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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
other: expert statement
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: An extended assessment of the toxicokinetic behaviour of TMOA was performed, taking into account the chemical structure, the available physico-chemical-data and the available toxicity data.

Data source

Reference
Reference Type:
other: expert statement
Title:
Toxicokinetic Statement for trimethyl orthoacetate (CAS 1445-45-0)
Author:
Chemservice S.A.
Year:
2018

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
Test guideline
Guideline:
other: ECHA Guidance R.7c
Principles of method if other than guideline:
An assessment of toxicological behaviour of TMOA is based on its physico-chemical properties and on the results of available toxicity data.
GLP compliance:
no

Test material

1
Chemical structure
Reference substance name:
Trimethyl orthoacetate
EC Number:
215-892-9
EC Name:
Trimethyl orthoacetate
Cas Number:
1445-45-0
Molecular formula:
C5H12O3
IUPAC Name:
1,1,1-trimethoxyethane
Test material form:
liquid

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
The absorption rate of TMOA is assumed to be 100 % via the oral, dermal and inhalation route.
Type:
distribution
Results:
The substance and the hydrolysis products are expected to be distributed widely through the body via blood circulation. Transport between cells through cell membranes might also be possible for the hydrolysis products methanol and acetic acid
Type:
metabolism
Results:
Methanol is metabolised in the liver leading to the formation of toxic formic acid.
Type:
excretion
Results:
The main excretion route for the hydrolysis products acetic acid is urinary excretion. Methanol is, besides urinary excretion, also excreted via exhalation.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Oral absorption
Based on the results of the hydrolysis study the registered substance is expected to readily hydrolyse completely in the acidic environment of the stomach into acetic acid and methanol. Therefore, the absorption rate and the toxicity profile are believed to be triggered by the hydrolysis products acetic acid and methanol. Absorption by passive diffusion is favoured for substances with moderate log P values (between -1 and 4). With a log P of -0.77 and -0.17, methanol and acetic acid are likely to follow this route of absorption. Additionally, based on their low molecular weight (< 200 g/mol) and high water solubility, both hydrolysis products may also be absorbed by passing through aqueous pores or being carried through the epithelial barrier by the bulk passage of water.
Since no signs of toxicity were observed in the acute oral toxicity study in rats (Hüls AG 1995a), this study does not give any indication regarding oral absorption.
Taken together, based on the physical-chemical properties of TMOA and its hydrolysis products acetic acid and methanol an oral absorption rate of 100 % is assumed.

Dermal absorption
Absorption in the stratum corneum is favoured for substances with a molecular weight below 100 g/mol and very unlikely for chemicals with a molecular weight above 500 g/mol. To cross the lipid-rich stratum corneum a certain degree of lipophilicity is required (Log P > 0). The registered substance has a molecular weight of 120 g/mol and a log P of 1.13. Based on the low molecular weight and the log P above 0, the registered substance might be able to be absorbed by the stratum corneum. To partition from the stratum corneum into the viable part of the epidermis, a substance must be sufficiently soluble in water (>1 mg/). TMOA has a water solubility of 10.8 g/L. Thus, penetration into the deeper, viable layers of the epidermis is likely.
In a skin irritation study according to OECD Guideline 404 TMOA was shown to have irritating effects (Hüls AG 1995c), which may additionally favour dermal absorption via uptake through a potentially compromised skin barrier. Furthermore, TMOA was tested positive in GPMT according to OECD Guideline 406 (Hüls AG 1995d). This underlines the assumption that the substance is absorbed by the viable part of the epidermis.
All in all, based on the physical-chemical properties and the toxicological profile of TMOA, a dermal absorption rate of 100 % is assumed.

Respiratory absorption
As the substance is a liquid, no inhalable particles occur. Due to the vapour pressure of 4.14 kPa at 25°C TMOA is moderately available for inhalation as a vapour. Thus, uptake of the substance into the lung cannot be excluded. Penetration to the lower respiratory tract is favoured for substances with low water solubility, which do not dissolve in the mucus lining the respiratory tract. The moderate water solubility indicates that TMOA may dissolve in the mucus to a certain degree. However, penetration of TMOA to the alveolar region of the lung cannot be ruled out. Having a log P value of 1.13, absorption directly across the respiratory tract epithelium by passive diffusion is favoured for TMOA. In addition, it is expected that TMOA will hydrolyse in the lung. The available hydrolysis study (AlessaChemie 2004) does not provide an estimate of the actual hydrolysis half-life of the substance in the respiratory tract. However, it indicates that the parent compound is only present in the lung for a limited time. The hydrolysis products acetic acid and methanol may also be absorbed by passive diffusion across the respiratory tract epithelium. Furthermore, their high water solubility also favours absorption by passing through aqueous pores or being carried through the epithelial barrier by the bulk passage of water.
Based on the available data, it can be concluded that inhalatory exposure is possible. If respiratory exposure takes place, a high systemic availability is assumed. As worst case, 100 % inhalation absorption is assumed.
Details on distribution in tissues:
Since TMOA readily hydrolyses into acetic acid and methanol, the distribution and accumulative potential of acetic acid and methanol can follow more or less independent ways. Due to their low molecular weight and high water solubility, acetic acid and methanol are expected to be widely distributed in the body via blood circulation. As small water soluble substances, acetic acid and methanol might be able to diffuse through aqueous channels and pores of cell membranes into cells.
Based on the low log P (< 3) accumulation in fatty tissue or stratum corneum is expected neither for the parent compound TMOA, nor for the hydrolysis products acetic acid and methanol.
Details on excretion:
A major excretion route of methanol from the circulatory system is exhaled air (30 to 60 % of absorbed methanol). In addition, methanol is metabolised in the liver. Here, methanol is converted to formaldehyde via alcohol dehydrogenase (ADH). This is readily oxidised to formic acid (formate) via aldehyde dehydrogenase (ALDH). Formic acid is further metabolised to carbon dioxide via tetrahydrofolate (FH4)-dependent C1 metabolism. However, the metabolism of formic acid is rather slow. Therefore, formic acid accumulates in the blood leading to acidosis. The neurotoxic effects occurring after methanol intoxication are attributed to this acidosis caused by the metabolite formic acid (Fuhrmann 2006).
Acetic acid is usually fully ionised to acetate at physiological pHs. It can be bound to Coenzyme-A forming acetyl-CoA. In this form it enters the citric acid cycle.
Besides the expiration of methanol itself and its metabolite CO2, urinary excretion is another route of elimination of methanol and formic acid. For acetic acid, urinary excretion is expected to be the main excretion route.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
formic acid

Applicant's summary and conclusion

Executive summary:

The absorption rate of TMOA is assumed to be 100 % via the oral, dermal and inhalation route. The substance and the hydrolysis products are expected to be distributed widely through the body via blood circulation. Transport between cells through cell membranes might also be possible for the hydrolysis products methanol and acetic acid. Methanol is metabolised in the liver leading to the formation of toxic formic acid. The main excretion route for the hydrolysis products acetic acid is urinary excretion. Methanol is, besides urinary excretion, also excreted via exhalation.

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