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EC number: 701-365-5 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Link to relevant study record(s)
- 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
- Objective of study:
- absorption
- distribution
- excretion
- 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
- Radiolabelling:
- yes
- Remarks:
- bisphenyl-U-14C
- 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 - 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
- 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
- Preliminary studies:
- NA
- 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 % - Metabolites identified:
- no
- Details on metabolites:
- see metabolism study HOE 88.1064
- 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.
- Endpoint:
- basic toxicokinetics
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 21. Dec. 1987 to 21. March 1988
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Objective of study:
- excretion
- metabolism
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics)
- Version / remarks:
- Tier 1
- Deviations:
- yes
- Remarks:
- exhalation determined in separate study
- Principles of method if other than guideline:
- Determination of radioactivity in the excreta of rats. Identification of metabolites in the excreta.
- GLP compliance:
- yes
- Radiolabelling:
- yes
- Remarks:
- bisphenyl-U-14C
- 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: -
- Weight at study initiation: 230 g
- Fasting period before study: -
- Housing: 2 per cage
- Individual metabolism cages: no
- Diet: Altromin 1321 ad libitum
- Water: tap ad libitum
- Acclimation period: 1 to 2 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 23 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): -
- Photoperiod (hrs dark / hrs light): -
IN-LIFE DATES: From: 21. Dec. 1987 To: 24 Dec. 1987 - Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 mg/kg bw
- concentration (if solution): 1.836 mg/g - Duration and frequency of treatment / exposure:
- single dose
- Remarks:
- Doses / Concentrations:
10 mg/kg body weight (nominal), 9.94 mg/kg bw actual dose - No. of animals per sex per dose / concentration:
- 5 males
- Control animals:
- no
- Positive control reference chemical:
- not investigated
- Details on study design:
- TS was dissolved in bidistilled water (5 minutes ultrasound ) to a final concentration of 1.836 mg/g
- Details on dosing and sampling:
- - Tissues and body fluids sampled: urine, faeces
- Time and frequency of sampling: 0-24 h, 24-48 h, 48-72 h after dosing
- From how many animals: pooled from all animals
- Method type(s) for identification: Liquid scintillation counting, HPLC-UV, HPLC-14C, TSP-HPLC-MS
- Limits of detection and quantification:
- Other:
TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable):
- acetylation
- enzyme cleavage with beta-glucoronidase/arylsulfatase - Statistics:
- -
- Preliminary studies:
- not available
- Details on absorption:
- see kinetic study HOE 89.0388
- Details on distribution in tissues:
- see kinetic study HOE 89.0388
- Details on excretion:
- More than 90 % were excreted within the first 24 hours. Excretion mainly via feces.
85 % excretion via feces
15 % excretion via urine
no unchanged test item excreted - Metabolites identified:
- yes
- Details on metabolites:
- Urine: 6 metabolites were separated, two main metabolites identified.
1. 8 % of total radioactivity: sulfate-ester
2. 4 % of total radioactivity: N-acetylate
Feces:
All extractable metabolites identified. About 17% of the radioactivity remained unextracted
1. 76% of total radioactivity: sulfate-ester amount decreased over time
2. N-acetylate increased over time - Conclusions:
- Interpretation of results: no bioaccumulation potential based on study results
The test item was almost completely metabolized. The majority of the metabolites were excreted via feces. - Executive summary:
A degradation pathway is proposed based on the results of these studies.
This means that reductive cleavage of the azo groups is the main metabolization step in the rat. The resulting amine is excreted mainly in the feces either directly or after N-acetylation.
Remarkable is the very high excretion rate of the metabolites via feces. Usually such behavior is caused by one of the following acts:
- almost total absorption of the test substance and subsequent biliary excretion of the metabolites
- degradation of the test substance by the intestinal flora
- abiotic hydrolysis of the test substance in the gastro intestinal tract
In this case, the last possibility can be excluded, as the hydrolysis experiments showed products different from those identified as metabolites in the excreta.
The fact that the metabolite pattern in feces is nearly identical with that in urine gives strong evidence that biliary excretion dominates for the test item. However, determination of the absorption rate was done in a further study.
Referenceopen allclose all
Description of key information
The kinetics and metabolism of the test substance was investigated in studies with radiolabeled substance. Studies revealed that only about 30 % of the substance orally applied is absorbed. About 80 to 88 % of the substance applied was found to be excreted with the faeces within 7 days. Renal excretion was found to be 11 to 18 %. Metabolization of the test substance was also found to take place in the rat while all metabolites detected have been found to be equally or more polar than the mother compound indicating that no bioaccumulation takes place.
Key value for chemical safety assessment
- Bioaccumulation potential:
- no bioaccumulation potential
- Absorption rate - oral (%):
- 28.6
Additional information
The kinetics and metabolism of the test substance was investigated in studies with radiolabeled substance. In the first part, the test substance was labeled at both phenyl rings (bisphenyl-U-14C), in the second part, in the naphthalene-part. Five male rats received 14C-labelled HOE CG 0062 as an aqueous solution at a nominal dose of 10 mg/kg body weight by gastric intubation. The reductive cleavage of the azo groups is the main metabolization step in the rat. The resulting amine is excreted mainly in the feces either directly or after N-acetylation.
The very high excretion rate of the metabolites via feces is remarkable. Usually such behavior is caused by one of the following acts:
1. almost total absorption of the test substance and subsequent biliary excretion of the metabolites
2. degradation of the test substance by the intestinal flora
3. abiotic hydrolysis of the test substance in the gastro intestinal tract
In this case, the last possibility can be excluded, as the hydrolysis experiments showed products different from those identified as metabolites in the excreta. The fact that the metabolite pattern in feces is nearly identical with that in urine gives strong evidence that biliary excretion dominates for the test item.
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 Cmaxof 0.7 to 0.8 µg equivalent/g after 5.6 hours in plasma and 21 hours in blood. T1/2were 5 and 34 hours in plasma and about 8 days in blood, leading to the assumption of binding of Reactive Black 5 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). TS levels in kidneys (0.1 µg eq/g) and other tissues were lower. Totally, 0.28 % of the administered dose was found in blood and tissues. The mean over-all recovery rate was 99 % of the administered dose.
In the naphthalene-labeled investigation, urine and feces from 0-24, 24-48 and 48-72 h after application were pooled and investigated using HPLC. Elimination of the administered radioactivity was rapid, quantitative and occurred mainly via feces. 72 h following administration of the dose 109.1 % of the applied radioactivity were recovered in the excreta (108.8 % via feces and 0.3 % via urine). Moreover, nearly 99 % of the dose was excreted in the first 24 h following administration.
No unchanged HOE CG 0062 was detected in urine or feces extract, indicating that rapid and complete metabolization of the test substance took place in the rat. Moreover, all excreted metabolites were even more polar than the test substance itself, which strongly supports the assumption that neither HOE CG 0062 nor any of its metabolites has a bioaccumulation potential. In urine clear separation of at least 3 metabolites (retention times: 3.5-3.8 min; 6.4 min and 13.9-14 min) was achieved and the retention behavior gives strong evidence that each metabolite lost at least one azo-linked side-chain. Moreover, it is very likely that the most polar metabolite (Rt=3.5-3.8 min) has no side-chains at all.
Following extraction with acetonitrile/water, in feces at least 7 metabolites were detected covering retention times from 3 to 23 minutes and containing one main metabolite (Rt=13-15 min). Again, the retention behavior gives strong evidence that the main metabolite has lost at least one azo-linked side-chain. The proposed degradation pathway is given above.
The non-extractable residues in feces accounted for approx. 53 % of the applied dose, indicating that significant amounts of radioactive residues are tightly bound to that matrix. Due to rapid excretion and limited bioavailability of such bound residues, this fraction should be of no toxicological concern. Nevertheless, hydrolysis experiments were performed and revealed a broad peak (Rt=10-20 min) in addition to a main product of very polar character (Rt=3 min), which had most probably lost both side-chains. As it is very likely that cleavage of azo groups will occur during hydrolysis, it may be concluded that the non-extractable residues in feces at least contain the intact naphthalene ring system.
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 (t½ ca. 75 h for feces and 71 h for urine) only about 1 % (feces) and 0.1 % (urine) or less were excreted.
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