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Administrative data

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Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
69
Absorption rate - dermal (%):
2

Additional information

Human data on Toluene-2,5-diamine

Inin vivotoxicokinetics study by dermal route (Aylward M & Protheroe D, 1981), in Human, toluene-2,5-diamine presented different rate of absorption rate in function of the oxidative conditions of the application of formulation. For formulation I (non-oxidative conditions), the absorption was 5% of the applied dose (71 ± 9.26μgeq/cm²) while for formulation II (oxidative conditions). The absorption was 1.4% of the applied dose (20 ± 2.02μgeq/cm²).

 

·        Rat data in vivo on Toluene-2,5-diamine sulphate

ADME:

By dermal route:dermal absorption of14C-toluene-2,5-diamine sulphate was moderate and mainly excreted through urine. N-acetylation was the most important metabolic reaction for14C-toluene-2,5-diamine sulphate. (Wenker M A M., 2005).

By oral route:14C-Toluene-2,5-diamine sulphate when administered orally was extensively absorbed, readily distributed into all organs, extensively metabolized and excreted via the urine and faeces. (Wenker M A M., 2005).

14C-Toluene-2,5-diamine sulphate (Haarbraun) was absorbed and excreted quickly after oral administration, following linear kinetics at the dose levels tested. (Wenker M A M., 2005).

By intravenous route:14C-Toluene-2,5-diamine sulphate when administered intravenously was readily distributed into all organs, extensively metabolized and excreted via the urine and faeces.(Wenker M A M., 2005).

 

Pharmacokinetics

Dermal absorptionwas rapid with tmax reached at 0.5 - 1 h after dosing in all groups. Mean plasma AUC values of Toluene-2,5-diamine sulphate increased proportionally with increasing concentration after dermal application in the concentration range tested.(Van De Kerkhof E G, 2009).

 

Oral absorption:14C-Toluene-2,5-diamine sulphate (Haarbraun) was absorbed and excreted quickly after oral administration, following linear kinetics at the dose levels tested. (Wenker, 2005)

 

Intravenous route:Toluene-2,5-diamine sulphate (Haarbraun) was rapidly metabolized and therefore was difficult to detect in plasma when administered once intravenously to female Sprague Dawley rats.(Wenker M A M., 2005).

Toxicokinetics:Radiolabelled Toluene-2,5-diamine sulphate [14C] when administered to male and female Sprague-Dawley at 5 and 10 mg/kg bw showed a rapid absorption following an oral dose. (Rodrigue M E, 2010).

 

·        Rat datain vitroon Toluene-2,5-diamine sulphate

Twoin vitrostudies of reliability 2 were available on similar compound Toluene-2,5-diamine sulphate.

Metabolisation:The aim of this study was to investigate the metabolism of toluene-2,5-diaminein vitrousing three different systems:

o  a microsomal system,

o  a recombinant Cytochrome P450 isozyme system, and

o  a human hepatocyte system from four different donors. 

Toluene-2,5-diamine sulphate was acetylated in human hepatocytes. There was no evidence to suggest that toluene-2,5-diamine sulphate undergoes oxidative metabolism in human microsomes, by cytochrome P450 isoenzymes or in human hepatocytes. (Powrie R, 2005).

Metabolic stability and metabolic profile: The metabolic rate of the 2,5-diaminotoluene sulfate was extensive for human, rat and mouse primary hepatocytes. Under the conditions applied in this study, the test substance was extensively metabolized by N-acetylation in all three species, but mouse hepatocytes additionally revealed extensive hydroxylation of the 2,5-diaminotoluene sulfate. (Krebsfanger N, 2003).

Dermal absorption

Nine entries inin vitrostudies were available for skin penetration of similar compound Toluene-2,5-diamine sulphate. They were coted of reliability 2.

-         A total of 3 test formulations/solutions were evaluated in the study of Bornatowicz (2002).

o  Formulation A : 21.9 mg (actual) of the formulation, containing 1.20 mg/cm² of test substance was applied to topically to the horny layer of the skin for 30 min and subsequently washed off with Tween 20 and deionized water.

The other 2 test formulation/solutions were:

o  Formulation B: Typical hair dye formulation of pTD-sulfate with developer containing H2O2, 20.8 µg/cm² (1.72% dose) of pTD-sulfate in a hair dye formulation without hydrogen peroxide was considered as biologically available (receptor fluid: 10.7 µg/cm², remaining skin other than stratum corneum: 10.1 µg/cm2) in the cutaneous absorption (in vitro) study.

o  Solution C: Aqueous solution of pTD-sulfate in ammonia. 42.0 µg/cm² (3.94% dose) of aqueous solution of pTD-sulfate was considered as biologically available (receptor fluid: 13.3 µg/cm², remaining skin other than stratum corneum: 28.6 µg/cm²) in the cutaneous absorption (in vitro) study. (Bornatowicz N, 2002)

 

-         Toluene-2,5-diamine sulphate when applied at a dose of 0.59 mg/cm² or 0.6% to pig skin (in vitro), 4.14 ± 1.21% (24,658 ± 7186 ng/cm²) of the applied dose passed through the skin and 1.55 ± 0.89% (9261 ± 5330 ng/cm²) and 1.21 ± 0.56% (7189 ± 3321 ng/cm²) was found in the upper and lower skin respectively.(Wyss, 2001)

 

-         10.5 ± 3.2 µg/cm² of Toluene-2,5-diamine sulphate when applied at a dose of 4.6 mg/cm² as a formulation (100 mg/cm²) containing 18.4 mg (4.6%) of test material was considered as biologically available in the cutaneous absorption (in vitro) study (receptor fluid: 5.6 µg/cm2; upper dermis: 4.9 µg/cm2). (Wyss, 2004)

 

-  [14C]-Toluene 2,5-diamine sulfate was used at a concentration of 9% (w/w) in two typical oxidative hair dye formulations:

o  Formulation A containing [14C]-Toluene 2,5-diamine sulfate only

o  Formulation B containing [14C]-Toluene 2,5-diamine sulfate plus a coupler (m-aminophenol) at an equimolar concentration

These two formulations were used to prepare three types of hair dye mixture:

o  Mixture 1 (Formulation A/H2O): Formulation containing 9% [14C]-Toluene 2,5-diamine sulfate mixed with water at a ratio of 50/50.

o   Mixture 2 (Formulation A/H2O2): Formulation containing 9% [14C]-Toluene 2,5-diamine sulfate mixed with hydrogen peroxide at a ratio of 50/50.

o  Mixture 3(Formulation B/H2O2): Formulation containing 9% [14C]-Toluene 2,5-diamine sulfate and the coupler, mixed with hydrogen peroxide at a ratio of 50/50.

Formulation A : 16.11 µg/cm² (1.87% of dose) and 32.03 µg/cm² (3.44% of dose) of Toluene 2, 5-diamine sulfate in a hair dye formulation with H2O2 when applied to isolated human epidermis (only receptor fluid: 16.11 µg/cm²) and dermatomed human skin (malpighian epidermis: 11.77 µg/cm², partial dermis: 1.34 µg/cm² and receptor fluid: 18.92 µg/cm²) respectively was considered as biologically available in the cutaneous absorption (in vitro) study.

Formulation B : 37.91 µg/cm² (4.02% of dose) and 31.26 µg/cm² (3.41% of dose) of Toluene 2, 5-diamine sulfate in a hair dye formulation with water (without H2O2) when applied to isolated human epidermis (only receptor fluid: 37.91 µg/cm2) and dermatomed human skin (malpighian epidermis: 1.35 µg/cm², partial dermis: 0.21 µg/cm² and receptor fluid: 1.85 µg/cm²) respectively was considered as biologically available in the cutaneous absorption (in vitro) study. (Leclerc, 1997)

 

-         The total absorption of Toluene-2,5-Diamine Sulfate (in non oxidative formulations) in the in vitro cutaneous absorption through human skin at 0.25, 0.8, 2.4 and 7.2% concentrations was 1.75 ± 0.52 (3.65%), 16.27±2.94 (9.55%), 47.23±13.35 (9.25%) and 101.03 ± 36.67 (6.43%) µg/cm², respectively. The mean recovery of [14C]Toluene-2,5-diamine sulphate ranged from 99.18 ± 3.21 % to 102.80 ± 5.05 % of the applied dose (Mass W J M, 2009)

 

CONCLUSION:

Comment on the SCCS opinion relative to Wenker (2005) study, was:

The bioavailability in Sprague-Dawley rats (derived from comparison to i.v. administration) after oral dosing was 69% while 2% bioavailability was found after dermal administration in a formulation.

The calculation was establish form study performed on Toluene-2,5-diamine sulphate.

In physiological fluids, system exists to buffer. Therefore after systemic absorption there is no difference of the derived active species (at pH 7.4: 88.4% is completed deprotonated in base form and 11.6% singly protonated without defined counter ion).

By oral route the bioavailability of toluene-2,5-diamine would be the same than for Toluene-2,5-diamine sulphate: 69 %.

For dermal absorption, the reasoning would be different:

-         The free base as lower molecular weight than the sulphate salt, and a higher bioavailability than ionized form.

-         The skin pH is around 5.5 and the calculation tool of Marvin Sketcher according to protonation indicated :

o  At pH 4.0: 0.27% of Toluene 2,5 Diamine are present in the non ionized form

o  At pH 5.0: 2.91% of Toluene 2,5 Diamine are present in the non ionized form

o  At pH 6.0: 23.25% of Toluene 2,5 Diamine are present in the non ionized form

o  At pH 6.4: 43.24% of Toluene 2,5 Diamine are present in the non ionized form

o  At pH 7.4: 88.6% of Toluene 2,5 Diamine are present in the non ionized form

 

The “non ionized form of toluene 2,5 Diamine” is supposed to be more present when skin was treated with free base than with sulphate salt.

Nevertheless the bioavailability of toluene 2,5 Diamine for dermal route is supposed to be rather similar than 2%, value for sulphate form comparing with the oral bioavailability of 69%, and the inhalation bioavailability supposed by default value to be 100%.