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Reference
Endpoint:
basic toxicokinetics
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
Please refer to IUCLID section 13 for a detailed justification of the category approach.
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Test material information:
Composition 1
Type:
metabolism
Results:
In vivo, the major urinary metabolites were the compounds p-menthane-3,8-diol and 3,8-dihydroxy-p- menthane-7-carboxylic acid. Further metabolites were p-menthane-3,9-diol and 3,8-oxy-p-menthane-7-carboxylic acid (1988).
Type:
distribution
Results:
recoved menthol 63%, thereof: 52% in urin, 4.5% in feces 17 h after administration;.in ileum 3.5%, fat 2.1%, liver 0.8%, serum 0.31%, kidney 0.2%, brain < 0.1%, testis < 0.1% (1982)
Type:
excretion
Results:
An average 40% recovery of oral Menthol uptake was found in urine (1990)
Details on excretion:
study from 1994: 71% of the dose was recovered in 48 hr with approximately equal amounts in urine and feces. Bilary metabolites underwent enterohepatic circulation (67% of administered dose).
study from 1988: The total recovery of the administered radioactivity was 63%. 52% appeared in the urine and 4.5% in feces 17 h after oral menthol administration.
Metabolites identified:
yes
Details on metabolites:
study from 1988: Metabolites isolated and characterized from the urine of rats after oral administration of L-Menthol were the following: p-menthane-3,8 -diol, p-menthane-3,9 -diol, 3,8 -oxy-p-menthane-7 -carboxylic acid, and 3,8 -dihydroxy-p-menthane-7 -carboxylic acid.
study from 1994: Urine: p-menthane-3,8-diol, p-menthane-3,9-diol (and additional a stereoisomer or p-menthane-3,9-diol),3-hydroxy-p-menthane-9-carboxylic acid (and an additional stereoisomer of this metabolite), 3 hydroxy-p-menthane-7-carboxylic acid (additional an geometric isomere of this metabolite), p-menthane-3,7,8-triol, 3,8-dihydroxy-p-menthane-7-carboxylic acid, menthol glucuronide, p-menthane-3,8-diol-glucuronide, p-menthane-3,9-diol-glucuronide.

study from 1988 (rats): No bioaccumulation potential based on study results. L-menthol has the ability to induce the hepatic microsomal cytochrome P-450 system and NADPH-cytochrome c (P-450) reductase by nearly 80% after oral administration to rats for  3 days.

4 different metabolites of L-menthol were identified in rat urine. L-Menthol has the ability to induce the hepatic microsomal P-450 and NADPH-cytochrome c (P-450) reductase in rats.

study from 1994 (rats): No bioaccumulation potential based on study results; rapidly metabolised and excreted. The investigations in rats demonstrated that L-Menthol was rapidly metabolised and excreted in urine and faeces. L-Menthol undergoes an intensive enterohepatic circulation.

study from 1982 (rat): No bioaccumulation potential based on study results. Rapid metabolism and excretion of oral menthol as menthol glucuronide in urine. It was shown that menthol can be rapidly excreted in urine. The tissue distribution of the remaining menthol 17 h after adminisatration was shown.

study 1938 (rabbits): Low bioaccumulation potential based on study results. Rabbits excreted L-menthol mainly in the urine. 48% conjugated L-menthol was recovered during 2 days as glucuronide in the urine from rabbits with 1000 mg/kg bw L-menthol.

study 1972 (human): More than 77% of administered menthol to skin or oral could be determined in urine after 36 hours. At least 77%  of menthol after oral or dermal administration was excreted in urine after 36 hours.

study 1984 (human): No bioaccumulation potential based on study results. Can be well absorbed after oral application in humans; most will be excreted by urine.

study 1967 (human): No bioaccumulation potential based on study results. The 19 test results obtained, ranging from 0.401 to 0.987 (as fraction of menthol) excreted via urine in glucuronidated form. A wide distribution in menthol glucuronide excretion capacity were found in the investigated urine of young healthy men.

study 1955 (human): These results supported the belief that preformed glucuronic acid and glucuronolactone cannot be activated for glucuronide synthesis in the mammal.

study 1990 (human): No bioaccumulation potential based on study results. On average 40% menthol of the peppermint oil menthol content was recovered (180 mg peppermint oil). Rapid absorbed by oral administration; excreted fast by urine.

study 1924 (rabbit): No bioaccumulation potential based on study results. When 2 g of menthol (unspecified isomer) were given to rabbits by stomach tube, menthol glucuronic acid appeared in the urine in less than an hour after the administration of the test substance and 90% of the conjugated acid was found to be excreted in 6 h; when 3.5 g were given, over 90% of the total amount excreted appeared in the urine during the first 24 h

Conclusions:
L-, DL, and unspecified Menthol isomers were well absorbed via the oral route of exposure. They were mainly excreted as glucuronic acid conjugates. In rats an extensive enterohepatic circulation leads in addition to various hydoxylated degradation products. Glucuronides and degradation products were mainly eliminated via urine, minor quantities via the faeces. Thus, both in animals and humans menthol seems to be metabolized in a similar way, being rapidly glucuronidated and excreted mainly via urine.
Executive summary:

Several studies observing the toxicokinetics and distribution of the category group members are available (CAS 2216-51-5, L-menthol and CAS 89-78-1, menthol). No bioaccumulation potential, a good oral absorption, rapid glucuronidation and excretion mainly via urine were observed and thus these results were also concluded for (±)-neomenthol (CAS 3623-51-6). As explained in the justification for type of information, the differences in molecular structure in the category group are unlikely to lead to differences in the toxicokinetics, metabolism and distribution.

Description of key information

Short description of key information on bioaccumulation potential result:
L-, D/L-, and menthol isomers were well absorbed via the oral and dermal routes of exposure. They are mainly excreted as glucuronic acid conjugates. In rats an extensive enterohepatic circulation leads in addition to various hydroxylated degradation products. Glucuronides and degradation products were mainly eliminated via urine, minor quantities via the faeces. Thus, both in animals and humans menthol seems to be metabolized in a similar way, being rapidly glucuronidated and excreted mainly via urine.

As (±)-neomenthol belongs to the category of the menthols (see category approach justification) the same toxicokinetic behavior for (±)-neomenthol is assumed.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information

(±)-neomenthol belongs to the category of menthols (see category approach justification). Therefore the same toxicokinetic behavior as analysed for menthol, L-menthol and D/L-menthol is assumed for (±)-neomenthol.

Absorption:

From the studies on metabolism with L-, D/L- and the menthol, it can be concluded that menthols are well absorbed by the oral route (Madhava Madyastha and Sri vatsan, 1988; Yamaguchi, et al., 1994, Williams, 1938, Atzl et al., 1972). Dermal absorption is slower than oral absorption (Atzl et al., 1972). In a human assay (Martin et al., 2004), three groups of 8 subjects (4 male and 4 female) applied a different number of commercial patches (2, 4, or 8) to the skin for 8 hours. Plasma samples were analysed by gas chromatographic methods. The total applied dose varied over a 4-fold range (ie, 2-8 patches). The corresponding quantities of menthol contained in those patches were 74.9 to 299.5 mg. The application of 2 patches resulted in low plasma concentrations that were near the limits of quantitation. However the 4- and 8-patch applications resulted in plasma concentration-time profiles and parameter values (Cmax and AUC values) for D/L-menthol that suggested linearity among the doses tested, well absorption of D/L-menthol via dermal route as well. Another study (Cal, 2008) investigated the ex vivo skin disposition of D/L-menthol after application of the commercial drug products containing aluminium acetotartrate, methyl salicylate, ibuprofen and naproxen, by using full human-skin mounted in flow-through diffusion cells. After 15, 30 and 60 minutes of application, the skin was progressively tape-stripped into three fractions of stratum corneum and the remaining epidermis with dermis. The concentration of D/L-menthol in the skin layers was determined by gas chromatograph. Varying degrees of penetration of D/L-menthol into the skin layers was observed, depending on its amount in the vehicle and the presence of drug substance. However, as there is still no quantitative data available, the absorption rate via the dermal route is considered to be same as via oral route, on the hypothesis of the worst case. Therefore, the default value of 100% of the absorption rate is applied to both oral and dermal routes. Due to low vapour pressure and low Henry's law constant, the inhalation route is not considered to be the likely exposure route to human for these substances.

Metabolism:

The metabolic pathways of L-menthol have been investigated in two studies with rats (Madhava Madyastha and Srivatsan, 1988; Yamaguchi, et al., 1994). In the first one IISc rats were treated by gavage with L-menthol at 800 mg/kg bw/d for 20 days. Urine was collected every day. Metabolites in urine were also analyzed daily. In the second study, L-menthol labeled by tritium was administered by gavage to intact and bile duct-cannulated male Fischer 344 rats at a dose of 500 mg/kg bw. The metabolites in urine, faeces and bile were analyzed up to 48 h after administration. The investigations on intact rats show that menthol can be rapidly glucuronidated and excreted in urine and faeces. The studies with bile duct-cannulated rats demonstrate that biliary excretion is fast and extensive and the menthol undergoes an intensive enterohepatic circulation. After cleavage of the glucuronide and reabsorption in the small intestine it is further metabolized in the liver. It is described, that the first step is hydroxylation at the C-8 position, followed by oxidation of the C -1 methyl group (C7) to a carboxylic group. Furthermore it is hydroxylated at the C-9 position. p-Menthane-3,8-diol (M-I) and 3,8-dihydroxy-p-menthane-7-carboxylic acid (M-VII) were identified as major metabolites (not further quantitated) in the urine in both studies. Further (minor urinary) metabolites were p-menthane-3,9-diol (M-II), 3,8-oxy-p-menthane-7-carboxylic acid (M-VIII), 3-hydroxy-p-menthane-9-carboxylic acid (M-IV), 3-hydroxy-p-menthane-7-carboxylic acid (M-V), p-menthane-3,7-diol (M-III) and p-menthane-3,7,8-triol (M-VI) (Madhava Madyastha and Srivatsan, 1988; Yamaguchi, et al., 1994, see attached Figure 1). Most of these metabolites are excreted as glucuronides.

In Madhava Madyastha's study, it was also found that repeated oral administration of L-menthol for 3 days can induce cytochrome P450 and the NADPH-cytochrom c reductase activity in the liver of rats, which causes nearly 80% L-menthol being reduced. The metabolism of L-menthol was induced in rats’ liver by phenobarbital, but not by methylcholanthrene, which was proposed in the same study.

Comparing the results of studies with rats, L-menthyl glucuronide was detected in the urine of sheep administrated with L-menthol in major amounts. Within 24 hours after application, the excretions were almost complete (Wright, 1945). Similarly rabbits also excreted L-menthol mainly in the urine. 48% conjugated L-menthol was recovered after 2 days as glucuronide in the urine from rabbits administrated with 1000 mg/kg bw L-menthol (Williams, 1938).

Also, humans excrete major amounts of L-menthol as the glucuronide. In a study with two human volunteers, 17 to 38% of menthol was excreted as menthyl glucuronide in urine within 24 hours after 8 daily doses of 750 mg L-menthol (Eisenberg et al., 1955). Glucuronide excretion was studied in the urine of several persons after oral ingestion of menthol (unspecified isomer) in a variety of studies. In older studies about 70% of the total dose (10 mg to 1560 mg) was found in the urine of humans as glucuronide 6 to 24 hours after ingestion (Atzl et al., 1972; Bolund et al., 1967). In a study of Somerville et al. (1984) 35 to 40% menthol was found in the urine of 6 volunteers 24 hours after ingestion of 180 to 190 mg menthol. In another study (Kaffenberger and Doyle, 1990) an average of 40% menthol was found in the urine of 4 volunteers 14 hours after dosing with 72 mg menthol.

In the urine of rabbits fed 1 g/kg bw of menthol and L-menthol, respectively, menthol glucuronides were found in similar amounts (59% of the dose) and L-menthol glucuronides (48 % of the dose) (Williams, 1938).

In summary, the studies show that both in animals and humans the menthol isomers can be rapidly glucuronidated and excreted mainly via urine.

Distribution:

After 17 hours oral administration of 470 mg/kg bw of [3-³11]-menthol (unspecified isomer) to rats, 2.1% was found in fat, 0.8% in the liver, 0.2% in the kidney, 0.3% in serum and traces (< 0.1%) in brain, and testes (Clegg et al., 1982) whereas the majority was excreted via urine (52%), faces (4.5%) and ileum (3.5%).

Excretion:

Investigations with male Fischer 344 rats showed that 48 h after administration of 500 mg/kg radiolabelled L-menthol, over 70% of the administered dose was recovered in urine and faeces (Yamaguchi, et al, 1994).

Rats were administered 470 mg/kg bw of [3 -³11]-menthol (unspecified isomer) orally. After 17 hours 52% of the administered radioactivity was found in the urine, 4.5% and 3.5% in the faeces and ileum respectively (Clegg et al., 1982).

In humans urinary elimination of menthol after oral application was almost completely excreted within about 12 to 24 hours (Atzl et al., 1972; Bolund et al., 1967; Kaffenberger and Doyle, 1990; Sommerville et al., 1984).

References:

Atzl G, Bertl M, Daxenbichler G and Gleispach H (1972): Determination of etheral oils from the urine by gas -liquid chromatography. Chromatog raphia 5: 250-255.

Bolund S, Falus F and Jo rgensen K (1967): A menthol loading test fo r glucu ronide synthesis normal values. Scand J Clin Lab Invest 19: 288 - 290.

Clegg, R.J. (1982): The Mechanism of Cyclic Monoterpene Inhibition of Hepatic 3-Hyd roxy-3-methylglutaryl Coenzyme A Reductase in Vivo in the Rat, J. Biol. Chem. 257, 2294-2299.

Eisenberg F, Field JB and Stetten D (1955): Studies on glyceronide conjugation in man. Arch Biochem Biophys 59: 297 — 299.

Kaffenberger, R.M. and Doyle, M.J. (1990), Determination of menthol and menthol glucuronide in human urine by gas chromatography using an enzyme-sensitive internal standard and flame ionization detection, J. Chromatogr. 527, 59-66.

Madhava Madyastha K and Srivatsan V (1988): Studies on the metabolism of L-menthol in rats. Drug Metab Dispos 16 (5): 765 — 772.

Martin D., Valdez J., Boren J. and Mayersohn M. (2004): Dermal Absorption of Camphor, Menthol, and Methyl Salicylate in Humans. J Clin Pharmacol. 44, 1151-1157.

Williams RT (1938): Studies in detoxication II.(a) The conjugation of isomeric 3 -Menthanols with glucuronic acid and the asymmetric conjugation of D/L-menthol, L-menthol and D/L-isomenthol in the rabbit. (b) D-isomenthylglucuronide, a new conjugated glucuronic acid. Biochem J. 32: 1849 — 1855.

Sommerville KW, Richmond CR and Bell GD (1984): Delayed release peppermint oil capsules (Colpermin) for the spastic colon syndrome: A pharmacokinetic study. Br J Clin Pharmacol 18: 638 - 640.

Wright S (1945): Etoxication mechanism in the sheep. Univ Queens Pape rs 1(25): 1 — 10.

Yamaguchi T, Caldwell J and Farmer P (1994): Metabolic fate of [3H]-L-menthol in the rat. Drug Metab Dispos 22 (4): 616 — 624.