Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
calculation (if not (Q)SAR)
Adequacy of study:
key study
Study period:
February 2018
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
accepted calculation method
Justification for type of information:
The calculation of acute toxicity values for N,N-BIS(2-HYDROXYETHYL)-P-PHENYLENEDIAMINE SULFATE is based on the current understanding and knowledge of the test substance.

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2018
Report Date:
2018

Materials and methods

Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
Using current knowledges and available experimental results on the test item, extrapolation calculation were performed in order to determine LC50inhalation and potential local effect on rats.
Test type:
other: extrapolation calculation.
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
light grey powder

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
0.9 mg/L air
Based on:
test mat.
Exp. duration:
4 h

Any other information on results incl. tables

Calculations:

Maximum volume of exposure in 4 hours:

0.074 L/min x 60 min x 4 hours = 17.76 L

Maximum achievable exposure regarding required 5 mg/L for 4 hours (OECD 403):

17.76 L x 5 mg/L = 88.8 mg/rat

88.8 mg/0.250 kg bw = 355 mg/kg bw

(caveat: this value is above the determined oral LD50 value)

Determination of the correction factor oral vs. inhalation route:

Ratio of 60% oral : 100% inhalation = 0.6

Determination of the LC50 calc inhal.:

[(107 mg/kg bw x 0.250 kg bw)/17.76L] x 0.6 = 0.90 mg/L

Hence, the LC50 for inhalation route was calculated at 0.90 mg/L

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

1201 mg = 100 %

0.90 mg/L air = 0.07% (w/w)

The concentration of 0.07% of N,N-BIS(2-HYDROXYETHYL)-P-PHENYLENEDIAMINE SULFATE is 14.3-fold lower than the highest diluted concentration tested in the in the rabbit Draize test (1%), at which concentration no irritation was observed.

Applicant's summary and conclusion

Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
Based on the LC50, calc, inhalation value, N,N-BIS(2-HYDROXYETHYL)-P-PHENYLENEDIAMINE SULFATE should be classified as Acute Tox Cat.3; H332: “Toxic if inhaled”, according to the CLP criteria.
Executive summary:

N,N-BIS(2-HYDROXYETHYL)-P-PHENYLENEDIAMINE SULFATE is 1,4-phenylenediamine with a single methoxy-methyl substituent on the benzene ring in ortho position. Therefore, it is a member of the p-phenylenediamine family. 2-METHOXY-METHYL-P-PHENYLENEDIAMINE is an ingredient used in oxidative hair coloring products.

Based on the available in vivo acute toxicityand OECD guideline compliant repeat dose toxicity and genotoxicity studies performed to measure MTD doses on N,N-BIS(2-HYDROXYETHYL)-P-PHENYLENEDIAMINE SULFATE,) to compare the impact of different exposure routes for systemic toxicity (ADME), the acute oral toxicity could be determined, as well as its acute inhalation toxic potential.

The acute oral toxicity of N,N-BIS(2-HYDROXYETHYL)-P-PHENYLENEDIAMINE SULFATE was investigated in rats in three studies and was determined to be between 107 and 427 mg/kg bw. These studies were not compliant with the OECD 423 test guideline but were considered to be useful for evaluation and, moreover, were confirmed using data from 28-Day repeated dose and UDS studies. For the calculations of the inhalation toxicity, an oral LD50 of 107 mg/kg bw was used for the route extrapolation calculations.

The acute inhalational toxicity of N,N-BIS(2-HYDROXYETHYL)-P-PHENYLENEDIAMINE SULFATE was determined using in vitro data from Caco-2 studies and the correlation of permeability in these assays to in vivo oral to estimate oral absorption. The predicted in vivo oral bioavailability was estimated to be between 20% and 60% of the applied dose. The oral bioavailability of structurally similar chemicals was almost 100%; therefore, the upper value of 60% was used for N,N-BIS(2-HYDROXYETHYL)-P-PHENYLENEDIAMINE SULFATE. Using this value, the calculated LC50 for inhalation (LC50 calc inhal.) was calculated to be 0.90 mg/L. When this concentration is combined with the results of in vivo eye irritation studies it can be concluded that N,N-BIS(2-HYDROXYETHYL)-P-PHENYLENEDIAMINE SULFATE would not have a local effect in the lungs.

Based on the LC50, calc, inhalation value, N,N-BIS(2-HYDROXYETHYL)-P-PHENYLENEDIAMINE SULFATE should be classified as Acute Tox Cat.3; H332: “Toxic if inhaled”, according to the CLP criteria.