Calcium 3-hydroxy-4-[(1-sulphonato-2-naphthyl)azo]-2-naphthoate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics

Type of information:

other: expert statement

Adequacy of study:

key study

Study period:

2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Theoretical assessment taking all currrently available relevant information into account, based on the REACH Guidance: Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance. Since this is a theoretical assessment, the Klimisch value cannot be 1.

Objective of study:

other: Theoretical assessment of toxicokinetics

GLP compliance:

no

Type:

absorption

Results:

For risk assessment purposes, absorption factors for this substance are derived to be 50% (oral), 100% (inhalation) and 100% (dermal) for risk assessment purposes.

Conclusions:

A toxicokinetic assessment was performed based on the available data of Pigment Red 63:1. Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 50% (oral), 100% (inhalation) and 10% (dermal) for risk assessment purposes. The bioaccumulation potential is expected to be low.

Description of key information

A toxicokinetic assessment was performed based on the available data of Pigment Red 63:1. Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 50% (oral), 100% (inhalation) and 10% (dermal) for risk assessment purposes. The bioaccumulation potential is expected to be low.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

After exposure, a substance can enter the body via the gastrointestinal tract, the lungs, and the skin. Since different parameters are relevant for absorption via the different routes of exposure, the three routes will be addressed individually. In general, a compound needs to be dissolved before it can be taken up from the gastrointestinal tract after oral administration. Pigment Red 63:1 (PR 63:1) is moderately water soluble (0.242 mg/L at 23°C). This means that the substance will only dissolve to some extent in the gastrointestinal fluids and it will hence have limited ability to make contact with the mucosal surface to be taken up. Although substances (with a molecular weight below 200) can pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water, this is not expected for PR 63:1 as the molecular weight of PR 63:1 is 460. Upon solution in fluid, C.I. Pigment Red 63:1 is expected to dissociate into two ions. It is generally assumed that ionized substances do not readily diffuse across biological membranes, and absorption is considered to be limited. Whether or not the anion will be present in an ionised form will dependent on the pH, which is known to vary along the GI tract. In an evaluation by the Canadian Authorities, an in vitro study is mentioned based on which it is concluded that PR63:1 is expected to go through substantial azo bond cleavage, as rapid and extensive azo bond cleavage with a half-life of 0.54 hour was measured under anaerobic conditions in a human fecal homogenate (the original report is not published). These results may indicate breakdown rapidly after oral uptake. The breakdown products, 2-amino-1-naphthalenesulfonic acid; CAS no. 81-16-3) and 1-amino-2-naphthol-3-carboxylic acid (CAS no. 13065-86-6) have a molecular weight of appr. 223 and 203, respectively, which would favour passive uptake. Furthermore, the calculated water solubility of 2-amino-1-naphthalenesulfonic acid is a lot higher with 83 g/L at pH 4 (very soluble at higher pH), therefore this breakdown product will dissolve and uptake will be facilitated. The water solubility of the second breakdown product, 1-amino-2-naphthol-3-carboxylic acid, is calculated to be limited (0.020 g/L at pH4), but related to its smaller size uptake of this breakdown product is expected to exceed uptake of PR63:1. Pigment Red 63:1 has a moderate partition coefficient (1.8), and also its expected breakdown products are expected to have moderate partition coefficients (calculated log Pow of the two breakdown products: 0.3 for 2-amino-1-naphthalenesulfonic acid and 2.4 for 1-amino-2-naphthol-3-carboxylic acid). This implies that the substance (or its breakdown products) will dissolve to some extent in lipids, which enables crossing of biological membranes. However, the anion is likely to be present in an ionised state, which is expected to hamper uptake. PR 63:1 is a powder with small particles (MMAD = 12.87 µm). Although undissolved particles would normally be considered too large to cross biological membranes, small amounts of such substances may be transported into epithelial cells by pinocytosis or persorption (passage through gaps in membranes left when the tips of villi are sloughed off). However, significant uptake via this route is only expected for particles in the nanometer size range, which is not the case for PR63:1. PR63:1 has a moderate log P value (1.8 at pH 7), therefore absorption by passive diffusion is expected.

Taken all data together, based on its moderate water solubility, molecular weight, log P, and formation of ions, for risk assessment purposes oral absorption of Pigment Red 63:1 is set at 50% (3). The toxicity data do not provide reason to deviate from the proposed oral absorption factor.

Once absorbed, distribution of PR63:1 throughout the body is expected to some extent based on its limited water solubility and moderate molecular weight. Absorbed PR 63:1 is expected to be excreted mainly via urine. Based on its moderate partition coefficient (1.8), it is unlikely that PR 63:1 will accumulate significantly in adipose tissue.

To determine absorption via inhalation, the processes of deposition of the substance on the surface of the respiratory tract and the actual systemic absorption have to be differentiated. A vapour pressure of less than 0.5 kPa and a boiling point above 150°C indicate a low volatility. No information on vapour pressure is available, however since PR63:1 decomposes at >290°C before it melts, it can be assumed that the substance is of low volatility. On the other hand, its particle size (MMAD = 12.87 µm) indicates potential to be inhaled. In fact, since particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract, PR63:1 can be expected to reach all parts of the lung after inhalation. If particles reach the tracheobronchial region, PR63:1 is likely to diffuse/dissolve into the mucus lining of the respiratory tract due to its moderate water solubility and subsequently it will be absorbed due to its limited molecular weight and moderate partition coefficient (1.8). Based on the above data, for risk assessment purposes the inhalation absorption of C.I. Pigment Red 63:1 is set at 100%. The toxicity data do not provide reason to deviate from the proposed inhaled absorption factor.

PR63:1 is a solid which can only penetrate the skin after it dissolves into the surface moisture of the skin. Although limited, its water solubility is sufficient to allow penetration of the skin. In addition, crossing the skin barrier will not be limited by its molecular weight (MW <500). Furthermore, a log Pow value of 1.8 favours dermal absorption as it is able to dissolve to some extent in lipid membranes. According to the criteria given in the REACH Guidance, a default value of 100% dermal absorption should be used unless MW >500 and log Pow <-1 or >4, in which case a value of 10% skin absorption should be chosen. Based on the MW (460) and log Pow (1.8) of C.I. Pigment Red 63:1 the criteria for 10% dermal absorption are not met. It is generally accepted that dermal absorption is not higher that oral absorption, which for C.I. Pigment Red 63:1 is set at 50%. Furthermore, data on dermal absorption of substance analogue PR57 are available. The outcome of in vitro studies with this analogue were evaluated by the Scientific Committee on Consumer Safety of the European Commission (5). Results of percutaneous absorption through pig skin in vitro, performed according to OECD guideline 428, revealed that only a maximum of 0.007% of the applied dose (test item tested at 0.4% in hair dye) was absorbed. In a second in vitro test, in which the skin penetration of PR 57 was evaluated in a flow-through Franz diffusion cell system using porcine ear skin, a skin penetration rate of 0.039% of the applied dose was found. The authors note that both studies have methodological limitations. In spite of this, it was concluded that overall these studies were scientifically valid and the conclusion was drawn hat only a minimal amount of the test item is absorbed through dermal layers. Based on the highly comparable structure of PR 57 and PR 63:1 as described further in the report that documents that read across rationale (CRL report 517469) it is considered justified to conclude that the dermal uptake of PR 63:1 will be very limited. This conclusion is also shared by the Canadian authorities. Based on these considerations, for risk assessment purposes the dermal absorption of C.I. Pigment Red 63:1 is set at 10%.