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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
other: Expert statement
Adequacy of study:
key study
Study period:
2021
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
other: Expert statement
Title:
Unnamed
Year:
2021
Report date:
2021

Materials and methods

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

Test material

Constituent 1
Chemical structure
Reference substance name:
N-(2,3-dihydro-2-oxo-1H-benzimidazol-5-yl)-3-oxo-2-[[2-(trifluoromethyl)phenyl]azo]butyramide
EC Number:
268-734-6
EC Name:
N-(2,3-dihydro-2-oxo-1H-benzimidazol-5-yl)-3-oxo-2-[[2-(trifluoromethyl)phenyl]azo]butyramide
Cas Number:
68134-22-5
Molecular formula:
C18H14F3N5O3
IUPAC Name:
3-oxo-N-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2-{[2-(trifluoromethyl)phenyl]diazenyl}butanamide
Test material form:
solid: nanoform

Results and discussion

Toxicokinetic / pharmacokinetic studies

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.

Metabolite characterisation studies

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)

Bioaccessibility (or Bioavailability) testing results:
The test item is considered "not bio-available"

Applicant's summary and conclusion

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.

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