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Description of key information

DIPN is absorbed and metabolized quite fast after administration and might accumulate in fat tissue during repeated exposure. In fat, elevated levels are attained. But the concentration reached is dependent on dose and not on duration of exposure. Thus extended exposure will presumably not result in continuing accumulation of DIPN. Based on dosage a maximal level (steady state) will be reached without further accumulation. After cessation of exposure, elimination of DIPN from fat will occur with a half-life of approx. 50 to 300 h (biphasic elimination characteristics).

Key value for chemical safety assessment

Additional information

Basic toxicokinetics

Information on DIPN

DIPN is absorbed from the gastrointestinal tract quite rapidly (Kawai/Iwahara 1974). It is distributed in the body and peak levels in blood and organs are reached within about 2 h (single dose administration). In adipose tissue, peak levels are attained considerably later (24 h p.a.). Tissue concentration in fat (ca. 90 µg/g) is higher than in other tissues (≤ ca. 30 µg/g). DIPN is cleared from organs quite rapidly and elimination is complete after 48 h. In fat, ca. 70% of the peak level is still found after 48 h (Hazegawa 1982_in vivo).

After repeated dose oral administration, final tissue levels are dependent on dose but not on exposure period (Anbe 1980). Organ concentrations of DIPN are in the same order as for single administration. But fat levels are doubled. Clearance of DIPN from organs is quite rapid and complete within 1 to 3 d thus comparable with single dose administration. In fat, elimination is much slower with still 4% DIPN present after 30 days (Hazegewa 1982_in vivo).

Elimination from organs indicates metabolic transformations. Metabolism was demonstrated by reaction of DIPN with liver homogenates showing decomposition rates of 40 to 50% within 2 h depending on the initial concentration (Hazegawa 1982_in vitro). Metabolites of DIPN (labeled substrate) in urine have been separated by TLC (Kawai/Iwahara 1974). But discrete metabolites of DIPN have not yet been isolated and characterized.

After single oral administration of 3H labeled DIPN, radioactivity is completely excreted within 96 h (30% in urine, 70% in feces). Native DIPN was not detected (Kawai/Iwahara 1974).

Information on supporting substance 2,6-DIPN

Comparable studies have been performed with 2,6-DIPN. This compound will be used as supporting substance.

For 2,6-DIPN similar results on absorption and distribution have been observed supporting the findings for DIPN (Kojima 1978, Kojima 1979). In addition, five metabolites were identified. In urine and bile, 40% of the total dose was excreted in form of these metabolites within 24 h after single oral administration of unlabeled native 2,6-DIPN. Two further metabolites were separated in TLC without elucidation of their structure. The metabolites identified are all transformed in the isopropyl side chain. The unidentified metabolites are considered to be phenolic compounds due to reaction with diazotized sulfanilic acid (Kojima 1982/1985).

Main facts

Overall, DIPN is absorbed and metabolized quite fast after administration and is not accumulated in organs during repeated exposure. However, in fat tissue, elevated levels are attained. But the concentration reached is dependent on dose and not on duration of exposure. Thus extended exposure will presumably not result in continuing accumulation of DIPN. Based on dosage a maximal level (steady state) will be reached without further accumulation. After cessation of exposure, elimination of DIPN from fat will occur with a half-life of approx. 50 to 300 h (biphasic elimination characteristics).