2,2'-[(3,3'-dichloro[1,1'-biphenyl]-4,4'-diyl)bis(azo)]bis[3-oxo-N-phenylbutyramide]

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

2020

Reliability:

2 (reliable with restrictions)

Details on 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 12 can be considered insoluble because it has an extremely low solubility in water and n-octanol. Therefore, it is unlikely that C.I. Pigment Yellow 12 becomes systemically bioavailable after oral, dermal or inhalation exposure.
Based on the chronic oral toxicity study with C.I. Pigment Yellow 12 absorption of toxicologically significant amounts via the gastrointestinal tract is considered unlikely, since C.I. Pigment Yellow 12 did not show any effects on inner organs and blood or urine. No metabolites could be detected.
The skin sensitisation studies with C.I. Pigment Yellow 12 indicate no local dermal bioavailability. Systemic availability also seems to be negligible after dermal exposure since no systemic signs of intoxication were seen after occlusive administration of 500 mg C.I. Pigment Yellow 12's structural analogue per kg body weight in rabbits in the acute dermal irritation study.
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 dissolve in the lung surfactant, the only 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:

The Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test as well as all older studies employing repeated exposure with C.I. Pigment Yellow 12 did not indicate any relevant histopathological changes in any of the investigated organs. 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 including excretory organs, like the kidney, indicating that even exposure to high doses of the pigment does not lead to bioaccumulation in special compartments 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 12 is not systemically available at relevant concentrations within the organism.
There were no signs of bioaccumulation of the test material. This view is supported by the physical-chemical properties (solubility in water and octanol)

Details on 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:

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 metabolizing 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 12 in investigations on car-cinogenicity.
The results of the mutagenicity tests provide qualitative information on the metabolic fate of C.I. Pigment Yellow 12. In the mutagenicity tests, the pigment proved to be non-mutagenic in the absence as well as in the presence of an exogenous metabolizing system, indicating that the pigment, even directly exposed to metabolizing enzymes, is not convert-ed into toxic or genotoxic metabolites. This conclusion is also supported by the lack of any morphological and histopathological changes of organs involved in xenobiotic metabolism, such as the liver, in the Chronic Toxicity Study with C.I. Pigment Yellow 12. Furthermore, the missing skin or eye irritating or skin sensitizing properties argue against any interaction with biological material.
Therefore, C.I. Pigment Yellow 12 is considered to just pass through the intestinal tract without significant metabolism.

Bioaccessibility (or Bioavailability) testing results:

Bio-accessability is not likely

Conclusions:

Based on all available data, C.I. Pigment Yellow 12 does not exhibit conspicuous toxicokinetic behaviour in the sense of accumulative and/or delayed effects with regard to the individual parameters absorption, distribution, metabolism and excretion.
The results from studies with dermal exposure indicate that C.I. Pigment Yellow 12 has a no relevant dermal absorptive potential. C.I. Pigment Yellow 12 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 toxicity occurred even after chronic exposure, which points to no bio-accumulation potential and complete excretion of all possibly available C.I. Pigment Yellow 12 and/or metabolites.

Executive summary:

Based on the available data base on C.I. Pigment Yellow 12 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 bulk- as well as nano-form. The available data have mostly been generated with non-nano 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 12. C.I. Pigment Yellow 12 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 12 and/or metabolites via faeces is likely.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

read-across source

Objective of study:

metabolism

Radiolabelling:

no

Species:

hamster

Strain:

other: Syrian Golden

Sex:

male

Route of administration:

oral: gavage

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

Bioaccessibility (or Bioavailability) 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.

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reason / purpose for cross-reference:

read-across source

Species:

rat

Strain:

Fischer 344

Sex:

male

Route of administration:

oral: gavage

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 (or Bioavailability) 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.

Reference 4

Endpoint:

dermal absorption in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reason / purpose for cross-reference:

read-across source

Species:

rat

Strain:

Fischer 344

Type of coverage:

occlusive

Signs and symptoms of toxicity:

not specified

Dermal irritation:

not specified

Key result

Time point:

24 h

Dose:

2.57-2.95 µCi/rat

Parameter:

percentage

Absorption:

0 %

Remarks on result:

other: 24 hours

Remarks:

1.9 +/- 0.4 µCi were detectable in skin samples

Conclusions:

The test item was not absorbed by rats after dermal application.

Executive summary:

Radioactive labelled test item was applied to male rats on the shaved skin of the mid-dorsal area for 24 hours under occlusive conditions. No test item was detected in blood, urine and liver on the first day after exposure. Radioactivity detected at the site of application and on the patch and pipet tip accounted for the entire applied dose. These data indicate, that the test item is not absorbed by rats after dermal application.

Reference 5

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key 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 / concentration:

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 (or Bioavailability) 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.

Reference 6

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key 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 for cross-reference:

reference to same study

Objective of study:

absorption

distribution

excretion

Qualifier:

equivalent or similar to guideline

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 / concentration:

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 (or Bioavailability) 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.

Reference 7

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

key 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 for cross-reference:

reference to same study

Principles of method if other than guideline:

testing of absorption, distribution and excretion after single dermal application

GLP compliance:

no

Radiolabelling:

yes

Remarks:

14-C labelled, 11 µCi/µmol

Species:

rat

Strain:

Fischer 344

Sex:

male

Type of coverage:

occlusive

Vehicle:

other: Emulphor EL-620:ethanol (1:1, v/v)

Duration of exposure:

24 hours

Doses:

- 2.57-2.95 µCi/rat

No. of animals per group:

>/= 3 (no further information)

Control animals:

no

Details on study design:

- region of exposure: mid dorsal area
- pretreatment: shaved with an electric clipper on the day before experiment
- area: 4 x 4 square centimeter

Signs and symptoms of toxicity:

not specified

Dermal irritation:

not specified

Total recovery:

- 112 +/- 3% of the administered dose

Key result

Time point:

24 h

Dose:

2.57-2.95 µCi/rat

Parameter:

percentage

Absorption:

0 %

Remarks on result:

other: 24 hours

Remarks:

1.9 +/- 0.4 µCi were detectable in skin samples

- No radioactivity above background levels were detectable in blood, urine and liver.

- The total dermally administered dose could be accounted for by the radioactivity at the site of application and on the patch and pipet tip.

Conclusions:

The test item was not absorbed by rats after dermal application.

Executive summary:

Radioactive labelled test item was applied to male rats on the shaved skin of the mid-dorsal area for 24 hours under occlusive conditions. No test item was detected in blood, urine and liver on the first day after exposure. Radioactivity detected at the site of application and on the patch and pipet tip accounted for the entire applied dose. These data indicate, that the test item is not absorbed by rats after dermal application.

Description of key information

Based on the available data base on C.I. Pigment Yellow 12 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 results of basic toxicity testing give no reason to anticipate unusual characteristics regarding the toxico-kinetics of C.I. Pigment Yellow 12. C.I. Pigment Yellow 12 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 12 and/or metabolites via faeces is likely.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential