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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)

Data source

Reference
Reference Type:
publication
Title:
Metabolism of the Hair Dye Component, Nitro-p-phenylenediamine, in the Rat
Author:
MITSUO NAKAO,*'a YUKIKO GOTOH,a YASUHIKO MATSUKI,a AKIRA HIRATSUKA,b and TADASHI WATABEb
Year:
1987
Bibliographic source:
Chem. Pharm. Bull. 35( 2 ) 785-791 (1987)

Materials and methods

Objective of study:
metabolism
Principles of method if other than guideline:
In Vivo metabolism of Nitro-p-phenylenediamine orally in rats
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report):Nitro-p-phenylenediamine (2-nitro-1,4-diaminobenzene)- Molecular formula (if other than submission substance):C6-H7-N3-O2- Molecular weight (if other than submission substance):153.1403 g/mole - Substance type:Organic- Physical state:No data available- Impurities (identity and concentrations):No data available
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male

Administration / exposure

Route of administration:
intraperitoneal
Vehicle:
not specified
Remarks:
2 % carboxymethyl cellulose sodium salt
Details on exposure:
The rats were injected intraperitoneally with Nitro-p-phenylenediamine dissolved in a 2% carboxymethyl cellulose sodium salt solution were administered at 100 mg/5 ml/kg.
Duration and frequency of treatment / exposure:
1 day
Doses / concentrations
Remarks:
Doses / Concentrations:100 mg/kg
No. of animals per sex per dose:
5
Control animals:
not specified
Positive control:
Data not available
Details on study design:
The urine was collected for 24 h. Prior to the collection of the urine, a concentrated solution ofsodium bisulfite had been put in the urine container, so that at the end of 24 h, its final concentration would be 0.2- 0.5%. The combined urine was frozen until use.
Details on dosing and sampling:
No data available
Statistics:
No data available

Results and discussion

Preliminary studies:
No data available
Main ADME results
Type:
metabolism
Results:
the metabolism of Nitro-p-phenylenediamine appears to proceed through regioselective N-acetylation of the amino groups.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
No data available
Details on distribution in tissues:
No data available
Details on excretion:
No data available

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Nitro-p-phenylenediamine appears to be metabolized successively to N4-acetyl-2-nitro-1,4-diaminobenzene, N4-acetyl-1,2,4-triaminobenzene and N1,N4-diacety1-1,2,4-triaminobenzene by regioselective N4-acetylation and subsequent nitro reduction, followed by regioselective N1-acetylation, because rats given N4-acetyl-2-nitro-1 ,4-diaminobenzene or N4-acetyl-1,2,4-triaminobenzene excreted N1,N4-diacety1-1,2,4-triaminobenzene in the urine. Nitro-p-phenylenediamine might be also metabolized through an alternative pathway to N1,N4-diacety1-1,2,4-triaminobenzene via 1,2,4-triaminobenzene formed by direct nitro reduction, because N1,N4-diacety1-1,2,4-triaminobenzene was excreted as a urinary metabolite in rats given 1,2,4-triaminobenzene or its N1- monoacetylated product. Thus, the metabolism of Nitro-p-phenylenediamine appears to proceed through regioselective N-acetylation of the amino groups.

Bioaccessibility

Bioaccessibility testing results:
No data available

Any other information on results incl. tables

Urinary Metabolites of Nitro-p-phenylenediamine and Its Derivatives in the Rat

 

 

 

 

Administration

R1

R2

R3

 

I

II

III

III-I

IV

VI

 

 

 

 

of dose

NH2

NO2

NHAc

(II)

4.7

4.8

-

-

-

-

NHAc

NO2

NH2

(II-1)

 ND

ND

-

-

-

-

NHAc

NO2

NHAc

(II-2)

 ND

ND

-

-

-

-

NH2

NH2

NHAc

(III)

 ND

ND

ND

ND

ND

ND

NHAc

NH2

NH2

 (III-1)

 ND

ND

ND

ND

ND

ND

NH2

NHAc

NH2

(III-2)

 ND

ND

ND

ND

ND

ND

NHAc

NH2

NHAc

(IV)

16.9

15.4

31.7

28.0

61.8

9.7

NH2

NHAc

NHAc

(IV-1)

 ND

ND

ND

ND

ND

ND

NHAc

NHAc

NH2

(IV-2)

 ND

ND

ND

ND

ND

ND

NHAc

NHAc

NHAc

(V)

 ND

ND

ND

ND

ND

ND

R1, R2and R3represent the substituents at the 1-, 2-, and 4-position of the benzene nucleus, respectively. ND: Not detectable (≤ 0.1 ‘’ ,, of dose compounds).

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study resultsNitro-p-phenylenediamine expected to have Low bio-accumulation potential based on study results.
Executive summary:

In a in vivo metabolism study, Sprague-Dawley were treated with Nitro-p-phenylenediamine dissolved in a 2% carboxymethyl cellulose sodium salt solution at 100 mg/5 ml/kginjected intraperitoneally. Nitro-p-phenylenediamineappears to be metabolized successively to N4-acetyl-2-nitro-1,4-diaminobenzene, N4-acetyl-1,2,4-triaminobenzene and N1,N4-diacety1-1,2,4-triaminobenzene by regioselective N4-acetylation and subsequent nitro reduction, followed by regioselective N1-acetylation, because rats given N4-acetyl-2-nitro-1 ,4-diaminobenzene or N4-acetyl-1,2,4-triaminobenzene excreted N1,N4-diacety1-1,2,4-triaminobenzene in the urine.Nitro-p-phenylenediaminemight be also metabolized through an alternative pathway to N1,N4-diacety1-1,2,4-triaminobenzene via 1,2,4-triaminobenzene formed by direct nitro reduction, because N1,N4-diacety1-1,2,4-triaminobenzene was excreted as a urinary metabolite in rats given 1,2,4-triaminobenzene or its N1- monoacetylated product. Thus, the metabolism ofNitro-p-phenylenediamineappears to proceed through regioselective N-acetylation of the amino groups. Therefore,Nitro-p-phenylenediamine considered to haveLow bio-accumulation potential based on study results.