2-methyl-p-phenylenediamine sulfate

Endpoint summary

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1975

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given, comparable to guideline/standards

Principles of method if other than guideline:

Acute oral toxicity or LD50 value was determined by oral administration of test substance to five dose groups of rats. Subsequently, observations of effects such as clinical signs, cage side observation and mortality are made for 14 d. The test method employed in this study is comparable to OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

no

Remarks:

pre-dates GLP

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: CFY strain

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Not reported
- Age at study initiation: Not reported
- Weight at study initiation: 98-120 g
- Fasting period before study: Overnight before treatment
- Housing: Not reported
- Diet: Not reported
- Water: Not reported
- Acclimation period: Not reported

ENVIRONMENTAL CONDITIONS: No details on environmental condition were provided in the report

Route of administration:

oral: gavage

Vehicle:

other: aqueous sodium sulphite (0.05%)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 10% Toluene-2, 5-diamine
- Amount of vehicle: 2.5 mL/kg bw
- Justification for choice of vehicle: Not reported
- Lot/batch no.: Not reported
- Purity: Not reported

MAXIMUM DOSE VOLUME APPLIED: 0.64-2.5 mL/kg bw

DOSAGE PREPARATION: 10% solution of test substance was prepared in aqueous sodium sulphite (0.05%)

Doses:

0, 64, 100, 160, and 250 mg/kg bw

No. of animals per sex per dose:

Five males and five females

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 d
- Frequency of observations and weighing: Daily for 14 days, body weights were taken prior to dosing, and on 7th and 14th day of dosing.
- Necropsy of survivors performed: Yes
- Other examinations performed: Clinical signs of toxicity, mortality, Autopsy of animals died during the study.

Statistics:

The LD50 and its 95% confidence limits were calculated by the method of Weil C.S. (1952) Biometrics 8, 249.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

102 mg/kg bw

Based on:

test mat.

95% CL:

69 - 152

Mortality:

3/5 males and 0/5 females at 64 mg/kg
4/5 males and 3/5 females at 100 mg/kg
0/5 males and 5/5 females at 160 mg/kg
5/5 males and 4/5 females at 250 mg/kg

No mortality with vehicle control

Clinical signs:

other: Signs of reaction to treatment, observed shortly after dosing, which included: lethargy, piloerection, ataxia and increased salivation. These sign were accompanied by increased respiratory rate in rats treated at 100mg/kg and decreased respiratory rate in

Gross pathology:

Mortality was observed within 1 h to 22 h of treatment. Autopsy of these animals revealed slight heamorrhage of the lungs, pallor of the spleen, darkening of the liver and injection of peritoneal blood vessels.

Terminal autopsy findings were normal

Other findings:

- Recovery of animals: Recovery of survivors, as judged by external appearance and behavior, was apparently complete within 5 days of treatment.

- Organ weights: Not reported
- Histopathology: Not reported
- Potential target organs: Not reported

Table1: Mortality data for group of rats dosed orally with toluene-2,5-diamine (range finding study) (study # 71169)

Dosage (mg/kg bw)	Mortality ratio (no. of deaths/no. of animal dosed)			Time of death after dosing
	Male	Female	Combined
0	0/2	0/2	0/4	-
64	0/2	0/2	0/4	-
250	2/2	1/2	3/4	<21 h
1000	2/2	2/2	3/4	<2 h

- The result of preliminary range finding study indicated that median lethal oral dose (LD50) was in range of 64 to 250 mg/kg bw

Table 2: Mortality ratio and of group mean bw (g) of rats dosed orally with toluene-2,5-diamine (study # 71169)

Sex	Dosage	Bodyweight (g) at			Mortality ratio (no. of deaths/no. of animal dosed)	Time of death after dosing
		Dosing	1 wk	2 wk
Male	0	101	177	222	0/5
	64	112	178	229	3/5	< 22 h
	100	102	167	234	4/5	< 2 h
	160	116	174	242	0/5
	250	106	Died		5/5	< 21 h
Female	0	106	153	171	0/5
	64	113	148	172	0/5
	100	107	136	174	3/5	< 2
	160	104	Died		5/5	< 22
	250	106	152	180	4/5	< 21

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The acute oral LD50 of Toluene-2, 5-diamine in 0.05% aqueous sodium sulphite vehicle was determined to be 102 mg/kg bw (95% CI= 69-150 mg/kg bw).

Executive summary:

The acute oral toxicity of Toluene-2, 5-diamine was determined following OECD Guideline 401 (Acute Oral Toxicity)

The study was designed to determine acute oral LD50 of Toluene-2, 5-diamine in 0.05% aqueous sodium sulphite vehicle when dosed to group of rats by oral gavage.

The study involved 5 groups of 10 rats each (5 males / 5 females) weighing 98 to 120 g, starved overnight before treatment with group specific concentration (0, 64, 100, 160 and 250 mg/kg bw) of Toluene-2, 5-diamine.

The selection of various concentrations was based on results from preliminary (range finding) study which indicated that median lethal oral dose (LD50) was in range of 64 to 250 mg/kg bw.

Post treatment, rats were observed for 14 days to record mortality and signs of toxicity. All rats that died during observation period were examined macroscopically to identify the target organ and those surviving were sacrificed terminally to detect possible residual damage.

Signs of toxicity were observed shortly after treatment and included lethargy, piloerection, ataxia and increased salivation. These signs were accompanied by increased respiratory rate in rats treated at 100mg/kg and decreased respiratory rate in rats treated above 100 mg/kg bw. Mortality was observed within 1 h to 22 h of treatment. Autopsy revealed slight heamorrhage of the lungs, pallor of the spleen, darkening of the liver and injection of peritoneal blood vessels. However, terminal autopsy findings of surviving animals were normal.

The recovery of surviving animals was apparently complete within 5 d of treatment as exhibited by external appearance and behavior. A slight depression in body weight gain during first week was observed in female rats treated with 64 and 100 mg/kg bw and all surviving male rats. However, bodyweight gain returned to normal during second week.

The acute median oral LD50 of Toluene-2, 5-diamine in 0.05% aqueous sodium sulphite vehicle was found to be 102 mg/kg bw (95% CI= 69-150 mg/kg bw).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

102 mg/kg bw

Quality of whole database:

reliability 2

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

weight of evidence

Study period:

2012

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable calculated/extrapolated data

Qualifier:

no guideline required

Principles of method if other than guideline:

To assess the acute inhalational toxicity of toluene-2,5-diamine (free base and sulphate salt), 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

Sex:

not specified

Dose descriptor:

LC50

Effect level:

0.99 mg/L air

Based on:

other: kinetic based calculation

Exp. duration:

4 h

Remarks on result:

other: The calculated inhalational LC50 of 0.99 mg/L for toluene-2,5-diamine is comparable to the determined value for p-phenylenediamine (0.92 mg/L)

Sex:

not specified

Dose descriptor:

LC50

Effect level:

1.77 mg/L air

Based on:

other: kinetic based calculation

Exp. duration:

4 h

Remarks on result:

other: The calculated inhalational LC50 of 1.77 mg/L for toluene-2,5-diamine sulphate salt is comparable to the determined value for p-phenylenediamine (0.92 mg/L)

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

Criteria 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 inhalation toxicity (4 h, LC50) of toluene-2,5-diamine was 0.99 mg/L for the free base and 1.77 mg/l for the sulphate salt. This value is comparable to the determined value for p-phenylenediamine (0.92 mg/L).

Executive summary:

To assess the acute inhalational toxicity of toluene-2,5-diamine (free base and sulphate salt) , 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 Opinion 1479/12, 26 – 27June 2012.In addition, the calculated data for toluene-2,5-diamine (free base and the sulphate salt) 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. A005	Toluene-2,5-diaminesulphate	615-50-9	183 mg/kg bw (rat, extrapolated)	> 2000 mg/kg bw (rat, extrapolated)	1.77 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:

Conversion Factor between the free base and the sulphate salt:

The toxic potential of both forms of 2 Toluene-2,5-diamine is attributable to the free base component. Therefore, study results derived with one of the two forms of Toluene-2,5-diamine, namely the free base or the sulphate salt, can be converted to the other form by applying a conversion factor that is related to the molecular weight and content of the free base in each form.

Molar Mass_sulfate: 218.23 g/mol

Molar Mass_{free base}: 122.71 g/mol

Conversion factor free base → sulphate = 1.79

Conversion factor sulphate →free base = 0.56

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)”.The study was carried out with the free base.

LD₅₀oral=102 mg/kg bw (Toluene-2,5-Diamine)

Conversion factor free base→sulphate = 1.78628

LD₅₀oral=182 mg/kg bw (Toluene-2,5-Diamine Sulphate)

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.”The Studies were carried out with the sulphate salt.

This summary provides calculation ofextrapolation of the acute inhalation toxicity of toluene-2,5-diamine. The summary of calculation of extrapolation of the acute dermal toxicity is provided under section 7.2.3 of IUCLID.

 

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

Required maximum exposure concentration to test material (OECD 403):           5 mg/L

Assumed body weight of the rat for the calculation:                                            250 g

Respiratory volume of the rat:                                                                            0.074 L/min

Required duration (OECD 403):                                                                          4 h

Ventilation in 4 hours                                                                              0.074 L/min x 60 min x 4 hour = 17.76L

Toluene-2,5-diamine LD₅₀oral = 102 mg/kg bw in the ratwith the free base

Calculation:

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

Exposure during 4 hours:17.76 L x 5 mg/L = 88.8 mg/rat

88.8 mg/0.250 kg bw = 355 mg/kg bw maximum achievable exposure

Oral Bioavailability = 69% (at 25 mg/kg bw, using the data from the toxicokinetic study in Sprague Dawley rats)

Inhalation Bioavailability: Assumed to be 100%

Determination of the correction factor oral vs. inhalation route:

69% oral vs. 100% inhalation = 0.69

LC_{50 calc}inhal. free base: 102 mg/kg bw x 0.250 kg bw x 0.69/17.76 L = 0.99 mg/L

LC_{50 calc}inhal. free base: 0.99 mg/L x 1.79 (conversion free base to sulphate) = 1.77 mg/L

LC₅₀inhal. forp-phenylenediamine = 0.92 mg/L

LC_{50 calc}inhal. for toluene-2,5-diamine     = 0.99 mg/L free base

LC_{50 calc}inhal.Toluene-2,5-diamine          = 1.77 mg/l sulphate salt

 

 

The calculated LC₅₀for toluene-2,5-diamine, namely 0.99 mg/L for the free base and 1.77 mg/L for the sulphate saltcomparable to the determined value forp-phenylenediamine (0.92 mg/L)

The calculated inhalation toxicity value for toluene-2,5-diamine is in the same order of magnitude (0.99 mg/lfor the free base and 1.77 mg/L for the sulphate salt) as the official classification of Acute Tox Cat 4; H332 in Annex VI of the CLP regulation which is being applied in case of 1 mg/L<LC₅₀≤5 mg/L (for dusts/mists).

ASSESSMENT OF VALIDITY:

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

In addition the completion of acute toxicity studies on toluene-2,5-diamine as 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-diamine by inhalation route was finally confirmed by the comparison of the extrapolated values on toluene-2,5-diamine with experimental values obtained on the primary member of the p-phenylenediamine family, p-phenylenediamine.

In conclusion, the extrapolated acute inhalation toxicity (4 h, LC50) of toluene-2,5-diamine was 0.99 mg/Lfor the free base and 1.77 mg/L for the sulphate salt. This value is comparable to the determined value for p-phenylenediamine (0.92 mg/L)

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

990 mg/m³ air

Quality of whole database:

reliability 2

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

weight of evidence

Study period:

2012

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable calculated/extrapolated data

Qualifier:

no guideline required

Principles of method if other than guideline:

To assess the acute dermal toxicity of toluene-2,5-diamine(free base and sulphate salt), 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

Sex:

not specified

Dose descriptor:

LD50

Effect level:

3 519 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

Sex:

not specified

Dose descriptor:

LD50

Effect level:

6 299 mg/kg bw

Based on:

other: kinetic based calculation

Remarks on result:

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

Interpretation of results:

GHS criteria not met

Remarks:

Criteria 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 can be assumed to be around 3519 mg/kg bw for the free base and 6299 mg/kg bw for the sulphate salt, while the determined LD50 dermal for p-phenylenediamine is > 7940 mg/kg bw.
In conclusion, the LD50 dermal for both forms of toluene-2,5-diamine is >2000 mg/kg bw.

Executive summary:

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 the SCCS Opinion 1479/12, 26 – 27June 2012. In addition, the calculated data for toluene-2,5-diaminewere 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. A005	Toluene-2,5-Diamine sulphate	615-50-9	183 mg/kg bw (rat, extrapolated)	> 2000 mg/kg bw (rat, extrapolated)	1.77 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:

Conversion Factor between the free base and the sulphate salt:

The toxic potential of both forms of 2 Toluene-2,5-diamine is attributable to the free base component. Therefore, study results derived with one of the two forms of Toluene-2,5-diamine, namely the free base or the sulphate salt, can be converted to the other form by applying a conversion factor that is related to the molecular weight and content of the free base in each form.

Molar Mass_sulfate: 218.23 g/mol

Molar Mass_{free base}: 122.71 g/mol

Conversion factor free base → sulphate = 1.79

Conversion factor sulphate →free base = 0.56

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)”.The study was carried out with the free base.

LD₅₀oral=102 mg/kg bw (Toluene-2,5-Diamine)

Conversion factor free base→sulphate = 1.78628

LD₅₀oral=182 mg/kg bw (Toluene-2,5-Diamine Sulphate)

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-DIAMINELD₅₀oral = 102 mg/kg bw in the ratwith the free base

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 free base: 102 mg/kg bw x 34.5 = 3519 mg/kg bw

LD_{50 calc}dermal sulphate: 3519 mg/kg bw x 1.79 (conversion free base to sulphate) = 6299 mg/kg bw

 

Thus, the calculated LD₅₀dermal for toluene-2,5-diamine is 3519 mg/kg bw for the free base and 6299 mg/kg bw for the sulphate salt, while the determined LD₅₀dermal for p-phenylenediamine is > 7940 mg/kg bw. This extrapolation is further supported by a dermal acute toxicity study carried out in rabbits. Even if this study was considered as insufficient for a determination of the dermal LD₅₀of TOLUENE-2,5-DIAMINE (no accordance to any guideline, not GLP compliant, no study report available, only citation of a publication, rated as Klimisch 4), the derived LD₅₀ of >5000 mg/kg bw is in accordance with the calculated values of 3519 mg/kg bw for the free base and 6299 mg/kg bw for the sulphate salt for TOLUENE-2,5-DIAMINE.

The calculated dermal toxicity is >2000 mg/kg for both forms of TOLUENE-2,5-DIAMINE (free base and sulphate salt) 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 analogue p-phenylenediamine based on a rat study.However, the latter also in contrast to the official classification of p-phenylenediamine as Acute Tox 3;H311 in Annex VI of the CLP regulation. Moreover, the official classification of toluene-2,5-diaminefor acute dermal and inhalation toxicityas laid down in Annex VI of the CLP regulation is not based on animal data, as stated by the ECHA.

ASSESSMENT OF VALIDITY:

 

Since the Weight 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-diamine in rats is 34.5 times higher than the dermal bioavailability

In addition, the completion of acute toxicity studies on toluene-2,5-diamine as 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-diamine by dermal routes was finally confirmed by the comparison of the extrapolated values on toluene-2,5-diamine with experimental values obtained on the primary member of the p-phenylenediamine family, p-phenylenediamine.

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 can be assumed to be around 3519 mg/kg bw for the free base and 6299 mg/kg bw for the sulphate salt, while the determined LD50 dermal for p-phenylenediamine is > 7940 mg/kg bw.

 

In conclusion, the LD₅₀dermal for both forms of toluene-2,5-diamine can be assumed to be > 2000 mg/kg bw, which is consistent with the LD₅₀dermal for the analogue, namely p-phenylenediamine.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

6 299 mg/kg bw

Quality of whole database:

reliability 2

Additional information

Acute oral toxicity or LD50 value was determined by oral administration of test substance to five dose groups of rats. Subsequently, observations of effects such as clinical signs, cage side observation and mortality are made for 14 d. The test method employed in this study is comparable to OECD Guideline 401 (Acute Oral Toxicity). The LD 50 = 102 mg/kg bw that mean that the subsnace is harmful by ingestion.

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 can be assumed to be around 3519 mg/kg bw for the free base and 6299 mg/kg bw for the sulphate salt.

Based on the available acute oral toxicity and kinetic data for toluene-2,5-diamine, the extrapolated acute inhalation toxicity (4 h, LC50) of toluene-2,5-diamine was 0.99 mg/L. This value is comparable to the determined value for p-phenylenediamine (0.92 mg/L). It indicate an harmful effect by inhalation

Justification for selection of acute toxicity – oral endpoint
Acute oral toxicity or LD50 value was determined by oral administration of test substance to five dose groups of rats. Subsequently, observations of effects such as clinical signs, cage side observation and mortality are made for 14 d. The test method employed in this study is comparable to OECD Guideline 401 (Acute Oral Toxicity)

Justification for selection of acute toxicity – inhalation endpoint
Based on the available acute oral toxicity and kinetic data for toluene-2,5-diamine, the extrapolated acute inhalation toxicity (4 h, LC50) of toluene-2,5-diamine was 0.99 mg/L. This value is comparable to the determined value for p-phenylenediamine (0.92 mg/L).

Justification for selection of acute toxicity – dermal endpoint
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 can be assumed to be around 3519 mg/kg bw for the free base and 6299 mg/kg bw for the sulphate salt.

Justification for classification or non-classification

 

Acute oral toxicity or LD50 value was determined by oral administration of test substance to five dose groups of rats. Subsequently, observations of effects such as clinical signs, cage side observation and mortality are made for 14 d. The test method employed in this study is comparable to OECD Guideline 401 (Acute Oral Toxicity). The LD 50 = 102 mg/kg bw that mean that the substance is toxic cat 3 by ingestion according to CLP.

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 can be assumed to be around 3519 mg/kg bw for the free base and 6299 mg/kg bw for the sulphate salt.

 

Based on the available acute oral toxicity and kinetic data for toluene-2,5-diamine, the extrapolated acute inhalation toxicity (4 h, LC50) of toluene-2,5-diamine was 0.99 mg/L. This value is comparable to the determined value for p-phenylenediamine (0.92 mg/L). It indicate an harmful effect by inhalation, warning cat 4 according to CLP