Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
calculation (if not (Q)SAR)
Remarks:
Migrated phrase: estimated by calculation
Adequacy of study:
weight of evidence
Study period:
2017
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable calculated/extrapolated data

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2017
Report date:
2017

Materials and methods

Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
Based on the available in vivo OECD guideline compliant studies on 2-METHOXY-METHYL-PPHENYLENEDIAMINE SULFATE, performed to measure MTD doses (genotoxicity) to compare the impact of different exposure routes for systemic toxicity (ADME), the acute oral toxicity could be determined, as well as its acute dermal and acute inhalation toxic potential.
The pre-clinical toxicity studies of 2-METHOXY-METHYL-P-PHENYLENEDIAMINE were carried out with two forms, namely the sulfate salt and the free base (Ref 1). The toxic potential of both forms is attributable to the free base component. Therefore, the studies carried out with the sulfate salt were also taken into consideration for the risk assessment of the free base. In all studies carried out with the sulfate salt, the concentrations used were converted to the concentration of the free base by applying a conversion factor of 0.61. This value is related to the molecular weight and content of the free base in each form. The same conversion factor was used here to convert the inhalation and dermal acute toxicity values for the sulfate salt to the free base. For the sulfate salt and the free base forms of 2-METHOXY-METHYL-P-PHENYLENEDIAMINE, the maximal water and DMSO solubility values are higher than the highest concentration used in dosing solutions for the toxicological studies. Therefore, no adjustment for the solubility of the two forms of 2-METHOXY-METHYL-P-PHENYLENEDIAMINE is needed.
The acute oral toxicity of 2-METHOXY-METHYL-P-PHENYLENEDIAMINE SULFATE was determined based on the maximum tolerated dose (MTD) after oral application in in vivo genotoxicity studies in rats carried out with the sulfate salt.

For the dermal end point, the data derived from the ADME study (with respect to the duration of test item and animal number) was in line with the OECD guideline 402 for acute dermal toxicity. The approach to determine dermal toxicity by using oral data is accepted by the German and EU regulatory agencies and is based on the current state-of-the-art science. For the determination of the acute dermal toxicity, the bioavailability after topical application was used, which is lower than the oral bioavailability, as demonstrated by kinetics data.
Test type:
other: Estimated data by calculation
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-(methoxymethyl)benzene-1,4-diamine
EC Number:
679-526-3
Cas Number:
337906-36-2
Molecular formula:
C8H12N2O
IUPAC Name:
2-(methoxymethyl)benzene-1,4-diamine
Constituent 2
Reference substance name:
2-METHOXY-METHYL-P-PHENYLENEDIAMINE
IUPAC Name:
2-METHOXY-METHYL-P-PHENYLENEDIAMINE
Details on test material:
- Name of test material: 2-METHOXY-METHYL-P-PHENYLENEDIAMINE
2-METHOXY-METHYL-P-PHENYLENEDIAMINE is 1,4-phenylenediamine with a single methoxy-methyl substituent on the benzene ring in ortho position.

Results and discussion

Effect levelsopen allclose all
Key result
Sex:
not specified
Dose descriptor:
LD50
Effect level:
ca. 366 mg/kg bw
Based on:
other: kinetic based calculation
Remarks:
free base
Remarks on result:
other: Dermal LD50 value for 2-METHOXY-METHYL-P-PHENYLENEDIAMINE free base
Key result
Sex:
not specified
Dose descriptor:
LD50
Effect level:
ca. 600 mg/kg bw
Based on:
other: kinetic based calculation
Remarks:
sulfate salt
Remarks on result:
other: Dermal LD50 value for 2-METHOXYMETHYL- PPHENYLENE DIAMINE SULFATE (sulphate salt)

Applicant's summary and conclusion

Interpretation of results:
Category 3 based on GHS criteria
Remarks:
Migrated information
Conclusions:
For the dermal end point, the data derived from the ADME study (with respect to the duration of test item and animal number) was in line with the OECD guideline 402 for acute dermal toxicity. The approach to determine dermal toxicity by using oral data is accepted by the German and EU regulatory agencies and is based on the current state-of-the-art science. For the determination of the acute dermal toxicity, the bioavailability after topical application was used, which is lower than the oral bioavailability, as demonstrated by kinetics data. The calculated LD50 for dermal toxicity (LD50 calc dermal) was 600 mg/kg bw and 366 mg/kg bw for the sulfate salt and free base, respectively.
Executive summary:

Based on the available acute oral toxicity and toxicokinetics data for 2-METHOXY-METHYL-PPHENYLENEDIAMINE SULFATE, the acute dermal and inhalation toxic potential for the sulfate and free base forms of 2-METHOXY-METHYL-P-PHENYLENEDIAMINE could be calculated.

As demonstrated by the toxicokinetics data, the bioavailability after application to the skin is lower than the oral bioavailability. The calculated LD50 value for the dermal toxicity of 2-METHOXY-METHYL-PPHENYLENEDIAMINE is 366 mg/kg bw. Therefore, it should be classified as Acute Tox Cat.3; H311: “Toxic in contact with skin”, according to the Globally Harmonized System of Classification and Labeling (GHS).

To confirm the scientific accuracy of the calculation/extrapolation method used here to evaluate the acute dermal and inhalation toxicity potential for both, the free base and the sulfate salt of 2-METHOXY-METHYL-PPHENYLENEDIAMINE, extrapolated results were compared with experimental values obtained with the two structurally similar compounds, p-phenylenediamine (Colipa No. A007) and toluene-2,5- diamine (Colipa No. A005). The acute oral, dermal and inhalation values for 2-METHOXY-METHYLP-PHENYLENEDIAMINE SULFATE were consistent with the measured values of acute inhalational toxicity for p-phenylenediamine and with the calculated values for toluene-2,5-diamine. In addition, a scientific expert/CRO provides an expert statement that the current dataset allows the calculation of scientifically robust LD50 values which in line with the OECD guideline for acute toxicity testing (OECD 423) and calculation of scientifically robust dermal LD50 and inhalation LC50 values, based on previously conducted in vivo studies and ADME data from which an oral LC50 value was derived.