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Link to relevant study record(s)

Reference
Endpoint:
dermal absorption
Type of information:
(Q)SAR
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification
Justification for type of information:
2. MODEL (incl. version number)
Potts and Guy prediction model

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
The physicochemical parameters of MW, Log P and saturated aqueous solubility have been used. An output of predicted steady-state flux has been calculated.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
QSPeRs are statistically-derived linear and non-linear relationships between the steady-state permeability of a compound, usually measured from water, and various physicochemical descriptors and/or structural properties of the molecule. Typically, the main input parameter is the octanol:water partition coefficient. The dermal absorption measurement that has been most commonly used in QSAR modelling is the permeability coefficient Kp, because it characterises the steady-state permeation rate of a chemical from a specific vehicle through a given membrane. Although Kp is not directly suitable for application in risk assessment, it can be used in conjunction
with measured (or estimated) solubility in the same vehicle (e.g. water) to predict a maximum flux through the skin. Also, it can be combined in mathematical models with partition coefficient values for the skin to estimate non-steady state or finite dose absorption (IPCS, 2006). The prediction model used in this investigation for a set of methacrylate chemicals is based on an established model (Potts and Guy, 1992), using data derived with human epidermal membranes.
Categorisation is based upon the dermal absorption database developed at the laboratory between 1992 and 2012.

5. APPLICABILITY DOMAIN
no data

6. ADEQUACY OF THE RESULT
In a risk assessment context, QSPeRs are often used to identify chemicals that need further testing to define their likely dermal absorption potential in man more accurately. For example, if a new chemical belongs to a class of compounds known to be toxic, a simple QSPeR assessment may identify whether the risk is likely to be greater or less than the standards that already have sound in vitro or in vivo toxicological assessments. This wouldn’t necessarily negate further testing, but it can be very useful to reduce the number of compounds that require the more costly and time-consuming studies to establish the systemic exposure following dermal application.
Qualifier:
no guideline followed
Principles of method if other than guideline:
The physicochemical parameters of MW, Log P and saturated aqueous solubility have been used in the evaluation of 56 methacrylate compounds. An output of predicted steady-state flux was calculated using the principles defined in the Potts and Guy prediction model. (Potts RO and Guy RH (1992). Predicting Skin Permeability. Pharm. Res. 9(5): 663- 669)
GLP compliance:
no
Details on test animals or test system and environmental conditions:
not applicable; in silico modelling
Type of coverage:
other: not applicable; in silico modelling
No. of animals per group:
not applicable; in silico modelling
Absorption in different matrices:
predicted flux: 1.366 µg/cm²/h; the relative dermal absorption is low

Based on a molecular weight of 144.08 g/mol and a log Kow of 1.00, the predicted flux of MTMA is 1.366 µg/cm²/h; the relative dermal absorption is low.

Conclusions:
The dermal absorption of MTMA is predicted to be low; the predicted flux is 1.366 µg/cm²/h.
Executive summary:

The dermal absorption (steady-state flux) of MTMA has been estimated by calculation using the principles defined in the Potts and Guy prediction model.

Based on a molecular weight of 144.08 g/mol and a log Kow of 1.00, the predicted flux of MTMA is 1.366 µg/cm²/h; the relative dermal absorption is low.

Description of key information

MTMA is likely to be absorbed by all routes. The ester is rapidly hydrolysed by carboxylesterases to methacrylic acid (MAA) and Methoxyethanol. MAA is subsequently cleared rapidly from blood by standard physiological pathways, with the majority of the administered dose being exhaled as CO2. Methoxyethanol can be oxidised to the corresponding carboxylic acid and excreted via the urine. 
Based on physicochemical properties, no potential for bioaccumulation is to be expected.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

Absorption

Oral absorption

The physicochemical properties of MTMA (log P = 1.3) and the molecular weight of 144.08 g/mol are in a range suggestive of absorption from the gastro-intestinal tract subsequent to oral ingestion.

For chemical safety assessment an oral absorption rate of 100% is assumed as a worst case default value in the absence of other data.

Dermal absorption

Based on a QSAR Prediction of Dermal Absorption (extract from Heylings JR, 2013) MTMA is predicted on the basis of their molecular weight and lipophilicity to have a relatively low ability to be absorbed through the skin. The predicted flux was1.366 μg/cm²/h.

However, for chemical safety assessment, a dermal absorption rate of 100% was assumed as worst case default value.

Inhalation absorption

Due to the low vapour pressure of MTMA (22.3 Pa at 20°C), exposure via inhalation is unlikely. For chemical safety assessment an inhalation absorption rate of 100% is assumed as a worst case default value in the absence of other data. By default, twice as high absorption is assumed compared to oral absorption in accordance with th eGuidance on Information Requirements and Chemical Safety Assessment, R8 (Extrapolation oral to inhalation: AF=2).

Distribution

As a small molecule a wide distribution can be expected. No information on potential target organs is available.

Metabolism and excretion

Ester hydrolysis is the primary step in the metabolism of methacrylate esters. The esters are rapidly hydrolysed by carboxylesterases.Those are a group of non-specific enzymes that are widely distributed throughout the body and are known to show high activity within many tissues and organs, including the liver, blood, GI tract, nasal epithelium and skin. Those organs and tissues that play an important role and/or contribute substantially to the primary metabolism of the short-chain, volatile, methacrylate esters are the tissues at the primary point of exposure, namely the nasal epithelia and the skin, and systemically, the liver and blood.

The alcohol, Methoxyethanol can be oxidised to Methoxyacetic acid and excreted via the urine (Mebus et al, 1992; Miller RR, 1987).

Methacrylic acid is subsequently cleared rapidly from blood and, as indicated by studies with MMA, this metabolism is by standard physiological pathways, with the majority of the administered dose being exhaled as CO2.

As the esters will not survive first pass metabolism in the liver, excretion of the parent compound is of no relevance.

 

Reference

Mebus CA et al. (1992) 2-methoxyethanol metabolism in pregnant CD-1 mice and embryos. Toxicol Appl Pharmacol, 112, 87-94

Miller RR (1987). Metabolism and distribution of glycol ethers. Drug Metab Rev, 18(1), 1-22