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Basic toxicokinetics

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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:
other: Acceptable, well-documented publication which meets basic scientific principles

Data source

Reference
Reference Type:
publication
Title:
Distribution and Excretion of Monoisopropylnaphthalene in Rats
Author:
Kojima S, Babasaki T, Kiyozumi M, Nakagawa M
Year:
1981
Bibliographic source:
Bull. Environ. Contam. Toxicol., 26, 626-633

Materials and methods

Objective of study:
distribution
excretion
metabolism
Principles of method if other than guideline:
Toxicokinetics study
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Monoisopropylnaphthalene (MIPN), isomer mixture [CAS no. 29253-36-9]
- Name of second comparative test material (as cited in study report): and 1-isopropylnaphthalene (1-IPN) [CAS no. 6158-45-8 / EC no. 228-177-1]
- Substance type: organic
- Isomers composition of MIPN isomer mixture: 60% 2-isoppropylnaphthalene, 40% 1-isopropylnaphthalene
plus 60% 2-isopropyl [14C]naphthalene, 40% 1-isopropyl[14C]naphthalene
- Specific activity (if radiolabelling): 5.65 µCi/mg
- Locations of the label (if radiolabelling): naphthalene ring

Test substances are obtained from Kureha Chemical Co., Tokyo

Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS (Oral administration experiment)
- Weight at study initiation: 190 - 210 g
- Housing: Individual metabolism cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

TEST ANIMALS (In situ biliary excretion experiment)
- The bile duct of animals anesthetised with ethyl ether was cannulated with PE-10 tubing in order to collect bile fluid.
- Weight at study initiation: 170 - 220 g
- Housing: Individual in Bollman cages (after oral administration of MIPN-14C in olive oil)
- Diet: ad libitum
- Water: ad libitum

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
olive oil
Duration and frequency of treatment / exposure:
single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
Group 1: Single dose of MIPN-14C (6.25 µCi/kg bw) plus non-labelled MIPN (100mg/kg bw)
Group 2: Single dose of non-labelled 1-IPN (100mg/kg bw)
No. of animals per sex per dose:
3 at each sampling time
Control animals:
no
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Distribution, excretion)
- Body fluids sampled: urine, faeces, bile, blood
- Examined tissues: Adipose, skin, liver, kidneys, brain, muscle, , spleen
- Time and frequency of sampling: Feces and urine were collected separately 24, 48, 72, and 96 hr after administration
- Animals treated with 14C-MIPN were sacrificed at 2, 4, 6, 12 and 24 hr after administration, and tissues were collected for analysis.
- Animals treated with 1-IPN were sacrificed at 2, 6, 12 and 24 hr after administration. and tissues were collected for analysis.
- Time and frequency of sampling of bile in the biliary excretion experiment: 2, 4, 6, 8, 24, and 48 hr after administration.

PREPARATION OF TISSUES AND ANALYSIS OF RADIOACTIVITY:
- Decoloration of 100 mg tissue by warming at 45°C (3-5 hr) with 0.3 ml H2O2 (30%)
- Dissolving by adding 1.2 ml NCS solubilizer and warming (45°C) for 5-6 hr.
- After neutralisation wtih 0.05 ml of glacial acetic acid 10 ml of PCS scintillation cocktail was added.
- Determination of radioactivity with a liquid scintillation counter

PREPARATION OF URINE AND BILE AND ANALYSIS OF RADIOACTIVITY:
- Differentiation of conjugated and unconjugated metabolites of MIPN-14C by extraction with chloroform after pH adjustment to 1.0 - 2.0.
- Determination of radioactivity of the chloroform and aqueous layer

PREPARATION OF FECES AND ANALYSIS OF RADIOACTIVITY:
- Aliquots of 100 mg of the dried and powdered faeces were oxidised (Tri-carb sample oxidizer) and 14-CO2 was trapped into Carbo-sorb carbon dioxide absorber.
- Permafluor V scintillation cocktail was added and counted in a liquid scintillation counter.

Recoveries of radioactivity was 80-85% with these procedures.


Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
Maximal levels of radioactivity in all tissues were reached after 4 h, except skin (6 h) and spleen (6 h). In blood the level kept nearly constant until 12 h after administration. Then levels decreased with time. The highest maximum level of radioactivity were found in adipose tissue followed in descending order by skin > liver, kidney >brain > spleen > muscle.

Maximal levels of 1-IPN in liver, kidney and adipose were reached after 2 - 6 h after administration (relative constant values in this interval). Then 1-IPN levels decreased with time. Maximum level in skin was reached after 6 h hours and then level decreased rapidly. Maximum 1-IPN concentration in brain, muscle and spleen as well in blood was measured after 2 h. Afterwards the levels decreased more or less rapidly.
The highest maximum 1-IPN concentration was found in adipose tissue followed in descending order by skin > liver, brain > kidney > spleen, muscle, blood.
Details on excretion:
More than 50% of the total dose of radioactivity was excreted after 24 h via urine. After 96 h 78% of the total dose was excreted via urine.
14% of total dose was excreted via faeces after 96 h.
The excretion of radioactivity in the bile fluid was approx. 60% of the total dose. In consideration of the result that faecal excretion is the minor route of excretion of radioactivity derived from MIPN-14C, it was concluded that enterohepatic circulation is important in the reabsorption of the metabolites excreted into the intestine via the bile.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
Conjugated and non-conjugated metabolites were found by TLC, but not identified.

Any other information on results incl. tables

The time courses of MIPN-14C and 1-IPN concentrations in tissues are different. Radioactivity descended less rapid than the level of 1-IPN. Especially in blood, the level of radioactivity kept nearly constant on the maximum level until 12 h, whereas the level of unchanged 1-IPM descended rapidly between 2 h and 12 h after administration. It can be concluded, that MIPN was metabolized with time, but the metabolites remained much longer in tissues and blood.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results