N-(2,3-dihydro-2-oxo-1H-benzimidazol-5-yl)-3-oxo-2-[[2-(trifluoromethyl)phenyl]azo]butyramide

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:

2021

Reliability:

2 (reliable with restrictions)

Objective of study:

absorption

distribution

excretion

metabolism

Principles of method if other than guideline:

Available data on the test item were evaluated with regard to kinetic parameters

GLP compliance:

no

Details on absorption:

A prerequisite for a relevant absorption is that the substance can be dissolved in either aque-ous (e.g., gastrointestinal fluid, blood plasma, sweat) or lipophilic (e.g., lipoproteins, lipid membranes, triglycerides) media or in both. PY 154 can be considered insoluble because it has an extremely low solubility in water and n-octanol. Therefore, it is unlikely that PY 154 becomes systemically bioavailable after oral, dermal or inhalation exposure.
Based on the acute and subacute oral toxicity studies with C.I. Pigment Yellow 154 in com-bination with its extremely low solubility absorption of toxicologically significant amounts via the gastrointestinal tract is considered unlikely, since C.I. Pigment Yellow 154 did not show any effects. This is confirmed by experience with other pigments of the acetolone group, which did not cause any effects even after prolonged exposure in sub-chronic studies.
The skin sensitisation studies with C.I. Pigment Yellow 154 indicate no local dermal bioa-vailability. 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. Pig-ment Yellow 154 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 muco-cilliary transport. As the pigment will not dissolve in the lung surfactant, the only way the pigment can enter the body is via phagocy-tosis 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 deliv-ered via this mechanism can be considered negligible.

Details on distribution in tissues:

There is not measured information on the distribution of PY 154 itself, but Repeated Dose Toxicity Studies with PY 154 and analogue Acetolone-Pigments did not indicate any rele-vant histopathological changes in any of the investigated organs. This may indicate that the pigment either does not affect special 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 these pigments does not lead to bioaccumulation in special com-partments of the body. There is just one exception: The insoluble particles can be found in the lung after inhalation. This however is no sign of absorption and distribution but a deposi-tion on the surface of first contact. This observation even indicates that the material is not absorbed at all.
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 154 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 ma-terial 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 acute study as the only alteration.

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 metabo-lizing systems in relevant amounts.
The results of the mutagenicity test provide useful indications for qualitative consideration of the metabolic fate of C.I. Pigment Yellow 154. In the mutagenicity test, the pigment proved to be non-mutagenic in the absence as well as in the presence of an exogenous me-tabolizing system, indicating that the pigment is not converted into toxic or genotoxic me-tabolites. This conclusion is also supported by the lack of any morphological and histo-pathological changes of organs involved in xenobiotic metabolism, such as the liver, in stud-ies with analogue pigments. Furthermore, the missing skin or eye irritating or skin sensitiz-ing properties argue against any interaction with biological material.
Therefore, C.I. Pigment Yellow 154 is considered to just pass through the intestinal tract without significant metabolism.

Bioaccessibility (or Bioavailability) testing results:

The test item is considered "not bio-available"

Conclusions:

Based on all available data, C.I. Pigment Yellow 154 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 results from studies with dermal exposure indicate that C.I. Pigment Yellow 154 has a no relevant dermal absorptive potential. C.I. Pigment Yellow 154 is most probably not ab-sorbed 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. Additionally, no systemic effects were observed in the repeated dose oral toxicity studies on analogue acetolone pigments, which points to no bio-accumulation poten-tial and complete excretion of all possibly available C.I. Pigment Yellow 154 and/or metabo-lites.

Executive summary:

Based on the available data base on C.I. Pigment Yellow 154 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 results of basic toxicity testing give no reason to anticipate unusual characteristics regarding the toxicokinetics of C.I. Pigment Yellow 154. The data indicate that there is no relevant dermal absorption. C.I. Pigment Yellow 154 is not absorbed from the gastro-intestinal tract in toxicologically significant amounts. Indications of a bio-accumulative potential as well as metabolism towards genotoxic sub-structures do not exist. Excretion of small amounts of possibly systemically available C.I. Pigment Yellow 154 and/or metabolites via faeces is likely.

Reference 2

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2011

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Method not validated

Objective of study:

metabolism

Principles of method if other than guideline:

Aqueous solutions of the test material were analysed via gas chromatography–mass spectrometry (GC-MS) in order to detect cleavage products. Fragments bearing CF-3 groups at m/z 69 should be identified. The results obtained with either neutral or acidic solutions (water or hydrochloric acid solutions with pH values of 7 or 2, respectively) were compared.

GLP compliance:

no

Radiolabelling:

no

Type:

metabolism

Results:

no cleavage products identified under the conditions used in GC-MS analysis

Metabolites identified:

no

Details on metabolites:

Results
m/z 69 was used for SIM-mode analysis. The following table shows the differences which were found for the two solvents (see table 1 in "Any other information on results incl. tables").
The signals at 25.51 min, 26.75 min and 28.25 min are close to the noise. The full-MS mode (m/z 35-650) shows that all peaks for which a difference could be found are relatively small (≤10%).
Some differences in the chromatograms were found (s. table). However, it was not possible to clearly identify cleavage products of the test material under the used conditions.

Table 1: Peaks in H2O and HCl solution	Retention time [min]	Difference in relative intensity
HCl	24.73	-
	25.51	-
	26.75	-
	28.25	-
	29.39	-
	48.90	yes
H2O	not existing	-
	not existing	-
	not existing	-
	not existing	-
	not existing	-
	48.90	yes

Conclusions:

Scope of this project was to find cleavage products of the test item. Hydrochloric acid was used for hydrolysis (in order to simulate the acidic conditions of the stomach) and GC-MS was used to detect fragments bearing CF3-groups at m/z 69. An aqueous solution of the test item was prepared as reference. Some differences in the chromatograms were found (s. table). In this study no fragments containing CF3-groups could be identified leading to the conclusion that no cleavage of the pigment occurs under the acid conditions applied.

Reference 3

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

2021

Reliability:

2 (reliable with restrictions)

Objective of study:

absorption

distribution

excretion

metabolism

Principles of method if other than guideline:

Available data on the test item were evaluated with regard to kinetic parameters

GLP compliance:

no

Details on absorption:

A prerequisite for a relevant absorption is that the substance can be dissolved in either aque-ous (e.g., gastrointestinal fluid, blood plasma, sweat) or lipophilic (e.g., lipoproteins, lipid membranes, triglycerides) media or in both. PY 154 can be considered insoluble because it has an extremely low solubility in water and n-octanol. Therefore, it is unlikely that PY 154 becomes systemically bioavailable after oral, dermal or inhalation exposure.
Based on the acute and subacute oral toxicity studies with C.I. Pigment Yellow 154 in com-bination with its extremely low solubility absorption of toxicologically significant amounts via the gastrointestinal tract is considered unlikely, since C.I. Pigment Yellow 154 did not show any effects. This is confirmed by experience with other pigments of the acetolone group, which did not cause any effects even after prolonged exposure in sub-chronic studies.
The skin sensitisation studies with C.I. Pigment Yellow 154 indicate no local dermal bioa-vailability. 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. Pig-ment Yellow 154 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 muco-cilliary transport. As the pigment will not dissolve in the lung surfactant, the only way the pigment can enter the body is via phagocy-tosis 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 deliv-ered via this mechanism can be considered negligible.

Details on distribution in tissues:

There is not measured information on the distribution of PY 154 itself, but Repeated Dose Toxicity Studies with PY 154 and analogue Acetolone-Pigments did not indicate any rele-vant histopathological changes in any of the investigated organs. This may indicate that the pigment either does not affect special 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 these pigments does not lead to bioaccumulation in special com-partments of the body. There is just one exception: The insoluble particles can be found in the lung after inhalation. This however is no sign of absorption and distribution but a deposi-tion on the surface of first contact. This observation even indicates that the material is not absorbed at all.
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 154 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 ma-terial 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 acute study as the only alteration.

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 metabo-lizing systems in relevant amounts.
The results of the mutagenicity test provide useful indications for qualitative consideration of the metabolic fate of C.I. Pigment Yellow 154. In the mutagenicity test, the pigment proved to be non-mutagenic in the absence as well as in the presence of an exogenous me-tabolizing system, indicating that the pigment is not converted into toxic or genotoxic me-tabolites. This conclusion is also supported by the lack of any morphological and histo-pathological changes of organs involved in xenobiotic metabolism, such as the liver, in stud-ies with analogue pigments. Furthermore, the missing skin or eye irritating or skin sensitiz-ing properties argue against any interaction with biological material.
Therefore, C.I. Pigment Yellow 154 is considered to just pass through the intestinal tract without significant metabolism.

Bioaccessibility (or Bioavailability) testing results:

The test item is considered "not bio-available"

Conclusions:

Based on all available data, C.I. Pigment Yellow 154 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 results from studies with dermal exposure indicate that C.I. Pigment Yellow 154 has a no relevant dermal absorptive potential. C.I. Pigment Yellow 154 is most probably not ab-sorbed 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. Additionally, no systemic effects were observed in the repeated dose oral toxicity studies on analogue acetolone pigments, which points to no bio-accumulation poten-tial and complete excretion of all possibly available C.I. Pigment Yellow 154 and/or metabo-lites.

Executive summary:

Based on the available data base on C.I. Pigment Yellow 154 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 results of basic toxicity testing give no reason to anticipate unusual characteristics regarding the toxicokinetics of C.I. Pigment Yellow 154. The data indicate that there is no relevant dermal absorption. C.I. Pigment Yellow 154 is not absorbed from the gastro-intestinal tract in toxicologically significant amounts. Indications of a bio-accumulative potential as well as metabolism towards genotoxic sub-structures do not exist. Excretion of small amounts of possibly systemically available C.I. Pigment Yellow 154 and/or metabolites via faeces is likely.

Description of key information

Based on the available data base on C.I. Pigment Yellow 154 relevant information exists to make a qualitative evaluation of the toxicokinetic profile of this compound. The substance is available in nano- as well as in bulk-form.

The results of basic toxicity testing give no reason to anticipate unusual characteristics regarding the toxicokinetics of C.I. Pigment Yellow 154. The data indicate that there is no relevant dermal absorption. C.I. Pigment Yellow 154 is not absorbed from the gastro-intestinal tract in toxicologically significant amounts. Indications of a bio-accumulative potential as well as metabolism towards genotoxic sub-structures do not exist. Excretion of small amounts of possibly systemically available C.I. Pigment Yellow 154 and/or metabolites via faeces is likely.

A study was conducted to find cleavage products of the test item. Hydrochloric acid was used for hydrolysis (in order to simulate the acidic conditions of the stomach) and GC-MS was used to detect fragments bearing CF3-groups at m/z 69. An aqueous solution of the test item was prepared as reference. Some differences in the chromatograms were found (s. table). In this study no fragments containing CF3-groups could be identified leading to the conclusion that no cleavage of the pigment occurs under the acid conditions applied.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential