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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1985
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study performed equivalent to guideline OECD 417.

Data source

Reference
Reference Type:
publication
Title:
Catabolism of premercapturic acid pathway metabolites of naphthalene to naphthols and methylthio-containing metabolites in rats
Author:
Bakke J, Struble C, Gustafsson J-A and Gustafsson B
Year:
1985
Bibliographic source:
Proc. Natl. Acad. Sci. USA Vol. 82, pp. 668-671, February 1985

Materials and methods

Objective of study:
excretion
metabolism
Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
not applicable
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Naphthalene
EC Number:
202-049-5
EC Name:
Naphthalene
Cas Number:
91-20-3
Molecular formula:
C10H8
IUPAC Name:
naphthalene
Details on test material:
- Name of test material (as cited in study report): [1-14C]Naphthalene
- Substance type: organic, aromatic hydrocarbon
- Physical state: solid
- Source: Amersham
- Specific activity (if radiolabelling): 5mCi/mmol; 1 Ci = 37 GBq
- Locations of the label (if radiolabelling): C1
Radiolabelling:
yes
Remarks:
[14C]Naphthalene

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Housing: restraining cages
- Individual metabolism cages: yes/no
- Diet (e.g. ad libitum): laboratory chow ad libitum
- Water (e.g. ad libitum): 0.9% NaCl ad libitum

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
ethanol
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
[14C]Naphthalene (2 mg/0.5 µCi in 0.5 ml of ethanol)
Duration and frequency of treatment / exposure:
one-time
Doses / concentrations
Remarks:
Doses / Concentrations:
[14C]Naphthalene (2 mg/0.5 µCi in 0.5 ml of ethanol
No. of animals per sex per dose / concentration:
[14C]Naphthalene (2 mg/0.5 µCi in 0.5 ml of ethanol) was administered orally to two groups of control rats (n = 5 and 8) and four groups of bile-duct-cannulated rats (n = 3, 4, 4 and 5) and to 4 germ-free rats (2 mg/1.0 µCi).
Control animals:
yes
Details on dosing and sampling:
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces, bile
- Time and frequency of sampling: for 72 hours after exposure
- From how many animals: Between 3 and 8 per group. Urine and bile from each group were separtely pooled.
- Method type(s) for identification: GC-MS, Liquid scintillation counting (limit of detection < 0.5% of 14C-dose)

PHARMACOKINETIC STUDY (excretion)
- Tissues and body fluids sampled: urine, faeces, bile
- Time and frequency of sampling: for 24 hours and for 72 hours after start of treatment

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on excretion:
In the control of uncannulated rats, 75.6% of the administered radioactivity was recovered in the urine after 24-hours. At 72 hours, 81.1-84.3% of the radioactivity had been recovered in the urine, 6.3-6.6% in the faeces and 2.6-6.6% remained in the carcass.
In the cannulated rats, the 24-hour urine and bile contained 29.9% and 66.8% of the 14C dose, respectively. At 72 hours, 27.4-33.2% of the radioactivity had been recovered in the urine, 58.5-75.2% was contained in the bile, less than 1% was excreted in the faeces and not more than 0.2% remained in the carcass.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
In the control of uncannulated rats, the urinary metabolites identified at 24-hours were: 1,2-dihydro-1-hydroxy-2-S-(N-acetyl)cysteinylnaphthalene (38.1% of the administered radioactivity), 1,2-dihydro-1,2-dihydroxynaphthalene glucuronide (23.9%), dihydroxynaphthalene (4.9%), naphthols and naphthol glucuronides (4.6%) and 1,2-dihydro-1-hydroxy-2-methylthionaphthalene glucuronide (4.6%).
At 24-hours in cannulated rats, 14.4% of the administered dose was present in the urine as 1,2-dihydro-1-hydroxy-2-S-(N-acetyl)cysteinylnaphthalene, and 14.5% as the dihydroxynaphthalene glucuronide conjugate. Naphthols, thionaphthols, CH3S-metabolites or their respective glucuronides and sulphates were not detected in either the 24-hour urine or bile.
Germ-free rats dosed with [14C]naphthalene did not excrete any of the CH3S-metabolite and, as with the bile and urine from cannulated rats, only traces of naphthols were detected by GC/MS analysis. The major urinary metabolites were 1,2-dihydro-1-hydroxy-2-S-(N-acetyl)cysteinylnaphthalene (89%), 1,2-dihydro-1,2-dihydroxynaphthalene glucuronide (4%), and dihydrodihydroxy and dihydroxynaphthalene (8.2%).
naphthalene (89%) and dihydroxynaphthalene glucuronide (4%).
Only traces of naphthols and no CH3S-metabolites could be detected

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results Extensive metabolism occurs and elimination is rapid, primarily through the urinary route.
Extensive metabolism occurs and elimination is rapid, primarily through the urinary route, following enterohepatic circulation.
Executive summary:

Three groups of Sprague-Dawley rats were treated orally with a single administration of 2 mg 14C-naphthalene. One group of

16 animals were bile-duct cannulated, the second group of 4 animals were uncannulated but with an altered intestinal microflora (germ free), and the third group of 13 animals were standard uncannulated rats. Urine, faeces and bile were collected for 72-hours after administration of naphthalene. In the control of uncannulated rats, 75.6% of the administered radioactivity was recovered in the urine witin 24-hours. At 72 hours, 81.1-84.3% of the radioactivity had been recovered in the urine, 6.3-6.6% in the faeces and 2.6-6.6% remained in the carcass. In the cannulated rats, the 24-hour urine and bile contained 29.9% and 66.8% of the 14C dose, respectively. At 72 hours, 27.4-33.2% of the radioactivity had been recovered in the urine, 58.5-75.2% was contained in the bile, less than 1% was excreted in the faeces and not more than 0.2% remained in the carcass.

Mayor metabolites in urine of controle and bile-duct-cannulated rats collected during the first 24 hours after treatment were 1,2- dihydro-1-hydroxy-2-S-(N-acetyl)cysteinylnaphthalene (38.1 and 14.4% of 14C dose) and 1,2 -dihydro-1,2-dihydroxynaphthalene glucuronide (23.9 and 14.5% of 14C dose). Mayor metabolites in bile of bile-duct cannulated rats collected during 24 hours after treatment were 1,2 -dihydro-1,2-dihydroxynaphthalene glucuronide (26.8% of 14C dose) and 1,2 -dihydro-1-hydroxy-2-S-cysteinylnaphthalene (16.9% of 14C dose). Only traces of naphthols and no CH3S-metabolites could be detected, indicating that intestinal microflora are probably involved in the production of both these metabolites. Overall, this study shows that there is rapid and complete absorption of naphthalene from the gastro-intestinal tract. Extensive metabolism occurs, and elimination is rapid, primarily through the urinary route, following enterohepatic circulation.