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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
year of publication: 1996
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication which meets basic scientific principles
Objective of study:
other: bioavailability of the hypothetical cleavage product 3,3'-dichlorobenzidine (DCB) from the submission substance after oral application
Qualifier:
no guideline followed
Principles of method if other than guideline:
investigation of formation of DCB-hemoglobin and DCB-DNA-adducts
GLP compliance:
no
Radiolabelling:
no
Species:
rat
Strain:
Wistar
Sex:
female
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Duration and frequency of treatment / exposure:
4 weeks
Remarks:
Doses / Concentrations:
0.2% in diet (corresponding to 170 mg/kg bw)
No. of animals per sex per dose / concentration:
6 females
Control animals:
no
Positive control reference chemical:
DCB, application via drinking water
Details on distribution in tissues:
- in three rats no DCB or AcDCB-hemoglobin adducts were detectable (limit of detection: 0.1 ng/g hemoglobin)
- in the remaining three animals adduct levels slightly higher than the individual detection limits for DCB and AcDCB of 0.1 ng/g hemoblobin were detected (total adduct levels < 0.24 - 0.41 ng/g hemoglobin)
- in 2/3 rats liver DNA-adducts slightly above the limit of detection (0.08 ng/g DNA) were detected (0.30 and 0.15 ng adducts/g DNA)

- no signs of toxicity were noticed during the 4 week treatment period

- food consumption and body weight development were similar in treated and in control animals

- the authors concluded that the DCB-adducts were due to the contamination of the test item with the monoazo compound

Conclusions:
Interpretation of results (migrated information): other: the test item is not metabolically splitted into DCB and no DCB becomes bioavailable after repeated oral application
The results indicate that the test item is not metabolically splitted into DCB and that no DCB becomes bioavailable after repeated oral application of the test item. Detection of minimal DCB-hemoglobin adducts in 3/6 rats and minimal DCB-DNA-adducts in the liver of 2/3 rats is probably due to the contamination of the test item with the monoazo compound.
Executive summary:

Female Wistar rats were treated for 4 weeks with 0.2% C.I. Pigment Yellow 13 in the diet. At the end of the exposure period. The hypothetical release of 3,3'-dichlorobenzidine was investigated by analysis of DCB-hemoglobin adducts and DCB-DNA-adduct levels in the liver. Minimal DCB-hemoglobin adducts in 3/6 rats and minimal DCB-DNA-adducts in the liver of 2/3 rats are probably due to the contamination of the test item with the monoazo compound. The results indicate that no DCB is bioavailable after oral ingestion of the test item.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented study report which meets basic scientific principles
Objective of study:
other: bioavailability of cleavage products
Qualifier:
no guideline followed
Principles of method if other than guideline:
investigation of urinary excretion of a potential cleavage product of the test item after oral application
GLP compliance:
not specified
Radiolabelling:
no
Species:
rat
Strain:
other: Tif:RAI f (SPF)
Sex:
male
Route of administration:
oral: gavage
Vehicle:
other: oil (no further information)
Duration and frequency of treatment / exposure:
single exposure
Remarks:
Doses / Concentrations:
0, 40, 400 mg/kg
No. of animals per sex per dose / concentration:
The test was performed with 30 male rats, not indicated how many animals were investigated per substance and dose group
Control animals:
yes
Positive control reference chemical:
3,3'-dichlorobenzidine
Details on excretion:
- no 3,3'-dichlorobenzidine metabolites were detected in the urine collected after administration of the test item

- animals receiving 3,3'-dichlorobenzidine excreted 2-4% of the administered dose within 24 hours and additional 0.2-1% between 24 and 48 hours after application

- limit of detection: 5 µg/l urine

Conclusions:
Interpretation of results (migrated information): other: no indication for a metabolic splitting of the pigment into 3,3'-dichlorobenzidine
The test item is not splitted into 3,3'-dichlorobenzidine after oral application.
Executive summary:

Single oral application of 40 or 400 mg test item/kg bw to male rats did not result in the excretion of 3,3'-dichlorobenzidine in the urine during 48 hours after exposure. After application of 3,3'-dichlorobenzidine about 2 -4% of the applied dose was detected in the urine excreted within 24 hours after application.

Endpoint:
basic toxicokinetics, other
Type of information:
other:
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other:
Remarks:
Expert statement based on available information
Objective of study:
absorption
bioaccessibility (or bioavailability)
distribution
excretion
toxicokinetics
Principles of method if other than guideline:
Evaluation of available toxicological information on the test material with regard to kinetic behvior
GLP compliance:
no
Details on absorption:
Absorption: A prerequisite for a relevant absorption is that the substance can be dissolved in either aqueous (e.g., gastrointestinal fluid, blood plasma, sweat) or lipophilic (e.g., lipoproteins, lipid membranes, triglycerides) media or in both. C.I. Pigment Yellow 176 as well as all its com-ponents can be considered insoluble because it has an extremely low solubility in water (2,3 µg/L) and n-octanol (41 µg/L). Therefore, it is unlikely that C.I. Pigment Yellow 176 be-comes systemically bioavailable after oral, dermal or inhalation exposure.
Based on the subchronic oral toxicity study with C.I. Pigment Yellow 13 absorption of toxi-cologically significant amounts via the gastrointestinal tract is considered unlikely, since C.I. Pigment Yellow 13 did not show any effects on inner organs and blood or urine. No metabo-lites were determined.
The skin sensitisation studies with C.I. Pigment Yellow 13 indicate no local dermal bioavail-ability. Systemic availability also seems to be negligible after dermal exposure since no sys-temic signs of intoxication were seen after occlusive administration of 500 mg C.I. Pigment Yellow 176 or PY 13 per kg body weight in rabbits in the acute dermal irritation studies.
Dermal absorption is, therefore, considered unlikely.
In the unlikely event of exposure to aerosolized pigment in respirable form, the substance is considered to behave like an inert dust. Therefore, the deposited pigment particles will mostly be cleared from the lung via the mucocilliary transport. As the pigment will not dis-solve quickly in the lung surfactant, the only efficient way the pigment can enter the body is via phagocytosis of pigment particles by lung macrophages followed by migration of the macrophages into the interstitium and into the draining lymph nodes. However, the internal dose delivered via this mechanism can be considered negligible.

Details on distribution in tissues:
Distribution:
The repeated dose toxicity study with C.I. Pigment Yellow 13 did not indicate any relevant histopathological changes in any of the investigated organs. In the sub-chronic inhalation study local effects were seen in the lungs, which were interpreted as the normal “clean-up” of the lung after inert dust exposure.
This may indicate that the pigment either does not affect specific organs as targets, i.e., is non-toxic, or is not distributed within the body in significant amounts. As indicated above, the physico-chemical parameters of the pigment support the conclusion that the pigment is not absorbed into the body and thus does not become systemically available. There were also no other signs of deposition of the pigment in any organ not exposed directly (except portal of entry: skin, lung, gut) including excretory organs, like the kidney, indicating that even exposure to high doses of the pigment does not lead to bioaccumulation in special compart-ments of the body.
Based on the available information on absorption distribution of the test material in the body in significant amounts is unlikely and specific hotspots of distribution cannot be identified.
Thus, it is concluded, that C.I. Pigment Yellow 176 as well as PY 13 is not systemically available at relevant concentrations within the organism.
There were no signs of bioaccumulation of the test material. The only exception could be the lung as portal of entry after prolonged exposure to excessive concentrations of dust (lung overload). This view is supported by the physical-chemical properties (solubility in water and octanol).

Details on excretion:
Excretion:
Considering the physico-chemical properties and the molecular structure and size of the mol-ecules and the absence of any indication of absorption and/or metabolism it is assumed that excretion, if any, is likely to occur via faeces. This notion is confirmed by the discoloration of faeces observed in the oral studies as the only alteration.
Metabolites identified:
no
Details on metabolites:
Metabolism:
Since the solution of the substance in cellular fluid or cellular membranes is a prerequisite for its metabolism, it is unlikely that the insoluble pigment becomes accessible for metabo-lizing systems in relevant amounts.
Diarylide yellow pigments are not or only to a negligible extend cleaved, taking into ac-count the negative results obtained with C.I. Pigment Yellow 13 in investigations on kinetic behavior.
The results of the mutagenicity tests provide qualitative information on the metabolic fate of C.I. Pigment Yellow 176 and PY13. In the mutagenicity tests, the pigment proved to be non-mutagenic in the absence as well as in the presence of an exogenous metabolizing sys-tem, indicating that the pigment, even directly exposed to metabolizing enzymes, is not converted into toxic or genotoxic metabolites. This conclusion is also supported by the lack of any morphological and histopathological changes of organs involved in xenobiotic me-tabolism, such as the liver, in the subacute and sub-chronic toxicity studies with C.I. Pig-ment Yellow 13. Furthermore, the missing skin or eye irritating or skin sensitizing properties argue against any interaction with biological material.
Therefore, C.I. Pigment Yellow 13 as well as Pigment Yellow 176 is considered to just pass through the intestinal tract without significant metabolism.
Conclusions:
Based on all available data, C.I. Pigment Yellow 176 does not exhibit conspicuous toxicoki-netic behaviour in the sense of accumulative and/or delayed effects with regard to the indi-vidual parameters absorption, distribution, metabolism and excretion. The only exception could be the lung as portal of entry after prolonged exposure to excessive concentrations of dust (lung overload).
The results from studies with dermal exposure indicate that C.I. Pigment Yellow 13 has a no relevant dermal absorptive potential. C.I. Pigment Yellow 176 is most probably not absorbed from the gastrointestinal tract in significant amounts.
Indications of an intense metabolism or a bio-accumulative potential do not exist as no tox-icity occurred even after chronic exposure, which points to no bio-accumulation potential and complete excretion of all possibly systemically available C.I. Pigment Yellow 176 and/or me-tabolites
Executive summary:

Based on the available data base on C.I. Pigment Yellow 176 relevant information exists to make a qualitative evaluation of the toxicokinetic profile of this compound. This is in line with animal welfare considerations because additional animal tests can be avoided by such an evaluation. The substance is available in nano-form. The available data have partly been generated with non-specified material, but the conclusions drawn are considered valid for the nano form as well, because the material is chemically identical, and the physical properties are widely overlapping.


 


The results of basic toxicity testing give no reason to anticipate unusual characteristics regarding the toxico-kinetics of C.I. Pigment Yellow 176. C.I. Pigment Yellow 176 is not absorbed from the gastro-intestinal tract in toxicologically significant amounts. The data indicate that there is no relevant dermal absorption. After inhalation unspecific reactions to unreactive dust can be expected. Indications of a bio-accumulative potential as well as metabolism towards genotoxic sub-structures do not exist. Excretion of traces of possibly systemically available C.I. Pigment Yellow 176 and/or metabolites via faeces is likely.

Description of key information

Based on the available data base on C.I. Pigment Yellow 176 relevant information exists to make a qualitative evaluation of the toxicokinetic profile of this compound. This is in line with animal welfare considerations because additional animal tests can be avoided by such an evaluation. The substance is available in nano-form. The available data have partly been generated with non-specified material, but the conclusions drawn are considered valid for the nano form as well, because the material is chemically identical, and the physical properties are widely overlapping.


 


The results of basic toxicity testing give no reason to anticipate unusual characteristics regarding the toxico-kinetics of C.I. Pigment Yellow 176. C.I. Pigment Yellow 176 is not absorbed from the gastro-intestinal tract in toxicologically significant amounts. The data indicate that there is no relevant dermal absorption. After inhalation unspecific reactions to unreactive dust can be expected. Indications of a bio-accumulative potential as well as metabolism towards genotoxic sub-structures do not exist. Excretion of traces of possibly systemically available C.I. Pigment Yellow 176 and/or metabolites via faeces is likely.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information