Pyrrolo[3,4-c]pyrrole-1,4-dione, 3,6-bis([1,1'-biphenyl]-4-yl)-2,5-dihydro-

Endpoint summary

Additional information

There are no studies available in which the toxicokinetic properties of the target substance was investigated. Therefore, the following assessment is based on the available data on physicochemical properties of the target and source substances as well as on the results from the toxicokinetic study with source substance 1.

 

Absorption

 

Oral:

Generally, solids have to dissolve before they can be absorbed. With regard to the poor water solubility, the substances are not expected to readily dissolve into the gastrointestinal fluids. However, the moderate molecular weights below 500 and moderate log P values are favorable for absorption by passive diffusion. For source substance 1 (Pigment Red 254, CAS 84632-65-5, bulk) a toxikokinetic study (OECD guideline 117, GLP) in rats is available and no significant uptake of the pigment after gavage dosing was observed. In this study, 14C-labelled test compound was administered at two target dose levels of 100 mg/kg (low dose) and 1000 mg/kg (high dose) to male rats and radioactivity appearing in urine, feces, blood/plasma and organs/tissues was measured for various intervals up to 168 hours. In plasma, values which exceeded the limit of quantitation by less than 1.5fold were found around 2h after dosing. This finding was considered to be related to the 0.2% extractable radioactive impurity in the test material and not to indicate uptake of the pigment. The target substance and source substance 1 are equally poorly soluble in water and organic solvents. The smaller size of source substance 1 is more favourable in regard to uptake. Therefore, since no uptake was observed for the smaller read-across substance, the same can be derived for the target substance. In line with the assumptions made on the poor gastrointestinal absorption, experimental data indicates the absence of systemic availability as no effects were observed. Single administration via the oral route did not overt acute toxicity in the available studies on target and source substances. Additionally, subacute repeated dose application via the oral route did not induce signs of local or systemic toxicity, the NOAELs were considered to be at the limit dose of 1000 mg/kg bw/d for all substances. This is typical for organic pigments that are neither sufficiently soluble in water or octanol for transport via biological membranes.

 

Dermal:

Dry particulates will have to dissolve into the surface moisture of the skin before uptake can begin. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Although the moderate log P values between 1 and 4  favour dermal absorption, dermal uptake is likely to be low based on the the poor water solubility of the target and source substances ( < 1 mg/L). In line with this, no effects, were seen in available studies on dermal acute toxicity as well as in studies on skin sensitization and skin irritation were negative, and therefore gave no indication on dermal absorption.

 

Inhalation:

The substances have a comparably very low vapor pressure. This indicates that absorption via vapour inhalation is not relevant. As the substances are powders, inhalation of particles is possible. In an acute inhalation toxicity study with source substance 1 (bulk), 2.25 mg/L air did not cause any signs of toxicity. However, exposure to the supporting substance 1 (nano) resulted in an LC0 value of 1 and a LC100 values of 5 mg/L. Therefore, supporting substance 1 fulfills the criteria for classification to Cat. 4 for acute inhalation toxicity according to Regulation (EC) No. 1272/2008. In a 90-day subchronic inhalation toxicity study on source substance 3, however, systemic effects were absent up to the highest tested dose (40mg/L).

 

 

 

Distribution and Accumulation

 

Since the substances are water-insoluble molecules, they will not diffuse through aqueous channels and pores. Therefore, a distribution into different organs is not assumed. No bioaccumulation hazard is expected based on results of sub-acute oral toxicity data in rats and physico-chemical properties. In line with this, the absence of uptake after oral dosing of a related pigment (source substance 1) was observed in a kinetic study in rats.

A test on biosolubility (static) and on dissolution kinetics (dynamic) in phagolysosomal simulant fluids was performed with the target, source substance 1 and supporting substances 1-4 to determine the persistence after uptake in cells, e.g., alveolar macrophages. All substances tested were insoluble in phagolysosomal simulant fluid at pH 4.5 in the static and dynamic dissolution assay.

 

Metabolism

 

No indication of uptake or reactivity was observed in any study, including acute studies, irritation, sensitization, repeated dose toxicity and study. Studies assessing genotoxicity were negative, i.e. there was no indication of a reactivity of the test substance or potential metabolites with macromolecules under the chosen test conditions.

Observation of stained feces in oral acute and subacute repeated dose toxicity studies indicate the absence of metabolic activities and suggest that the substances are excreted unchanged.

In the unlikely case of uptake, potential metabolism might involve hydroxylation of the ring systems and phase-II reaction, i.e. glucuronidation.

 

 

Excretion

 

The substances are expected to be excreted unchanged via the feces. In line with this, discoloured feces was observed in the toxicity studies. In a toxicokinetic study on source substance 1, mentioned above, minimal amounts (<0.6% of the total dose) were excreted via the urine at both dose levels. This was considered to be caused by contamination with feces, but it may also be related to the radioactive impurity in the test material. Excretion of 14C-labelled pigment proceeded exclusively via the feces and amounted after 168 hours, on average, to 119.7 % and 96.0 % at the low and high dose level, respectively.