Registration Dossier

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Type of information:
other: Expert statement
Adequacy of study:
other information
Study period:
2021
Reliability:
2 (reliable with restrictions)
Objective of study:
absorption
distribution
metabolism
toxicokinetics
GLP compliance:
no
Type:
absorption
Results:
See Summary and discussion of toxicokinetics
Type:
distribution
Results:
See Summary and discussion of toxicokinetics
Type:
metabolism
Results:
See Summary and discussion of toxicokinetics
Details on absorption:
See Summary and discussion of toxicokinetics
Details on distribution in tissues:
See Summary and discussion of toxicokinetics
Details on metabolites:
See Summary and discussion of toxicokinetics
Conclusions:
Overall, since the substance is not soluble in organic solvents, accumulation in fat tissues is not possible and the substance has no potential for bioaccumulation.
Executive summary:

The toxicokinetic assessment is mainly based on the absence of adverse findings upon acute and subacute oral toxicity testing and on physic-chemical properties. It concludes that the pigments are inert and are not taken up by the body. Therefore, there is no potential for bioaccumulation. 

 

An overview on the structures is given in the attachment of the CSR as part of the read-across justification for the ecotoxicological endpoints.

The high molecular weight of 844.5 g/mol (Pigment Brown 41) is just below the general threshold of 1000 g/mol for cellular uptake. Both water and octanol solubility are less than 0.1 mg/L which impedes transport in both aqueous and non-aqueous compartments. Pigment Brown 41 is ionisable at physiological pH; specifically no increased solubility or degradation in stomach acid is possible.

Modelling of the molecular dimensions shows that the substance is large and bulky. As the pigments completely consist of conjugated systems, the molecule is not flexible which again hinders uptake.

 

The pigment contains azo and amide bonds which according to textbook knowledge on xenobiotic metabolism are susceptible to enzymatic cleavage. This would in all cases result in the formation of aromatic mono- and p-di-amines. Available toxicity data on these amines is summarized in table C below. Their hazard potential depends on the electron-donating or withdrawing character of the substituent as well as its position on the ring. For example, if structure analogue Pigment Red 166 would be metabolized, p-phenylene diamine would be released and for this substance, a NOAEL of 16 mg/kg bw for subchronic oral exposure was obtained (ECHA dissiminated dossier on CAS 106-50-3).

 

Therefore, absence of systemic toxicity upon subacute oral exposure to analogue substances Pigment Red 220 and 166 is a strong argument against systemic uptake and consequential metabolism of disazocondensation red pigments.

Release of aromatic amines would also have been detected via genotoxicity in the in-vivo micronucleus assays with analogue substance Pigment Red 166. However, all of these tests were negative, as were the in-vitro tests both with and without Prival modification for azo compounds. Analogue substances Pigment Red 144 and 166 were tested with the Prival modification. Absence of uptake into cells and the body is consistent with the physico-chemical properties. Indeed, the red chromophore of the pigment remains intact during the passage through the gastrointestinal tract, as indicated by the red color of the feces of orally treated rats.

 

Dermal route of exposure

The molecular weight is well above the threshold of 500 g/mol which is given in the EU guidance document on dermal absorption (Sanco/222/2000 rev. 7, March 19, 2004). This threshold allows the assumption of 10% dermal permeation if the n-octanol/water partition coefficient is either very low (-1) or high (> 4). The threshold for log Pow is not reached for every member, but this is due to the overall very poor solubility of the pigments. Solubility is in the low mg/L range which is hindering any transport process.

None of the available data indicates that the pigments cause skin irritation which would damage the dermal barrier. Absence of systemic uptake after ingestion postulated.

 

Inhalation route of exposure

Considering the size and the poor solubility, disazocondensation red pigments are considered to behave like inert nuisance dust. Significant systemic uptake via the respiratory epithelium is not expected.

 

Overall, since the substance is not soluble in organic solvents, accumulation in fat tissues is not possible and the substance has no potential for bioaccumulation.

 

Description of key information

The substance is considered to be too large to be taken up after ingestion or after dermal uptake. This consideration is based on the physico-chemical properties and the findings of the subacute oral toxicity studies. It is insoluble in both hydrophilic and lipophilic solvents and cannot accumulate in tissues.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

The toxicokinetic assessment is mainly based on the absence of adverse findings upon acute and subacute oral toxicity testing and on physic-chemical properties. It concludes that the pigments are inert and are not taken up by the body. Therefore, there is no potential for bioaccumulation. 

 

An overview on the structures is given in the attachment of the CSR as part of the read-across justification for the ecotoxicological endpoints.

The high molecular weight of 844.5 g/mol (Pigment Brown 41) is just below the general threshold of 1000 g/mol for cellular uptake. Both water and octanol solubility are less than 0.1 mg/L which impedes transport in both aqueous and non-aqueous compartments. Pigment Brown 41 is ionisable at physiological pH; specifically no increased solubility or degradation in stomach acid is possible.

Modelling of the molecular dimensions shows that the substance is large and bulky. As the pigments completely consist of conjugated systems, the molecule is not flexible which again hinders uptake.

 

The pigment contains azo and amide bonds which according to textbook knowledge on xenobiotic metabolism are susceptible to enzymatic cleavage. This would in all cases result in the formation of aromatic mono- and p-di-amines. Available toxicity data on these amines is summarized in table C below. Their hazard potential depends on the electron-donating or withdrawing character of the substituent as well as its position on the ring. For example, if structure analogue Pigment Red 166 would be metabolized, p-phenylene diamine would be released and for this substance, a NOAEL of 16 mg/kg bw for subchronic oral exposure was obtained (ECHA dissiminated dossier on CAS 106-50-3).

 

Therefore, absence of systemic toxicity upon subacute oral exposure to analogue substances Pigment Red 220 and 166 is a strong argument against systemic uptake and consequential metabolism of disazocondensation red pigments.

Release of aromatic amines would also have been detected via genotoxicity in the in-vivo micronucleus assays with analogue substance Pigment Red 166. However, all of these tests were negative, as were the in-vitro tests both with and without Prival modification for azo compounds. Analogue substances Pigment Red 144 and 166 were tested with the Prival modification. Absence of uptake into cells and the body is consistent with the physico-chemical properties. Indeed, the red chromophore of the pigment remains intact during the passage through the gastrointestinal tract, as indicated by the red color of the feces of orally treated rats.

 

Dermal route of exposure

The molecular weight is well above the threshold of 500 g/mol which is given in the EU guidance document on dermal absorption (Sanco/222/2000 rev. 7, March 19, 2004). This threshold allows the assumption of 10% dermal permeation if the n-octanol/water partition coefficient is either very low (-1) or high (> 4). The threshold for log Pow is not reached for every member, but this is due to the overall very poor solubility of the pigments. Solubility is in the low mg/L range which is hindering any transport process.

None of the available data indicates that the pigments cause skin irritation which would damage the dermal barrier. Absence of systemic uptake after ingestion postulated.

 

Inhalation route of exposure

Considering the size and the poor solubility, disazocondensation red pigments are considered to behave like inert nuisance dust. Significant systemic uptake via the respiratory epithelium is not expected.

 

Overall, since the substance is not soluble in organic solvents, accumulation in fat tissues is not possible and the substance has no potential for bioaccumulation.