N-1-naphthylaniline

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1981

Report date:

1981

Materials and methods

Objective of study:

distribution

excretion

metabolism

toxicokinetics

Principles of method if other than guideline:

- Kinetic determination of plasma and tissue radioactivity of rats following an oral dose of 14C-PNA.
- Determination of radioactivity in rat tissues 24 hours after administration of an oral dose of 14C-PNA.
- Radiolabeled PNA and metabolites were determined in urine samples pooled over 48 hours.
- Excretion was determined by investigation of total radioactivity in urine and feces of rats after various intervals of time following application of 14C-PNA.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

N-1-naphthylaniline

EC Number:

201-983-0

EC Name:

N-1-naphthylaniline

Cas Number:

90-30-2

Molecular formula:

C16H13N

IUPAC Name:

N-phenylnaphthalen-1-amine

Details on test material:

- Name of test material (as cited in study report): 14C-labeled PNA (N-phenyl-14C(U) and naphtyl-1-14C)
- Analytical purity: no data
- Radiochemical purity (if radiolabelling): >98 %
- Specific activity (if radiolabelling): 5.68 mCi/mM
- Locations of the label (if radiolabelling): N-phenyl-14C(U) and naphtyl-1-14C, respectively
- Storage condition of test material: refrigerated and protected from light
- Other: Source: New England Nuclear, Boston, Mass.

Radiolabelling:

yes

Remarks:

14C

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic Farms, Germantown, New York
- Weight at study initiation: 225 - 250 g
- Acclimation period: at least 1 week


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

DMSO

Duration and frequency of treatment / exposure:

single exposure

Doses / concentrations

Dose / conc.:

160 mg/kg bw/day

No. of animals per sex per dose / concentration:

- Kinetics and Tissue distribution: 3 males per observation interval
- Metabolism and excretion: not specified

Control animals:

not specified

Details on study design:

no information given

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (Plasma kinetics): blood, plasma
- Tissues and body fluids sampled (Tissue distribution): heart, lung, pancreas, spleen, kidney, testes, liver, fat, stomach, small intestine and contents, caeca, large intestine and contents
- Tissues and body fluids sampled (Excretion): urine, feces
- Time and frequency of sampling (Plasma kinetics): 0.5, 1, 2, 4, 8, 12, 16, 24, 48 and 72 hours
- Time and frequency of sampling (Tissue distribution): 24 hours; for tissue kinetics: 0.5, 1, 2, 4, 8, 12, 16, 24 and 48 hours
- Time and frequency of sampling (Excretion): 2, 4, 8, 12, 24, 32, 48, 72 and 120 hours

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: pooled over 48 hours
- From how many animals: no data on animal numbers, no data if individual samples were pooled, individual samples were pooled over sampling period
- Method type(s) for identification: HPLC-UV, Liquid scintillation counting
- Limits of detection and quantification: no data

Statistics:

Percentage of radioactivity in urine extracts.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

Kinetics: the concentration of total radioactivity in the plasma reached a peak of 116 µg PNA equivalents/ml four hours after dosing, thereafter it declined in a biphasic manner. About 3 % of the radioactivity in the plasma could be attributed to the parent compound 4 hours after dosing. The appearance and disappearance of plasma radioactivity shown was fitted to a pharmacokinetic two-compartment open-system model, in which a central blood compartment is in reversible equilibrium with a peripheral tissue compartment, with first-order-absorption. Analysis of the plasma radioactivity according to this relationship gave half-life values of 1.59 hr for the appearance process and 1.68 and 33 hr, respectively, for the two elimination processes. The level of unchanged PNA in the plasma followed a kinetic pattern similar to that of the total 14C but reached its peak level off 1.25 µg PNA/ml plasma at 2 hr after dosing, after which it declined in a biphasic manner. Analysis of the plasma levels of PNA gave half-life values of 0.66 hr for the appearance process and 1.24 and 11.1 hr, respectively, for the two disappearance processes.

Tissue distribution: Appreciable radioactivity was detected in all tissues at 24 hours indicating a rapid absorption and distribution of 14C-PNA and its metabolites. The major sites of distribution of 14C were fat, liver, kidney and lungs with large amounts in the gastro-intestinal tract plus contents. In all four major tissues (liver, fat, kidney, lung), radioactivity reached a maximum about 4 hours after dosing, reflecting a rapid uptake and distribution of the chemical. The levels of radioactivity then appeared to decrease in a biphasic manner. At all times, the highest concentration of 14C was found in the liver followed by fat, kidney, and lung. When radioactivity is expressed in terms of percent of the total dose received, only liver and fat are important tissues which retained most of the unexcreted radioactivity.

Details on excretion:

More than 90 % of the administered dose had been excreted into the urine and feces within 48 hours of administration. The primary route of excretion of radioactivity was via the feces, although appreciable amounts of 14C were excreted via the urine. After 72 hours, 60 % of the total dose had been excreted in the feces and about 35 % in the urine. The bulk of the excretion in urine and feces occurred during the first 24 hours after administering the chemical.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Urine contained a high percentage of 14C as materials which remained in the aqueous phase following extraction at pH 12 and 2, suggesting that PNA was extensively metabolized by the rat. HPLC analysis of the ether extract of the urine showed at least five 14C-metabolites (see table), no PNA could be detected in the ether extracts.

Any other information on results incl. tables

Tissue distribution

Distribution of radioactivity in rat tissues 24 hours after oral administration of¹⁴C-PNA:

Tissue	^14C-PNA Equivalent µg/g wet tissue	Percent of administered dose
Heart	6.49	0.0130
Lung	10.2	0.0280
Pancreas	3.62	0.00432
Spleen	3.18	0.00377
Kidney	28.7	0.123
Testes	3.30	0.0200
Liver	33.8	0.415
Fat	66.0	2.35
Stomach	488	5.62
Small intestine (+ contents)	235	5.34
Caeca	362	5.67
Large intestine (+ contents)	435	3.10

Metabolism

Distribution of radioactivity in 0-48 hr pooled urine samples:

Fraction	Percent of total radioactivity in the urine
Ether extract (pH 12)	16
Ether extract (pH 2)	19
Aqueous residue (unextractable)	65

Retention volumes and relative abundance of¹⁴C-PNA metabolites in the ether extract (pH 2):

^14C-Compound	HPLC Retention Volume (ml)	% of^14C in the Extract
Area A           1	2.3	14
2	3.4	20
3	4.2	11
4	5.8
5	7.5
6	9.0	Σ 18
Area B	12.0	23
Area C	14.5	14
PNA	28.0	0