Menthane, monohydroperoxy derivative

Endpoint summary

Description of key information

 The toxicokinetic assessment is based on the test results and a(n) (theoretical) evaluation of uptake, distribution, metabolism and excretion.

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

Toxicokinetic assessment

Introduction

 

The test substance is an organic hydroperoxide that is anticipated to be relatively stable (Tice, 1998, HPV The Terpene Consortium, Test Plan for Terpenoid Tertiary Alcohols and Related Esters, 2001).The formal substitution of a hydrogen atom in hydrogen peroxide by an alkyl group gives a hydroperoxide with the general formula R–OOH. Primary, secondary, and tertiary hydroperoxides are known[1].PMHP is a cyclohexane ring substituted with a methyl- and isopropyl-moiety. The hydroperoxide group can either be attached directly to the ring or to one of the substituents.Tertiary carbon atoms are preferentially attacked because of the lower dissociation energy of the C – H bond compared with those of primary and secondary centers¹.

Cumenehydroperoxide is a structural analogue. Its structure is a methyl and isopropyl substituted benzene ring where the peroxide group is attached to one of the alkyl groups. Here also tertiary carbons atoms are preferred for attack. The rationale for read-across is included in a document in chapter 13.

Toxicokinetics

 

One of the mechanisms of free radical production from hydroperoxides involves the homolytic cleavage of the hydroperoxide O-O bond to produce alkoxyradicals.The thermal decomposition of primary alkyl hydroperoxides takes place with homolytic cleavage, whereas for secondary and tertiary hydroperoxides homolytic cleavage can be observed for both thermal and photolytic decomposition²The mechanism can also be induced by enzymes like cytochrome P450[2]^,[3]. 

 

P-menthane hydroperoxide and cumenehydroperoxide are liquids with a molecular weight of 152 and 194 Da, respectively. Their logKow is between 2.15 and 2.76. Other physicochemical parameters are summarised in the table below.

 

Table phys-chem properties of selected hydroperoxides

	P-menthane hydroperoxide	Cumene hydroperoxide
Molecular weight	194.28	152.19
State of the substance at 20°C and 101,3 kPa	Liquid	Liquid
Vapour pressure	418 Pa at 20^◦C	0.436 Pa at 25^◦C
Water solubility	444 mg/L at 20^◦C	13900 mg/L at 25^◦C
Partition coefficient n-octanol/ water	2.76	2.16 at 25^◦C

EPI= data from US-EPA Epiwin suite QSAR

 

Absorption

Although no data on absorption, distribution excretion and metabolism of the test substance or its structural analogue is available, it is expected that, based on molecular weight, water solubility and logKow, cumene hydroperoxide, as well as p-menthane hydroperoxide can be taken up via the gastro-intestinal tract. Due to the aromatic ring, the structural analogue is expected to be more polar than the test substance and thus more water soluble. Therefore its chances to pass the biological membranes may be slightly lower than those for the test substance. In addition, cumene hydroperoxide has been shown hydrolytically instable at low pH. Therefore hydrolysis of the hydroperoxide under the acidic conditions in the stomach can be assumed, so that uptake of the intact molecules is not very likely. This is more or less confirmed by the fact that in the acute oral toxicity studies no clear effects related to the corrosiveness of the peroxide binding were reported.

The molecular weight is < 500 and logKow is between -1 and 4, and therefore dermal absorption is expected to be substantial (default 100% in absence of data).

The vapour pressure of p-menthane hydroperoxide indicates a potential for exposure. As the logKow is above 0 there is a potential for absorption directly across the respiratory tract epithelium (default 100% in absence of data). This is confirmed by the fact that in the available 90-day inhalation study next to the local effects systemic effects were observed at the highest dose level. This is indicative for some absorption (either by intact or damaged lung epithelium). In this study p-menthane hydroperoxide was administered as an aerosol (particle size not reported).

The reasoning above does not take into consideration the corrosive properties of the substances.The hydroperoxide group is expected to react with (mucous) membranes at the entrance site inducing strong local effects. In this process the hydroperoxide group is reduced to the concomitant alcohol which might be taken up via the damaged contact site.

 

Metabolism

When the substances would be taken up as a whole, their metabolism would involve reduction to the alcohol, and concomitant elimination from the body via oxidative metabolism pathways. The alcohols conjugate with glucuronic acid and are excreted in the urine and faeces. No potential for accumulation is expected in view of the hydrophilic nature of the alcohol molecules.

Under the acidic conditions in the stomach cumene hydroperoxide is expected to be hydrolysed. It is very likely that this is also the case for p-menthane hydroperoxide and that the substance that may enter the body is indeed the concomitant alcohol metabolite.

 

Conclusion

It is expected that after inducing local effects at the site of entrance, p-menthane hydroperoxide as well as the analogue cumenehydroperoxide, are rapidly taken up either already as the alcohol metabolite or as such with concomitant metabolism to the alcohol and excretion via urine and faeces.

 

[1]Ullmann's Encyclopedia of Industrial Chemistry, online edition, chapterPeroxy Compounds, Organic

[2]Minor J. Coon and Al;fin D. N. Vaz, Radical intermediates in peroxide-dependent reactions catalyzed by

cytochrome P-450, J. Biosci., Vol. 11, Numbers 1–4, March 1987, pp. 35–40.

[3]Tice R, Brevard B, Integrated Laboratory Systems, Cumene Hydroperoxide [80-15-9] Review of Toxicological Literature Prepared for Errol Zeiger, National Institute of Environmental Health Sciences, September 1998