Reaction products of 4-amino-5-hydroxynaphthalene-2,7-disulfonic acid, coupled twice with diazotized 2-[(4-aminophenyl)sulfonyl]ethyl hydrogen sulfate, sodium salts

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

14. Dec. 1987 to 30. Sep 1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1989

Report date:

1989

Materials and methods

Objective of study:

absorption

distribution

excretion

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics)

Deviations:

yes

Remarks:

metabolism determined in separate study

GLP compliance:

yes

Test material

Test material information

Constituent 1

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Radiolabelling:

yes

Remarks:

bisphenyl-U-14C

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hoechst AG
- Age at study initiation: 7 to 8 weeks
- Weight at study initiation: 160 to 230 g
- Fasting period before study: -
- Housing: single (excretion) 2/cage (plasma levels, exhalation)
- Individual metabolism cages: yes (excretion) / no (plasma levels, exhalation)
- Diet: Altromin 1321 ad libitum
- Water: tap ad libitum
- Acclimation period: -


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 26
- Humidity (%): 30 to 50
- Air changes (per hr): -
- Photoperiod (hrs dark / hrs light): -


IN-LIFE DATES: From: 14. Dec To: 24. Dec. 1987
23. Sep. To: 26. Sep. 1988

Administration / exposure

Route of administration:

other: oral gavage and intravenous

Vehicle:

other: water and NaCl

Details on exposure:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): - oral: 10 mg/kg bw
- IV: 1 mg/kg bw
- concentration (if solution): - oral: 2 mg/g in aqua bidest
- IV: 0.3 mg/g in NaCl solution

Duration and frequency of treatment / exposure:

single dose

Doses / concentrations

Remarks:

Doses / Concentrations:
p.o.: 10 mg/kg body weight (nominal) - Concentration: 2 mg/g solution
i.v.: 1 mg/kg body weight (nominal) - Concentration: 0.3 mg/g solution

No. of animals per sex per dose / concentration:

Exhalation: 2
Plasma levels: 5
Excretion/remaining concentration p.o.: 5
Excretion i.v.: 3

Control animals:

other: one rat

Positive control reference chemical:

not examined

Details on dosing and sampling:

- Tissues and body fluids sampled: urine, faeces, blood, plasma, exhalate, tissues (spleen, stomach, small intestines, liver, kidneys, gonads, heart, lungs, skeletal muscle, subcutaneous fat, retroperitoneal fat, brain, eyes)
- Time and frequency of sampling:
- Blood sampling (tip of tail): 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 24, 32, 48, 72, 96, 120, 144, 168 h after test item administration
- Urine sampling: in polyethylen bottles 0 -2, 2 -4, 4 -8, 8 -24, 24 -48, 48 -72, 72 -96, 96 -120, 120 -144, 144 -168 h after test item administration
- Feces sampling: in glass vessels: 0 - 24, 24 -48, 48 -72, 72 -96, 96 -120, 120 -144, 144 -168 h after test item administration
- Organ/tissue sampling: directly after sacrifice - 7 days after test item administration
- Exhaled air: continuous aspiration at 0.2 m³/h
- Method type(s) for detection: Liquid scintillation counting
- Limits of detection and quantification: determination of blank value

Statistics:

no data

Results and discussion

Preliminary studies:

NA

Toxicokinetic / pharmacokinetic studies

Details on absorption:

oral: 28.6 %

Details on distribution in tissues:

Blood: 0.25 µg equivalent/mL
Liver: 0.18 µg equivalent/g
Kidneys: 0.10 µg equivalent/g
All other organs: <0.1 µg equivalent/g

In sum 0.28 % of the administered dose; with mean values of 0.13 % in the blood and 0.10 % in the liver

Details on excretion:

Oral administration:
Excretion mainly via feces: 83.71 % of the administered dose
Renal excretion: 14.79 % of the administered dose
Bi-phasic elimination
no excretion by exhalation

Intravenous administration:
Main excretion renal: 51.72 % - bi-phasic
Fecal excretion: 26.5 %

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

see metabolism study HOE 88.1064

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Incomplete absorption (ca. 28.6 %) after oral administration. About 85 % of the administered dose were excreted via feces and about 15 % via urine. The highest doses of radioactivity were found in blood and liver, 7 days after test item administration (about 0.28 % of the administered dose together with all other organs). After intravenous administration, about 52 % of the radioactivity were found in urine within 3 days after test item administration.

Executive summary:

The kinetics of [14]C-labeled the test substance was investigated in 5 male rats after oral gavage of 10 mg/kg body weight. For assessment of the absorption rate after oral gavage, one group of 3 rats were treated intravenously with 1 mg/kg bw.

The mean absorption rate was 28.6 % - determined by comparison of the renal excretion after oral and IV administration. The slow increase of radioactivity resulted in similar Cmax of 0.7 to 0.8 µg equivalent/g after 5.6 hours in plasma and 21 hours in blood. T1/2 were 5 and 34 hours in plasma and about 8 days in blood, leading to the assumption of of binding of the test substance to, presumably, erythrocytes.

After oral administration, excretion of radioactivity was mainly via feces (80 % to 88 % within 7 days); renal excretion was about 11 % to 18 % in a bi-phasic manner with half-times of 4 to 7 hours and 40 to 69 hours, respectively.

The highest remaining concentration after 7 days was found in blood (0.25 µg eq/mL) and liver (0.18 µg eq/g). Test substance levels in kidneys (0.1 µg eq/g and other tissues were lower. Totally, 0.28 % of the administered dose were found in blood and tissues. The mean over-all recovery rate was 99 % of the administered dose.