Tetrasodium 4-amino-5-hydroxy-3,6-bis[[4-[[2-(sulphonatooxy)ethyl]sulphonyl]phenyl]azo]naphthalene-2,7-disulphonate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

other: Data sharing dispute

Adequacy of study:

key study

Study period:

1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP compliant guideline study

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Objective of study:

absorption

distribution

excretion

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

not specified

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: 75/318 EWG, Appendix IV

Deviations:

not specified

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Tetrasodium 4-amino-5-hydroxy-3,6-bis[[4-[[2-(sulphonatooxy)ethyl]sulphonyl]phenyl]azo]naphthalene-2,7-disulphonate

EC Number:

241-164-5

EC Name:

Tetrasodium 4-amino-5-hydroxy-3,6-bis[[4-[[2-(sulphonatooxy)ethyl]sulphonyl]phenyl]azo]naphthalene-2,7-disulphonate

Cas Number:

17095-24-8

Molecular formula:

C26H25N5O19S6.4Na

IUPAC Name:

tetrasodium 4-amino-5-hydroxy-3,6-bis[(4-{[2-(sulfonatooxy)ethyl]sulfonyl}phenyl)diazenyl]naphthalene-2,7-disulfonate

Test material form:

solid: particulate/powder

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: 6 to 8 weeks
- Weight at study initiation: 197 to 225 g
- Fasting period before study: -
- Housing: single (excretion/tissues); 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: 1 day
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 27
- Humidity (%): 30 to 55
- Air changes (per hr): -
- Photoperiod (hrs dark / hrs light): -
IN-LIFE DATES: From: 23. Aug. To: 14. Sep. 1990

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Duration and frequency of treatment / exposure:

single dose

Doses / concentrations

Dose / conc.:

10 mg/kg bw/day (nominal)

Remarks:

Doses / Concentrations:
Concentration: 2 mg/g solution
analytically verified

No. of animals per sex per dose / concentration:

Exhalation: 2
Blood/plasma levels: 5
Excretion/remaining concentration: 5
Excretion i.v.: 3

Control animals:

not specified

Positive control reference chemical:

not examined

Details on dosing and sampling:

- Tissues and body fluids sampled: urine, feces, blood, plasma, exhalate, tissues (spleen, stomach,
intestines, liver, kidneys, gonads, heart, lungs, skeletal muscle, subcutaneous fat, retroperitoneal fat,
brain, eyes)
- Time and frequency of sampling:
- Blood sampling: 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
- Cage washings: 0-8, 8-24, 24-96, 96-168 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:

ca. 1 % (estimated from study HOE 98.0388)

Details on distribution in tissues:

Kidneys: 0.1228 μg equivalent/g
Spleen: 0.0332 μg equivalent/g
subcutaneous fat: 0.0174 μg equivalent/g
Lungs: 0.013 μg equivalent/g
All other organs: < 0.01 μg equivalent/g
In sum 0.0344% of the administered dose

Transfer into organs

Observation:

not determined

Details on excretion:

Excretion mainly via feces: 95.58% of the administered dose; t1/2(I): 4.9 h, t1/2(II): 75 h
Renal excretion: 1.22% + 014% (cage washing) of the administered dose; t1/2(I): 5 h, t1/2(II): 71 h
Bi-phasic elimination
no excretion by exhalation

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

Cmax: 0.19 μg eq/g

Toxicokinetic parameters 2

Test no.:

#1

Toxicokinetic parameters:

Tmax: 6.8 hours

Toxicokinetic parameters 3

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 22.1 hours

Toxicokinetic parameters 4

Test no.:

#1

Toxicokinetic parameters:

AUC: AUC: 48: 5.85 μg eq*h/g

Toxicokinetic parameters 5

Test no.:

#1

Toxicokinetic parameters:

AUC: AUC: oo: 6.66 μg eq*h/g

Toxicokinetic parameters 6

Test no.:

#2

Toxicokinetic parameters:

Cmax: Cmax: 0.29 μg eq/g

Toxicokinetic parameters 7

Test no.:

#2

Toxicokinetic parameters:

Tmax: Tmax: 6.4 hours

Toxicokinetic parameters 8

Test no.:

#2

Toxicokinetic parameters:

half-life 1st: half-life 1st: 18.5 hours

Toxicokinetic parameters 9

Test no.:

#2

Toxicokinetic parameters:

AUC: AUC: 72: 7.14 μg eq*h/g

Toxicokinetic parameters 10

Test no.:

#2

Toxicokinetic parameters:

AUC: AUC: oo: 8.8 μg eq*h/g

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

see metabolism study DM90/001

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
After oral gavage, the radioactivity was predominantly eliminated via the feces (95.58 ± 1.86 %) within
7 days. The renal (including cage wash) eliminated part was 1.36 ± 0.53 %. Excretion in feces and
urine was biphasic. There was no tendency for the test item or its metabolites to bioaccumulate in
blood or tissues.

Executive summary:

The kinetics of in the naphthalene-part14C-labelled HOE CG 0062 was examined in male rats after
single oral treatment at about 10 mg/kg body weight.
The slow increase of the radioactivity led to concentration maxima of 0.19 and 0.29 μg equivalent/g
after on average 6.8 and 6.4 h in blood and plasma, respectively. The concentration decrease occurred
with biological half times of 22.1 and 18.5 hours in blood and plasma, respectively. The comparable
kinetics in blood and plasma is a hint for the fact that binding of radioactivity to formed blood components
does not occur.
After oral gavage, the radioactivity was predominantly eliminated within 7 days via the feces (95.58
± 1.86%). The renal (including cage wash) eliminated part was 1.36 ± 0.53%. Excretion in feces and
urine was biphasic. For the first rapid phase, half times of 4.9 h (feces) and approx. 5 h (urine) were
calculated or estimated, respectively. In the slow second phase (t½ca. 75 h for feces and 71 h for urine)
only about 1% (feces) and 0.1% (urine) or less were excreted.
At the end of the study, 7 days after oral administration, the highest remaining concentrations were
measured in the kidneys (0.12 μg equivalent/g), followed by spleen (0.03 μg equivalent/g), subcutaneous
fatty tissue (0.02 μg equivalent/g) and lung (0.01 μg equivalent/g). The remaining tissues contained
less than 0.01 μg equivalent/g. Overall, 0.03% of the administered dose was found in the tissues
investigated.

The recovery rate was 96.98 ± 1.45% of the administered radioactivity.