP Publications

Principles of method if other than guideline:

OECD SIDS Initial Assessment Report provided by an expert OECD group.

GLP compliance:

no

Remarks:

Comprehensive documentation on the available information and conclusions given in the SIDS Initial Assessment Report

Test material

Test material information

Constituent 1

Reference substance name:

Menthol

EC Number:

201-939-0

EC Name:

Menthol

Cas Number:

89-78-1

Molecular formula:

C10H20O

IUPAC Name:

2-isopropyl-5-methylcyclohexanol

Specific details on test material used for the study:

SIDS Initial Assessment Report is on the menthols Category:
L-Menthol CAS No: 2216-51-5
D-Menthol CAS No: 15356-60-2
D/L-Menthol CAS No: 89-78-1
Menthol CAS No: 1490-04-6

Radiolabelling:

other: not applicable - SIDS Initial Assessment Report; UNEP Publications

Test animals

Species:

other: not applicable - SIDS Initial Assessment Report; UNEP Publications

Strain:

other: not applicable - SIDS Initial Assessment Report; UNEP Publications

Details on species / strain selection:

not applicable - SIDS Initial Assessment Report; UNEP Publications

Details on test animals or test system and environmental conditions:

not applicable - SIDS Initial Assessment Report; UNEP Publications

Administration / exposure

Route of administration:

other: not applicable - SIDS Initial Assessment Report; UNEP Publications

Vehicle:

other: not applicable - SIDS Initial Assessment Report; UNEP Publicationsion

Details on exposure:

not applicable - SIDS Initial Assessment Report; UNEP Publications

Duration and frequency of treatment / exposure:

not applicable - SIDS Initial Assessment Report; UNEP Publications

Doses / concentrations

Remarks:

not applicable - Menthols Category Justification OECD SIDS UNEP Publications

No. of animals per sex per dose / concentration:

not applicable - SIDS Initial Assessment Report; UNEP Publications

Control animals:

other: not applicable - SIDS Initial Assessment Report; UNEP Publications

Positive control reference chemical:

not applicable - SIDS Initial Assessment Report; UNEP Publications

Details on study design:

not applicable - SIDS Initial Assessment Report; UNEP Publications

Details on dosing and sampling:

not applicable - SIDS Initial Assessment Report; UNEP Publications

Statistics:

not applicable - SIDS Initial Assessment Report; UNEP Publications

Results and discussion

Preliminary studies:

not applicable - SIDS Initial Assessment Report; UNEP Publications.

Main ADME results

Type:

other: Menthols Category Justification OECD SIDS UNEP Publications

Results:

Investigations  on  toxicokinetics  show  that  menthols  are  well  absorbed via  the  oral  route.  For  all  of the isomers,  elimination  is rapid  and mainly  occurs  as glucuronic  acid conjugates  via  urine,  minor  amounts  via  faeces.  

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Investigations  on  toxicokinetics  show  that  L-,  D/L-  and  the  unspecified  menthol  are  well  absorbed via  the  oral  route.  For  all  of the isomers,  elimination  is rapid  and mainly  occurs  as glucuronic  acid conjugates  via  urine,  minor  amounts  via  faeces.  Significant  differences  in  toxicokinetic  properties of menthol isomers were not reported.

Details on distribution in tissues:

Investigations  on  toxicokinetics  show  that  L-,  D/L-  and  the  unspecified  menthol  are  well  absorbed via  the  oral  route.  For  all  of the isomers,  elimination  is rapid  and mainly  occurs  as glucuronic  acid conjugates  via  urine,  minor  amounts  via  faeces.  Significant  differences  in  toxicokinetic  properties of menthol isomers were not reported.

Details on excretion:

Investigations  on  toxicokinetics  show  that  L-,  D/L-  and  the  unspecified  menthol  are  well  absorbed via  the  oral  route.  For  all  of the isomers,  elimination  is rapid  and mainly  occurs  as glucuronic  acid conjugates  via  urine,  minor  amounts  via  faeces.  Significant  differences  in  toxicokinetic  properties of menthol isomers were not reported.

Toxicokinetic parameters

Toxicokinetic parameters:

other: For  all  of the isomers,  elimination  is rapid  and mainly  occurs  as glucuronic  acid conjugates  via  urine,  minor  amounts  via  faeces.  

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Investigations  on  toxicokinetics  show  that  L-,  D/L-  and  the  unspecified  menthol  are  well  absorbed via  the  oral  route.  For  all  of the isomers,  elimination  is rapid  and mainly  occurs  as glucuronic  acid conjugates  via  urine,  minor  amounts  via  faeces.  Significant  differences  in  toxicokinetic  properties of menthol isomers were not reported.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

Investigations  on  toxicokinetics  show  that  L-,  D/L-  and  the  unspecified  menthol  are  well  absorbed via  the  oral  route.  For  all  of the isomers,  elimination  is rapid  and mainly  occurs  as glucuronic  acid conjugates  via  urine,  minor  amounts  via  faeces.  Significant  differences  in  toxicokinetic  properties of menthol isomers were not reported.

Any other information on results incl. tables

SIDS Initial Assessment Report 2003 evaluated L, D, and racemic L/D mentols together and gives the rational for a menthol category as follows:

"Category Rationale: The menthols category is comprised of the isomers L-menthol, D-menthol, the racemate and menthol (unspecified isomers). The menthols can be considered as a category because of their similarity in physico-chemical, toxicological, ecotoxicological and environmental fate properties.

...

In summary, the available toxicity data indicate very similar toxicity profiles for all of the menthol isomers investigated."

The category justification is documented in a comprehensive 15 page annex to the SIDS Assessment report (Annex 1: Menthols Category JustificationCategory Justification). The annex is attached to this study entry as attached background material. The main information of the Annex 1 is also copied below:

"As  structural  isomers,  the  members  of  the  menthol  category  share the same molecular  weight.  Of particular  importance  to  environmental   effects  are  the  values  for  partition  coefficient  (log  Kow), vapour pressure and water solubility.

The  enantiomeric   menthols  have  identical  physical  properties  (apart  from  their  specific  rotation), but  the  racemates   differ  from  the  optically   active  forms  in,  for  example,   their  melting   points.  The slight differences are within  the range of  uncertainty range of laboratory tests.

The  water  solubility  was  determined  for  three  products.  Due  to  the  similar  molecular  structures,  no significant differences in the solubility are expected. The vapour pressure at environmental relevant temperatures was  determined  for  L-menthol  and an unspecified  isomer  mixture.  As well as for the parameters above, similar values are expected for D-menthol and the racemate.

Investigations  on  toxicokinetics  show  that  L-,  D/L-  and  the  unspecified  menthol  are  well  absorbed via  the  oral  route.  For  all  of the isomers,  elimination  is rapid  and mainly  occurs  as glucuronic  acid conjugates  via  urine,  minor  amounts  via  faeces.  Significant  differences  in  toxicokinetic  properties of menthol isomers were not reported.

The  available  toxicity  data  indicate  very  similar  toxicity  profiles  for  D -,  L-,  D/L-menthol  and  the unspecified  menthol  isomer  mixture.  In  mammalian  species  the  low  toxicity  is  manifested  in  LD50 values  generally  greater  than  2000  mg/kg  bw  in  acute  studies,  limited  toxicity  in  repeated  dose studie s,  and  no  effects  in  teratology  evaluations.  Irritation  to  skin  and  eyes  was  slight  to  moderate. The low hazard potential is not unexpected, since the FDA regulates menthol as a GRAS (generally recognized  as  safe)  component  and  an  acceptable  daily  intake  (ADI)  of  0-4  mg/kg  bw  for  L- menthol and D/L-menthol was adopted in 1999 by the Joint FAO/WHO Committee.

All of the products  have  been  tested  for acute  oral  toxicity,  skin  and  eye  irritation  in rodents,  often following identical test protocols.

Data   for   sensitization,   repeated   dose   toxicity,   genetic   toxicity,   fertility,   and   carcinogenicity are available for D/L-menthol and mostly for L-menthol as well.

D/L-menthol  is  a  racemic  mixture  of  the  D-  and  L- isomers  and  contains  both  isomers  in  equal proportion.  Data  gaps  for  D-menthol  and  the  unspecified  isomer  mixture  can  therefore  be  filled  by the respective results with the racemic mixture and the doses for each isomer might be equivalent to half of the total tested D/L -dose.

L-menthol   showed  no  embryotoxic   or  teratogenic   properties  at  not  maternally  toxic  dose  levels (maternally  toxic dose levels were not tested).  No experimental  data with the other menthol  isomers is  available   with   regard   to  developmental   toxicity.   Since   there   is  no  indication   of  a  relevant difference  between  the  isomers  in  their  toxicokinetics   and  metabolism,   and  since  this  is  further supported  by all other  available  toxicological  data,  which  do not show  any evident  differences  in the respective  toxicological  profiles,  there  is no  reason  to  assume  that  the stereoisomeric  properties  may affect  the  toxicological  properties  of  the  menthol  isomers.  Hence,  a  similar  result  in  developmental toxicity  studies  would  reasonably  be  expected  from  studies  with  D-menthol,  the  racemate  or  the unspecified menthol isomer.

Because  of  the  low  hazard  potential  of  the  chemicals  in  the  menthols  category,  no  further  toxicity tests are recommended."

(OECD SIDS Assessment Report, Annex 1: Menthols Category JustificationCategory Justification).

The OECD SIDS Initial Assessment Report concludes on toxicokinetics, metabolism and distriburion:

"L-, D/L- and the unspecified menthol isomer are well absorbed by the oral route of exposure and are mainly excreted as glucuronides. In rats an extensive enterohepatic circulation additionally leads to various hydroxylated degradation products. Glucuronides and degradation products are eliminated mainly via urine, minor quantities via the faeces."

Applicant's summary and conclusion

Executive summary:

The OECD SIDS Initial Assessment Report concludes on toxicokinetics, metabolism and distriburion:

"L-, D/L- and the unspecified menthol isomer are well absorbed by the oral route of exposure and are mainly excreted as glucuronides. In rats an extensive enterohepatic circulation additionally leads to various hydroxylated degradation products. Glucuronides and degradation products are eliminated mainly via urine, minor quantities via the faeces."

IDS Initial Assessment Report 2003 evaluated L, D, and racemic L/D mentols together and gives the rational for a menthol category as follows:

"Category Rationale: The menthols category is comprised of the isomers L-menthol, D-menthol, the racemate and menthol (unspecified

isomers). The menthols can be considered as a category because of their similarity in physico-chemical, toxicological,

ecotoxicological and environmental fate properties.

...

In summary, the available toxicity data indicate very similar toxicity profiles for all of the menthol isomers investigated."