Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
An assessment of toxicokinetics, based on available data, in accordance with Annex VIII, Section 8.8.1 of Regulation (EC) No 1907/2006 (REACH)
Type of information:
other: Desk-based assessment
Adequacy of study:
key study
Study period:
Not applicable
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
An assessment of toxicokinetics, based on available data, in accordance with Annex VIII, Section 8.8.1 of Regulation (EC) No 1907/2006 (REACH)
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-methoxy-4-methylphenyl methyl carbonate
EC Number:
700-673-7
Cas Number:
132638-45-0
Molecular formula:
C10H12O4
IUPAC Name:
2-methoxy-4-methylphenyl methyl carbonate
Test material form:
solid
Details on test material:
Detailed information on the 'test material identity' is provided in the attached document including information on individual constituents.

Test animals

Details on species / strain selection:
No animals were used in this desk-based assessment.
Details on test animals or test system and environmental conditions:
Not applicable

Administration / exposure

Details on exposure:
No animals were used in this desk-based assessment.
Duration and frequency of treatment / exposure:
Desk-based assessment.
No. of animals per sex per dose / concentration:
No animals were used in this desk-based assessment.
Positive control reference chemical:
Desk-based assessment.
Details on study design:
Not applicable
Details on dosing and sampling:
Not applicable
Statistics:
Not applicable

Results and discussion

Preliminary studies:
Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The molecular weight of the substance constituents is low i.e. < 200 g/mol. The n-octanol/water partition coefficient is relatively low (log Pow = 2.27), with a water solubility of 376 mg/L and vapour pressure 0.1 Pa. This is suggestive of favourable absorption from the GI tract following oral administration. Oral absorption of the substance is mainly via passive diffusion to into portal circulation with delivery into the liver i.e. first pass metabolism and relative high pulmonary uptake. This is supported by the systemic availability repeated dose toxicity studies. Although these physicochemical properties indicate the substance will demonstrate moderate dermal absorption, the substance is not expected to be surface active which mean transfer between the stratum corneum and the epidermis is restricted, thus overall uptake via the dermal route is limited. This is demonstrated by the lack of significant systemic and local toxicity following dermal exposure studies. Based on the vapour pressure of the test item and being crystalline solid, volatility is expected to be very low therefore systemic availability via the inhalable route is expected to be very low. This is supported by tolerability of the test item in rats following acute exposure.
Details on distribution in tissues:
The substance possesses physico-chemical properties which indicate test item can easily pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water into the liver. This will limit distribution of the parent compound systemically and limited half-life of the parent compound in blood plasma. A wide distribution of the substance via inhalation is expected as it can easily be taken up into circulatory system, however, being of low volatility availability of the test item via the inhalation route is limited.
Details on excretion:
Parameters in liver, lung and thyroid demonstrate possible hepatic metabolism and renal elimination. The n-Octanol/water partition coefficient (log Pow = 2.27) and the molecular weight of the substance is suggestive of low accumulation of the substance in fatty tissues after absorption from gastro-intestinal tract, the substance may enter circulation via lymphatic system. Based on the molecular structure and solubility, excretion into urine as conjugated metabolites is assumed to be a preferred route of elimination. A small percentage of the parent compound may also be excreted via bile and faces.

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
Metabolism of the substance is expected to be mainly through the liver and to a small extent via GI tract phase I and II enzymes with principal alcohol metabolizing enzymes being alcohol dehydrogenase [ADH] and aldehyde dehydrogenase [ALDH2]. Hydrolysis of the carbonate esters (R1OCOOR2) would result in the production of metabolites containing alcohol (R1OH, R2OH) and acidic (containing HO2/CO2) derivatives. The acidic and alcohols derivatives will be further conjugated with glucuronides and sulphate via glucuronsyl transferase and sulphotransferase with subsequent elimination via urine. This is demonstrated by centrilobular hepatocyte hypertrophy in the liver in male rats9, 10. This is considered as an adaptation reaction following exposure to xenobiotic(s).

Applicant's summary and conclusion

Conclusions:
The substance possesses physico-chemical properties which are favourable for ADME. Exposure from oral and inhalation routes are most favourable and therefore the substance is expected to be widely distributed especially via inhalation exposure. Based on the log Pow of < 3 and BCF < 2,000, bioaccumulation is not significant and elimination is expected to be rapid. The lack of systemic and local toxicity observed following in vivo skin irritation and sensitisation studies shows that systemic bioavailability of this substance is limited via dermal exposure. The clinical signs observed following oral sub-acute exposure support oral absorption of teste item and clinical signs reported in organs such as the liver is demonstrative of distribution, biotransformation and elimination of the test item. It can be concluded that the basic toxicokinetics of the test item does not pose significant toxicological concern through evaluation of the available data.
Executive summary:

A desk-based assessment of the basic toxicokinetics of the substance, in accordance with Regulation (EC) 1907/2006: Annex VIII - Section 8.8.1. The substance possesses physico-chemical properties which are favourable for ADME. Exposure from oral and inhalation routes are most favourable and therefore the substance is expected to be widely distributed especially via inhalation exposure. Based on the log Pow of < 3 and BCF < 2,000, bioaccumulation is not significant and elimination is expected to be rapid. The lack of systemic and local toxicity observed following in vivo skin irritation and sensitisation studies shows that systemic bioavailability of this substance is limited via dermal exposure. The clinical signs observed following oral sub-acute exposure support oral absorption of teste item and clinical signs reported in organs such as the liver is demonstrative of distribution, biotransformation and elimination of the test item. It can be concluded that the basic toxicokinetics of the test item does not pose significant toxicological concern through evaluation of the available data.

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