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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
year of publication: 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
metabolism
Qualifier:
no guideline followed
Principles of method if other than guideline:
investigation of metabolism after single oral application
GLP compliance:
not specified
Radiolabelling:
no
Species:
hamster
Strain:
other: Syrian Golden
Sex:
male
Route of administration:
oral: gavage
Vehicle:
other: trioctanoin
Duration and frequency of treatment / exposure:
192 hrs, single exposure
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Remarks:
Doses / Concentrations:
100 mg/kg
No. of animals per sex per dose:
3 males
Control animals:
no
Type:
excretion
Results:
no 3,3'-dichlorobenzidine, monoacetyldichlorobenzidine, diacetyldichlorobenzidine or alkali hydrolyzable conjugates detectable
Key result
Test no.:
#1
Toxicokinetic parameters:
other: no 3,3'-dichlorobenzidine, monoacetyldichlorobenzidine, diacetyldichlorobenzidine or alkali hydrolyzable conjugates were detectable in urine
Metabolites identified:
no
Details on metabolites:
None of the possible metabolites analysed for (3,3'-dichlorobenzidine, monoacetyldichlorobenzidine, diacetyldichlorobenzidine and alkali hydrolyzable conjugates) were detected in any of the urine samples.
Bioaccessibility testing results:
no detected
Conclusions:
Hamsters treated orally with the test item did not excrete 3,3'-dichlorobenzidine, monoacetyldichlorobenzidine, diacetyldichlorobenzidine or alkali hydrolyzable conjugates in the urine collected up to 192 hours after the end of the exposure period.
Executive summary:

Male Syrian Golden Hamsters were applied a single dose of 100 mg test item per kg bw by gavage and urine was collected for up to 192 hours after exposure. No metabolites (3,3'-dichlorobenzidine, monoacetyldichlorobenzidine, diacetyldichlorobenzidine or alkali hydrolyzable conjugates) were detectable in urine by HPLC or EC-GC. Fecal analysis was not performed.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
year of publication: 1978
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Reason / purpose:
reference to same study
Objective of study:
other: excretion of possible metabolites
Qualifier:
no guideline followed
Principles of method if other than guideline:
investigation of excretion of possible metabolites in the urine
GLP compliance:
no
Radiolabelling:
no
Species:
rat
Strain:
not specified
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Duration and frequency of treatment / exposure:
23 month
Dose / conc.:
9 000 ppm
Remarks:
Doses / Concentrations:
9000 ppm in diet
No. of animals per sex per dose:
10
Control animals:
yes, plain diet
Details on study design:
Rat were exposed to 9000 ppm test item in diet for two years
Details on dosing and sampling:
- 2-h urine samples were collected after 6 and 23 month of exposure (no further information)
Type:
excretion
Results:
no 3,3'-dichlorobenzidinedetected in urine
Details on excretion:
- no 3,3'-dichlorobenzidine was detected in the urine
Key result
Test no.:
#1
Toxicokinetic parameters:
other: no 3,3'-dichlorobenzidine found in urine
Details on metabolites:
No 3,3'-dichlorobenzidine was detectable in urine.
Conclusions:
The test item seems not to be absorbed after oral application and there is no evidence for a metabolic splitting of the test item to 3,3'-dichlorobenzidine.
Executive summary:

Rat were exposed to 9000 ppm test item in diet for two years. Two-hour urine samples were collected after 6 and 23 months from 10 male and female rats and were analysed by thin layer chromatography for the presence of the hypothetical cleavage product 3,3'-dichlorobenzidine. No 3,3'-dichlorobenzidine was detectable in urine of treated and control animals.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
year of publication: 1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose:
reference to same study
Objective of study:
absorption
distribution
excretion
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
not applicable
Principles of method if other than guideline:
testing of absorption, distribution and excretion after oral application
GLP compliance:
no
Radiolabelling:
yes
Remarks:
14-C labelled, 11 µCi/µmol
Species:
rat
Strain:
Fischer 344
Sex:
male
Route of administration:
oral: gavage
Vehicle:
other: Emulphor EL-620:ethanol:water (1:1:8, v/v)
Duration and frequency of treatment / exposure:
24 h, single exposure
Dose / conc.:
1.11 mg/kg bw/day (actual dose received)
Remarks:
Doses / Concentrations:
1.11 mg/kg (corresponding to 3.89 µCi/rat or 0.354 µmol/rat)
No. of animals per sex per dose:
3-6 males
Control animals:
no
Type:
absorption
Results:
no radioactivity detected in blood and liver
Type:
excretion
Results:
Radioactivity detected in feces accounted for the entire applied dose; no radioactivity detected in urine
Details on absorption:
No radioactivity above background levels were detectable in blood.
Details on distribution in tissues:
No radioactivity above background levels were detectable in liver.
Key result
Test no.:
#1
Transfer type:
other:
Observation:
no transfer detectable
Details on excretion:
- No radioactivity above background levels were detectable in urine.
- Radioactivity detected in feces and cecum contents accounted for the entire orally administered dose (recovery: 104% of the administered dose).
Key result
Test no.:
#1
Toxicokinetic parameters:
other: no absorption detectable
Metabolites identified:
not measured
Details on metabolites:
n.a. since no absorption occurs
Bioaccessibility testing results:
no bioavailability observed
Conclusions:
The test item was not absorbed by rats after oral application.
Executive summary:

Radioactive labelled test item was applied to male Fischer rats by gavage. No test item was detected in blood, urine and liver during 8 hours following exposure. Radioactivity detected in feces accounted for the entire applied dose. These data indicate, that the test item is not absorbed by rats after oral application.

Description of key information

Investigations on the toxicokinetics of diarylide yellow pigments are available for five members of this category:

Pigment Yellow 12, Pigment Yellow 13, Pigment Yellow 17, Pigment Yellow 83, and Pigment Yellow 174. Main focus of these investigations was on the question whether the azo-bonds of these azo-pigments are cleaved under liberation of 3,3'-dichlorobenzidine. After single oral application of the pigments to rat, rabbits, hamsters and monkeys mostly no 3,3'-dichlorobenzidine was detectable in blood and urine, indicating that the test substance is not cleaved under liberation of 3,3'-dichlorobenzidine. No radioactivity was detectable in blood, urine or liver after single oral application of radiolabelled Pigment Yellow 12. Investigations with repeated oral application are somehow contradictory. Whereas the investigations of Zwirner-Baier and Neumann with Pigment Yellow 17 (detection of hemoglobin adducts) indicated that small amounts of the pigment might be cleaved under liberation of 3,3'-dichlorobenzidine, these findings could not be confirmed by Sagelsdorff et al. (1996) using a more sensitive analytical detection method. Therefore, they concluded the the detection of 3,3'-dichlorobenzidine hemoglobin-adducts (Bartsch et al., 2001; Zwirner-Baier and Neumann, 1994) due to insuffucient specificity of the analyticasl method and/or probably due to a contamination of the test material and analytical instruments with the monoazo compound (Sagelsdorff et al., 1996).

After single and repeated inhalation exposure/intratracheal instillation of Pigment Yellow 17 or Pigment Yellow 83 only minimal amounts of 3,3’-dichlorobenzidine, if at all, were detectable in the blood.

Investigations after single dermal application using radiolabelled Pigment Yellow 12 indicate that no test item is absorbed as no radioactivity was detectable in blood, urine or liver and that the test item is excreted via faeces.

In summary, absorption of diarylide yellow pigments of this category after oral, dermal or inhalation application seems to be negligible, if at all. Upon inhalation of a pigment product with a particle size distribution allowing deposition in the lower respiratory tract, uptake and transport of pigments particles by macrophages may occur as for other inert dust particles.

Diarylide yellow pigments of this category are not or only to a negligible extend cleaved under liberation of the carcinogenic compound 3,3’-dichlorobenzidine. Taking into account the negative results obtained with diarylide yellow pigments of this category in investigations on carcinogenicity and genotoxicity in vitro and in vivo it is concluded that this is of no further biological relevance.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Investigations on the toxicokinetics of diarylide yellow pigments have been performed for several members of this category after oral, dermal or inhalative/intratracheal instillation exposure:

Oral exposure:

- single application

After single oral application of radiolabelled Pigment Yellow 12 to rats no radioactivity was detectable in blood, urine and liver during 8 hours following exposure. Radioactivity detected in faeces accounted for the entire applied dose (Decad et al., 1983). After single oral application of 100 mg Pigment Yellow 12/kg bw to male hamsters no metabolites were detectable in urine (Nony et al., 1980). Also, no 3,3'-dichlorobenzidine was detectable in the urine of rats collected for 48 hours after single application of 40 or 400 mg Pigment Yellow 13 or Pigment Yellow 174 per kg bw (CIBA., 1989). Similar results were obtained in rabbits, rats and monkeys which received single oral applications of up to 400 mg Pigment Yellow 13/kg bw: No 3,3'-dichlorobenzidine was detectable in urine collected for 48 hours after dosing (Mondino et al., 1978). No 3,3'-dichlorobenzidine hemoglobin adducts were detectable in rats after single oral application of Pigment Yellow 17 (Zwirner-Baier and Neumann, 1994). In a study which was judged not to be reliable (documentation insufficient for assessment) it was calculated that the amount of 3,3'- dichlorobenzidine detected in the urine of rabbits accounted for 0.05% of the single oral dose of 50 mg Pigment Yellow 13 (Akiyama, 1970).

- repeated application

Formation of 3,3'-dichlorobenzidine (DCB) hemoglobin and liver DNA-adducts was investigated in female rats which were fed for 4 weeks with diet containing 0.2% Pigment Yellow 13 or Pigment Yellow 17 (Sagelsdorff et al., 1996). Neither DCB-hemoglobin adducts nor DCB-DNA-adducts were detectable in rats fed with Pigment Yellow 17 (limits of detection: 0.1 ng/g hemoglobin and 0.08 ng/g DNA). Minimal amounts of DCB-hemoglobin adducts and DCB-DNA adducts were detected in 3/6 rats and 2/3 rats fed with Pigment Yellow 13, respectively. The authors concluded that these adducts are probably due to the contamination of the test item with the monoazo compound and not due to metabolically splitting of the test item into DCB. Zwirner-Baier and Neumann (1994) reported the formation of minimal amounts of 3,3'-dichlorobenzidine hemoglobin adducts after 4 weeks exposure of rats via diet to Pigment Yellow 17 (limit of detection: 6 ng/g hemoglobin). The authors calculated that 0.6% of the total dose of Pigment Yellow 17 was decomposed in the intestine and a corresponding amount of DCB was absorbed. However, this result could not be confirmed by Sagelsdorff et al. (1996), who concluded that the detection of 3,3 -dichlorobenzidine hemoglobin adducts was due to insufficient specificity of the analytical method. No 3,3'- dichlorobenzidine was detectable in the urine of rats after chronic oral treatment with 9000 ppm Pigment Yellow 12 or Pigment Yellow 83 in diet (Leuschner, 1978).

Inhalation exposure:

- single application

Rats were exposed by inhalation to the technically highest administrable concentration of 230 mg Pigment Yellow 17/m3 air for 4 h (nose only; mass-median aerodynamic diameter: 1.0 -1.1 μm). For 14 days after exposure, urine and serum samples ere analysed for 3,3'-dichlorobenzidine. No 3,3'-dichlorobenzidine was detectable, neither in urine nor blood (detection limit 5 ng/ml urine or 10 ng/0.5 ml blood) (Hoechst, 1990; Hofmann and Schmidt, 1993). Minimal 3,3'-dichlorobenzidine hemoglobin adducts which were in the range of the values measured for the control animals were found in rats after single intratracheal application of Pigment Yellow 17 (Zwirner-Baier and Neumann, 1994).

- repeated application

Male Wistar rats were exposed for five times to 10 or 20 mg Pigment Yellow 17 or Pigment Yellow 83/animal by intratracheal instillation at weekly intervals. Urine and faeces were collected during the exposure and 28 days observation period, blood was collected at the end of the exposure and post observation period. Urine, faeces and haemoglobin were analysed for the presence of 3,3'-dichlorobenzidine after acid hydrolysis, the pigment content of the lungs was determined gravimetrically and the lungs and lung associated lymph nodes were investigated histopathologically (Bartsch et al., 2001). Pigment Yellow 17 and Pigment Yellow 83 were deposited in the lung and persisted in the lung during the observation period. No 3,3'- ichlorobenzidine was detectable in the urine, faeces and haemoglobin of Pigment Yellow 17 treated rats during the exposure period. Traces of 3,3'-dichlorobenzidine were detected in control animals, probably due to impurities of the analytical instruments. 3,3'-Dichlorobenzidine was detectable in the urine, and partially in the faeces and haemoglobin of Pigment Yellow 83 treated rats during the exposure period. Nevertheless, no proof of bioavailability of the pigment was obtained, since 3,3'-dichlorobenzidine was still detectable in the blood at the end of the post exposure period, but not in the urine and feces during the post exposure period. Based on this observation a constant absorption and metabolisation of the applied pigment can be excluded. Furthermore, since traces of 3,3'-dichlorobenzidine were also found in blood, urine and feces of control animals, it cannot be concluded if the detection of 3,3'-dichlorobenzidine is due to the absorption and biotranformation of the applied pigment or due to the contamination of analytical instruments. Concerning the pigment content of the lung at the end of the exposure period the authors calculated a bioavailability of 0.0012 Mol%/24 hours for the high exposure group. At the end of the observation period the bioavailability was only 0.00006 Mol%/24 hours for the high exposure group.

Dermal exposure:

- single application

No radioactivity was detectable in blood, urine and liver of male rats after single application of radiolabelled Pigment Yellow 12 to the shaved skin for 24 hours under occlusive conditions. The entire applied dose was detectable on the application site or the patch (Decad et al., 1983).