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Toxicological information

Acute Toxicity: dermal

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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

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
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 mgeqx h/l) and dermal application (33 mg/kg bw in formulation: 2.27 mgeqx h/l). Following 2.5 mg/kg bw the AUC was 8.53 mgeqx 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)

LD50 calcdermal: 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.