Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
other: 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:
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 and toluene-2,5- diamine. 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.
Since the Weight of Evidence Approach (WoE) used was considered as sufficiently robust to determine the acute dermal and inhalation toxic potential of 2-METHOXY-METHYL-P-PHENYLENEDIAMINE SULFATE, the performance of an animal test for hazard identification purposes was considered to be not justified. In addition, the conduct of acute toxicity studies on 2-METHOXY-METHYL-P-PHENYLENEDIAMINE as an ingredient used in cosmetic products would not be in compliance with the EU regulations regarding animal testing. Furthermore, applying WoE complies with the REACH regulation to avoid animal testing.
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:
LC50
Effect level:
ca. 1.77 other: mg/L
Based on:
other: kinetic based calculation
Remarks:
sulfate salt
Remarks on result:
other: Inhalation LC50 value for 2-METHOXY-METHYL-P-PHENYLENEDIAMINE free base
Key result
Sex:
not specified
Dose descriptor:
LC50
Effect level:
ca. 1.08 other: mg/L
Based on:
other: kinetic based calculation
Remarks:
free base
Remarks on result:
other: Inhalation LC50 value for 2-METHOXYMETHYL- PPHENYLENE DIAMINE SULFATE (sulphate salt)

Any other information on results incl. tables

Values and assumptions used in the calculations:

  • 2-METHOXY-METHYL-P-PHENYLENEDIAMINE SULFATE LD50 oral = 150 mg/kg bw in the rat
  • Oral Bioavailability = 84% (at 100 mg/kg bw, using the data from the toxicokinetics study in Wistar rats). This value was selected because incorporation of this value into Equation 5 results in a lower LC50 calc inhal. value than if the 99% value was selected (although, paradoxically, a lower absorption per se would correlate to lower systemic toxicity).
  • Required max. exposure conc. to test material (OECD 403): 5 mg/L
  • Assumed body weight of the rat: 250 g
  • Respiratory volume of the rat: 0.074 L/min
  • Required duration (OECD 403) 4 h
  • Inhalation Bioavailability (assumed, worst case assumption): 100%
  • Conversion factor from the sulfate salt to the free base 0.61

Calculations:

Maximum volume of exposure in 4 hours:

0.074 L/min x 60 min x 4 hours = 17.76 L --> Equation 1

Maximum achievable exposure regarding required 5 mg/L for 4 hours (OECD 403): 17.76 L x 5 mg/L = 88.8 mg/rat --> Equation 2

88.8 mg/0.250 kg bw = 355 mg/kg bw (caveat: this value is above the determined oral LD50 value) --> Equation 3

Determination of the correction factor oral vs. inhalation route:

Ratio of 84% oral : 100% inhalation = 0.84 --> Equation 4

Determination of the LC50 calc inhal. for the sulfate salt:

[(150 mg/kg bw x 0.250 kg bw)/ 17.76 L ]x 0.84 = 1.77 mg/L --> Equation 5

Determination of the LC50 calc inhal. for the free base:

LC50 calc inhal. for the sulfate salt x 0.61 = 1.77 x 0.61 = 1.08 mg/L --> Equation 6

Result:

LC50 calc inhal. 2-METHOXY-METHYL-P-PHENYLENEDIAMINE SULFATE = 1.77 mg/L

LC50 calc inhal. 2-METHOXY-METHYL-P-PHENYLENEDIAMINE (free base) = 1.08 mg/L

Assessment of possible local effects of 2-METHOXY-METHYL-PPHENYLENEDIAMINE in the lung

Local irritation of the lung mucosal membranes can lead to death; therefore, the potential for 2-METHOXYMETHYL-P-PHENYLENEDIAMINE to cause local lung mucous membrane effects was evaluated by comparing the LC50 calc inhal. for 2-METHOXY-METHYL-P-PHENYLENEDIAMINE with the local irritating effect measured in the in vitro Isolated Chicken Eye (ICE) Test and the conditions of the acute inhalation toxicity maximal tested dose.

Calculations:

Comparison with eye irritation effects:

2-METHOXY-METHYL-P-PHENYLENEDIAMINE tested neat in the ICE Test is irritant to eyes. 2-METHOXYMETHYL- P-PHENYLENEDIAMINE, tested at 1.83 and at 6.1% (w/w) aqueous in the ICE Test is not irritating to eyes.

Conversion of LC50 calc inhal. to % (w/w):

1 L air: 1.2041 kg/m³ = 1204.1 g/m³ = 1204100 mg/m³ = 1204100/1000 L = 1201 mg/L --> Equation 7

1201 mg = 100 %

1.77 mg/L air = 0.15% (w/w) sulfate salt

1.08 mg/L air = 0.09% (w/w) free base

The concentrations of 0.15% and 0.09% (w/w) of the sulfate salt and the free base of 2-METHOXY-METHYLP- PHENYLENEDIAMINE are 40.7- and 68-fold lower than the highest diluted concentration of the free base tested in the in the ICE Test, at which concentration no irritation was observed.

Result: The concentrations of the 2-METHOXY-METHYL-P-PHENYLENEDIAMINE sulfate salt and free base represents 0.15% and 0.09% in an aerosol, respectively. When these concentrations are combined with the results of in vitro eye irritation studies (ICE) it can be concluded that 2-METHOXY-METHYL-PPHENYLENEDIAMINE would not have a local effect in the lungs.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Remarks:
Migrated information
Conclusions:
The acute inhalational and dermal toxicity of 2-METHOXY-METHYL-P-PHENYLENEDIAMINE was determined using kinetics-based data derived from an ADME study in rats with the sulfate salt. The calculated LC50 for inhalation (LC50 calc inhal.) was 1.77 mg/L and 1.08 mg/L for the sulfate salt and free base, respectively.
Executive summary:

The calculated inhalation toxicity value for 2-METHOXY-METHYL-P-PHENYLENEDIAMINE free base (1.08 mg/L) is similar to that of p-phenylenediamine (0.92 mg/L). When these concentrations are combined with the results of in vitro eye irritation studies, it can be concluded that 2-METHOXY-METHYL-PPHENYLENEDIAMINE would not have a local effect in the lungs. Based on the LC50, calc, inhalation value, 2-METHOXY-METHYL-P-PHENYLENEDIAMINE should be classified as Acute Tox Cat.4; H332: “Harmful if

inhaled”, 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.