Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: expert statement
Adequacy of study:
supporting study
Study period:
2014-02-10
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: expert statement

Data source

Reference
Reference Type:
other: theoretical assessment
Title:
Unnamed
Year:
2014
Report Date:
2014

Materials and methods

Objective of study:
toxicokinetics
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline

Results and discussion

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no data
Since no toxicokinetic studies are available for MPA the assessment of the toxicokinetic behavior is based on the physico-chemical properties of the substance.

a) Absorption

Oral absorption:

The very water soluble substance MPA will readily dissolve in the gastrointestinal fluids.
Its relatively low molecular weight of 153 g/Mol, the relative high water solubility and the moderate log Pow of 0.76 favors its absorption in the gastrointestinal tract by passive diffusion. However, since the molecular weight is below 200 g/Mol the substance may also be taken up by passing through aqueous pores of the epithelial barrier.

Therefore, for evaluation of MPA in the chemical safety assessment, the oral absorption of MPA is set at 100 %.

The results of the toxicity studies with MPA do not provide any reason to deviate from this proposed degree of oral absorption.

Dermal absorption:

Making use of the data for molecular weight and the log Pow the skin permeability can be calculated according to the model of Potts and Guy (Potts, R. O., and Guy, R. H.: “Predicting skin permeability” Pharm. Res. 9, 663-669 (1992)).

The model estimates the figure for the skin permeation coefficient kp, which is a measure of the conductance of skin to a particular chemical substance from a particular vehicle. The kp was calculated to be 7.33E-04 cm/hour, therefore a relevant skin penetration may be possible for the substance MPA.

According to the criteria given in the ECHA guidance document “Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance”, November 2012 (version 1.1) 10 % dermal absorption will be considered in case MW > 500 g/Mol and log Pow <-1 and >4, otherwise 100 % dermal absorption is assumed.

In consequence, 100 % dermal absorption is proposed for MPA.

Respiratory absorption:

Deposition pattern for dusts depends on the particle sizes of the substance to be inhaled. In general, particles having an aerodynamic diameter of greater than 10 µm are deposited in the nasopharyngeal region. Particles smaller than 10 µm are capable for reaching the alveolar region of the respiratory tract.

Since the measurement of the particle size distribution of MPA indicates no particles smaller than 10 µm, deposition of MPA after inhalation predominately takes place in the nasopharyngeal region.

After deposition water soluble particles of MPA may readily diffuse/dissolve into the mucus lining of the nasopharyngeal region and may then be dermally absorbed.

b) Distribution

After absorption MPA is expected to distribute easily throughout the body based on its low molecular weight, the log Pow > 0 (some lipophilicity) and the high water solubility.

Since the log Pow is only slightly above zero, MPA can also distribute into cells to a minor extent so that the intracellular concentration may be higher than the extracellular concentration, particularly in fatty tissues.

Since the log Pow of MPA is < 4 the substance is not expected to accumulate within the body.

c) Metabolism

Once absorbed, the mammalian organism may metabolize the substance MPA by hydroxylation of appropriate carbon and nitrogen atoms which may be followed by conjugation.

Executive summary:

Since no toxicokinetic studies are available for MPA the assessment of the toxicokinetic behavior is based on the physico-chemical properties of the substance.

 

a)    Absorption

 

Oral absorption:

 

The very water soluble substance MPA will readily dissolve in the gastrointestinal fluids.

Its relatively low molecular weight of 153 g/Mol, the relative high water solubility and the moderate log Pow of 0.76 favors its absorption in the gastrointestinal tract by passive diffusion. However, since the molecular weight is below 200 g/Mol the substance may also be taken up by passing through aqueous pores of the epithelial barrier.

 

Therefore, for evaluation of MPA in the chemical safety assessment, the oral absorption of MPA is set at 100 %.

 

The results of the toxicity studies with MPA do not provide any reason to deviate from this proposed degree of oral absorption.

 

Dermal absorption:

The maximum absorbed quantity into the skin was determined as 2.44 µg.cm-2for MPA after 24 hours contact with the skin. This corresponds to 0.21 % of the applied dose MPA.

Based on these results, it can be stated that there will be a negligible transport of MPA into or through human skin.

 

 

Respiratory absorption:

 

Deposition pattern for dusts depends on the particle sizes of the substance to be inhaled. In general, particles having an aerodynamic diameter of greater than 10 µm are deposited in the nasopharyngeal region. Particles smaller than 10 µm are capable for reaching the alveolar region of the respiratory tract.

 

Since the measurement of the particle size distribution of MPA indicates no particles smaller than 10 µm, deposition of MPA after inhalation predominately takes place in the nasopharyngeal region.

 

After deposition water soluble particles of MPA may readily diffuse/dissolve into the mucus lining of the nasopharyngeal region and may then be dermally absorbed.

 

b)   Distribution

 

After absorption MPA is expected to distribute easily throughout the body based on its low molecular weight, the log Pow > 0 (some lipophilicity) and the high water solubility.

 

Since the log Pow is only slightly above zero, MPA can also distribute into cells to a minor extent so that the intracellular concentration may be higher than the extracellular concentration, particularly in fatty tissues.

 

Since the log Pow of MPA is < 4 the substance is not expected to accumulate within the body.

 

c)    Metabolism

 

Once absorbed, the mammalian organism may metabolize the substance MPA by hydroxylation of appropriate carbon and nitrogen atoms which may be followed by conjugation.