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Basic toxicokinetics

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basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference Type:
Alkylnaphthalenes. II. Tissue Accumulation of 2,6-Diisopropylnaphthalene administered continuously to Rats
Kojima S, Nakagawa M, Suzuki R, Horio M, Taniguchi Y, and Tanaka Y
Bibliographic source:
Esei Kagaku, 25(4), 221-224 (Engl.)
Report Date:

Materials and methods

Objective of study:
Test guideline
no guideline followed
Principles of method if other than guideline:
toxicokinetic study in rats; investigation of tissue distribution and elimination from tissues after oral administration of repeated doses for 17 or 31 days
GLP compliance:

Test material


Test animals

Details on test animals and environmental conditions:
- Weight at study initiation: 130 - 160 g
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

Administration / exposure

Route of administration:
oral: feed
unchanged (no vehicle)
Details on exposure:
rats were fed diet containing 0.1% or 0.2% 2,6-DIPN
Duration and frequency of treatment / exposure:
17 and 31 d; continuous uptake
Doses / concentrations
Doses / Concentrations:
0.1% and 0.2% test substance in diet
No. of animals per sex per dose:
Control animals:
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood, liver, kidney, adiose tissue, skin (only for sampling group 2)
- Time and frequency of sampling:
1a: after 17 d and 31 d of treatment
1b: after 18 d and 32 d; 24 h feeding on normal diet after termination of treatment (day 17 and 31)
2: at day 0, 7, 14, 21, 28, and 35 after dosing with 0.1% test substance in diet for 14 days (starting at day 1, feed was control diet)

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
1a: Following continuous dosing in the feed, tissue levels increased in proportion of the dose and approached a steady state (no difference between tissue levels after 17 and 31 d). Levels in adipose tissue were 50 to 100 fold higher than that in other organs, corresponding to 200 and 550 µg DIPN/g fat tissue, related to the dose.
1b: When continuous dosing (17 and 31 d) was followed by a 24 h period feeding control diet, 2,6-DIPN concentrations in blood, liver, and kidney were greatly reduced by > 90% compared to levels immediately after the end of dosing. In contrast, 2,6-DIPN decrease in adipose tissue was only 10 to 30% within the 24 h period after cessation of DIPN administration.

Metabolite characterisation studies

Metabolites identified:

Any other information on results incl. tables

Elimination of 2,6-DIPN from various tissues after administration of 0.1% DIPN in diet for 14 days (dosing and sampling group 2)


Immediately after the end of administration (day 0), levels in blood, liver, and kidney were 0.25 ± 0.04, 2.46 ± 0.66, and 1.77 ± 0.30 (µg/mL or µg/g) respectively (n = 3 to 4). At day 7, no 2,6-DIPN could be detected any more in these tissues.


At day 0, levels in skin and adipose tissue were 23.41 ± 5.28 and 198.48 ± 4.69 µg/g respectively. After 28 days, still 10 % of the original concentration was left in skin. In adipose tissue, DIPN levels of 23.97 ± 8.30 and 4.09 ± 0.05 µg/g were detected after 7 and after 14 days. For the elimination of 2,6-DIPN from adiose tissue, a biphasic course was determined with a half-life of 55 h for the first phase (until ca. 21 days) and a half-life of 270 h for the second phase (from 21 to 35 days).

Applicant's summary and conclusion

Interpretation of results (migrated information): low bioaccumulation potential based on study results
After continuous administration of 2,6-DIPN in feed for 17 and 21 days, DIPN levels in various tissues were elevated in proportion to the dose but were not affected by the difference of the administration period thus indicating approaching of a steady state. Levels in adipose tissue were 50 to 100 fold higher compared to other organs. Elimination from tissues exept adipose tissue and skin was fast (> 90% within on day). Skin still retained about 10% of the starting concentration at day 28. For adipose tissue, a biphasic elimination was determined with half-lifes of 55 and 270 h.