2-methyl-p-phenylenediamine

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

calculation (if not (Q)SAR)

Remarks:

Migrated phrase: estimated by calculation

Adequacy of study:

key study

Study period:

2012

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable calculated/extrapolated data

Data source

Reference

Reference Type:

other: Expert opinion

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

To assess the acute dermal toxicity of toluene-2,5-diamine, a kinetic based calculation was done. The kinetic data were derived from various kinetic studies, and the details of the test methods and the results are provided in this summary (refer to executive summary for details). The derived data were consistent with the determined acute toxicity values (derived by in-vivo studies) from p-phenylenediamine, the most appropriate analogue for toluene-2,5-diamine.

Test type:

other: Estimated data by calculation

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-methyl-p-phenylenediamine

EC Number:

202-442-1

EC Name:

2-methyl-p-phenylenediamine

Cas Number:

95-70-5

Molecular formula:

C7H10N2

IUPAC Name:

2-methylbenzene-1,4-diamine

Constituent 2

Reference substance name:

TOLUENE-2,5-DIAMINE

IUPAC Name:

TOLUENE-2,5-DIAMINE

Test material form:

not specified

Details on test material:

- Name of test material: Toluene-2,5-diamine is 1,4-phenylene diamine with a single methyl substituent on the benzene ring. Therefore, it is a member of the p-phenylenediamine family

Results and discussion

Effect levels

Sex:

not specified

Dose descriptor:

LD50

Effect level:

3 520 mg/kg bw

Based on:

other: kinetic based calculation

Remarks on result:

other: The calculated dermal LD50 for toluene-2,5-diamine can be assumed to be > 2000 mg/kg bw, which is consistent with the LD50 dermal for the analogue, p-phenylenediamine

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated informationCriteria used for interpretation of results: EU

Conclusions:

Based on the available acute oral toxicity and kinetic data for toluene-2,5-diamine, the extrapolated acute dermal toxicity of toluene-2,5-diamine was 3520 mg/kg bw, while the determined LD50 dermal for p-phenylenediamine is > 7940 mg/kg bw. In conclusion, the LD50 dermal for toluene-2,5-diamine can be assumed to be > 2000 mg/kg bw, which is consistent with the LD50 dermal for the analogue, namely p-phenylenediamine

Executive summary:

To assess the acute dermal and inhalational toxicity of toluene-2,5-diamine, a kinetic based calculation was done. The kinetic data were derived from various kinetic studies, and the details of the test methods and the results are provided in the SCCS Opinion1479/12, 26 – 27June 2012.In addition, the calculated data for toluene-2,5-diamine were compared with those of the most appropriate analogue, the p-phenylenediamine (refer to below table).

COLIPA Number	Chemical Name	CAS Number	Acute Toxicity
			Oral LD50	Dermal LD50	Inhalation LC50
Colipa No. A005	Toluene-2,5-Diamine	95-70-5 (free base)	102 mg/kg bw (rat)	> 2000 mg/ kg bw (rat, extrapolated)	0.99 mg/l,  (4h, rat, extrapolated)
Colipa No. A007	p-phenylenediamine	106-50-3 (free base)	80-100 mg/kg bw (rat)	> 7940 mg/kg bw (male/female rabbit)	0.92 mg/L air (4 h ,rat)

Studies used for the determination of acute toxicity of TOLUENE-2,5-DIAMINE:

Acute Oral Toxicity study result

LD₅₀oral: 102 mg/kg bw in the rat (CFY strain); “The acute median lethal oral dose was calculated to be 102 mg/kg bw (95% confidence limits of 69-152 mg/kg bw)”

Toxicokinetic study results in Sprague Dawley rats:

Dose levels:

IV: 2.5 mg/kg bw

Oral: 2.5, 25 mg/kg bw

Dermal:0.5 mg/cm² equal to 33.3 mg/kg bw

Bioavailability, assuming 100% bioavailability IV

Oral dosing: 69 %

Dermal dosing: 2 %

The studies are summarized as follows in SCCS 1479/12:

“In toxicokinetic studies with Sprague-Dawley rats the comparison of AUCs showed differences between oral (25 mg/kg bw: 112 mg_eqx h/l) and dermal application (33 mg/kg bw in formulation: 2.27 mg_eqx h/l). Following 2.5 mg/kg bw the AUC was 8.53 mg_eqx h/l. The bioavailability (derived from comparison to iv administration) after oral dosing of 10 mg/kg bw was 69% while 2% bioavailability was found after dermal administration in a formulation.”

This summary provides calculation ofextrapolation of the acute dermal toxicity of toluene-2,5-diamine. The summary of calculation of extrapolation of the acute inhalation toxicity is provided under section 7.2.2 of IUCLID.

Extrapolation of the acute dermal toxicity of TOLUENE-2,5-DIAMINE:

TOLUENE-2,5-DIAMINE LD₅₀oral = 102 mg/kg bw in the rat

Oral bioavailability = 69% (at 25.0 mg/kg bw, using the data from the toxicokinetic study in Sprague Dawley rats)

Dermal bioavailability =2% (at 33.3 mg/kg bw)

Calculation:

Determination of the correction factor oral vs. dermal route

69 % oral vs. 2 % dermal = 34.5 (69 : 2 = 34.5)

LD_{50 calc}dermal: 102 mg/kg bw x 34.5 = 3520 mg/kg bw

Thus, the calculated LD₅₀dermal for toluene-2,5-diamine is 3520 mg/kg bw, while the determined LD₅₀dermal for p-phenylenediamine is > 7940 mg/kg bw.

The calculated dermal toxicity is >2000 mg/kg and does not support the official classification of toluene-2,5-diamine as Acute Tox Cat 4; H312. The calculated classification as not harmful in contact with skin is the same as that determined for the analoguep-phenylenediamine based on a rat study. This is also in contrast to the official classification ofp-phenylenediamine as Acute Tox 3;H311 in Annex VI of the CLP regulation. However, the official classification fortoluene-2,5-diamine as laid down in Annex VI of the CLP regulation is not based on animal data, as stated by the ECHA

ASSESSMENT OF VALIDITY:

 

Since theWeight of Evidence Approach (WoE)used was considered as sufficiently robust to determine the acute dermal toxic potential of toluene-2,5-diamine, the performance of an animal test for hazard identification purposes was considered to be not justified.

Based on the REACH regulation “REACH VO - Annex VIII, 8.5.3., (3).), testing of the dermal route is only required, if there is a potential for a significant rate of absorption through the skin. The ADME data demonstrated, that the oral bioavailability of toluene-2,5-diaminein rats is 34.5 times higher than the dermal bioavailability

In addition, the completion of acute toxicity studies ontoluene-2,5-diamineas an ingredient used in cosmetic products would not be considered to comply with the EU regulations regarding animal testing. Furthermore, applying WoE complies with the REACH regulation to avoid animal testing. The validity of the WoE/extrapolation approach used in order to estimate the acute toxicity potential of toluene-2,5-diamineby dermal routes was finally confirmed by the comparison of the extrapolated values on toluene-2,5-diaminewith experimental values obtained on the primary member of thep-phenylenediamine family,p-phenylenediamine.

In conclusion, the LD₅₀dermal for toluene-2,5-diaminecan be assumed to be > 2000 mg/kg bw, which is consistent with the LD₅₀ dermal for the analogue, namely p-phenylenediamine.