Disodium 7-amino-4-hydroxy-3-[[4-[(4-sulphonatophenyl)azo]phenyl]azo]naphthalene-2-sulphonate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: expert statement

Adequacy of study:

key study

Study period:

2017

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

toxicokinetics

Qualifier:

according to guideline

Guideline:

other: according to ECHA Guidance R.7c, June 2017, v.3

Type:

absorption

Results:

estimated for risk assessement purposes: oral 30%; dermal 10%; inhalation 50%

Conclusions:

No bioaccumulation potential based on available data and a qualitative assessment accordind to ECHA Guidance R.7c, June 2017, v.3

Description of key information

1. Short description of key information

The toxicokinetics of the substance CAS 6300-50-1 / EC 228-589-1 has been assessed based on the physicochemical properties and available toxicological data and following the ECHA Guidance R.7c from June 2017 (version 3.0).

Toxicity is low via the oral and dermal routes due to the high molecular weight, water solubility and electronegativity of Direct Red 254 in comparison to some other azo-dyes.

As a result of the assessment, it has been found thatthe substance is expected to be absorbed from the gastro-intestinal tract in some extent. The respiratory deposition is assessed to be low and the dermal absorption could occur on certain extent too.

Distribution in the body is expected to take place, mainlybased upon the water solubility.

Limited data were available for estimation on how this substance is metabolized in the human body.Based on the chemical structure it is known that the existing double bonds or –N=N- might react with strong acids (pH << 4) to give new structures.Reductive cleavage of the azo bond is considered to be a necessary metabolic reaction for these substances to exert their toxicity, as it releases some aromatic amines that are further converted to reactive electrophilic intermediates through metabolic activation. There are references that these dyes are reduced following oral administration and the released aromatic amines are absorbed into systemic circulation. Bioabsorption of the relatively smaller aromatic amine metabolites is expected to dominate over absorption of the intact parent dye.

From the biodegradability test results it was concluded that the substance isnot readily biodegradable. However, bioaccumulation is not expected, based on the log K_owand the calculated BCF values.

Based on the physicochemical properties of the substance one route of excretion (urine) was assessed as possible. Based on observations from a study conducted on an analogue substance, faeces are assessed too as route of excretion.

Key value for chemical safety assessment (proposal)

-         Bioaccumulation potential: no

-         Absorption rate oral (%): 30%

-         Absorption rate dermal (%): 10%

-         Absorption rate inhalation (%): 50%

 

2. Discussion

The assessment below is based on theECHA Guidance on information requirements and chemical safety assessment (Chapter R.7c: Endpoint specific guidance, June 2017, v. 3), for which physicochemical data may be used for a qualitative Toxicokinetic behaviour assessment. All data needed are part of the REACH registration dossier of the substance.

 

2.1 Absorption

 Absorption of CAS 6300-50-1 / EC 228-589-1 was assessed based on physicochemical and available toxicological data. The substance is a solid with a molecular weight of ca. 572 and a water solubility of 198,000 mg/L. The octanol-water partition coefficient (log K_ow) is -1.68.

These values of log K_owand molecular mass of the substance don’t suggest an absorption into the body.

 

(a)  Oral/Gastro Intestinal (GI) absorption:

 

The compound is ionisable and highly soluble in water. According to its molecular weight and because of the log K_owvalue of -1.68 (not in the range -1 to 4), the compound should not be easily involved in a lipophilic micellular solubilisation and this fact doesn’t favor the oral absorption.

No signs of toxicity appeared in acute oral toxicity. In a repeated dose toxicity study conducted with rats on an analogue substance, all findings in both sexes were considered to be of no toxicological significance, but suggest absorption of the substance.

The compound is absorbed from the gastro-intestinal tract in a certain level.

 The considered value for Chemical Safety Assessment of oral absorption 30% is an estimated value calculated for this substance using Advanced Chemistry Development, Inc. (ACD/Labs).

 

(b)  Respiratory absorption - Inhalation:

 

N-octanol/water partition coefficient and molecular weight of the substance don’t favor absorption. The substance is a solid and not volatile and it is not expected a high exposure by inhalation route. However, if some of the substance is inhaled, it can be expected to be absorbed, based on the high solubility. In practice, absorption is assumed to be low based on the physicochemical properties and the physical status (solid) with a particle size >100 μm.

 

The considered value for Chemical Safety Assessment of inhalation absorption 50% is considered to better reflect the substance behaviour than the value of the ECHA Guidance proposed to be 100%.

 

(c)  Dermal absorption:

 

This route of exposure is the most probable one.

Based upon the fact that the substance is a solid with a molecular weight of 572 g/mol, log K_owof -1.68 and not showing skin irritation, sensitization and/or acute dermal toxicity, it might be expected that the substance is not absorbed by the skin. The dermal absorption degree is increased when the substance is dissolved in water.

Having all this factors into account the dermal absorption is considered to be low.

 

As the molecular mass is above 500 g/mol and the log Kow is outside the range (-1, 4), the value of 10% skin adsorption is chosen for Chemical Safety Assessment as default, like it is given in ECHA GuidanceChapter R.7c.

For the assessment of distribution, metabolism and excretion, physicochemical and available toxicological properties are also taken into account according to ECHA Guidance Chapter R.7c.

2.2 Distribution:

Based upon the molecular weight ca. 572 g/mol, high water solubility of 198,000 mg/L and logK_ow-1.68, the distribution in the body is expected to take place slowly but in certain extent. This is further confirmed by findings (considered of no toxicological relevance) and observations from the toxicity study conducted on a structural analogue substance.

 

2.3 Metabolism and accumulation potential:

Metabolism cannot be deduced from the data available. In the repeated dose toxicity study conducted on an analogue substance there are no signs of toxicity observed.

Based on the chemical structure it is known that the existing double bonds -N=N- might react with strong acids (pH << 4) to give new structures.Reductive cleavage of the azo bond is considered to be a necessary metabolic reaction for these substances to exert their toxicity, as it releases some aromatic amines that are further converted to reactive electrophilic intermediates through metabolic activation.

 

There are references that these dyes are reduced following oral administration and the released aromatic amines are absorbed into systemic. Bioabsorption of the relatively smaller aromatic amine metabolites is expected to dominate over absorption of the intact parent dye.

 

Regarding bioaccumulation potential, the available data from biodegradation indicate that the substance is “not readily biodegradable”. However, the calculated Log BCF from regression-based method = 0.500 (BCF = 3.162 L/kg wet-wt), is well below the threshold value of 2000 L/kg for a PBT substance as indicated by the REACH Guidance on PBT assessment. Therefore, the substance is not expected to bioaccumulate in the body.

The relatively smaller aromatic amine metabolites are neither expected to bioaccumulate.

 

2.4 Excretion:

Based on the high molecular weight, the urinary excretion of the parent compound would not be expected. But, on the other side the high water solubility, could favor this route of elimination. Excretion via the saliva and sweat is considered less possible based on the log Kow value (-1.68). Also exfoliation should not be applicable. Excretion in the breast milk is not considered to be the main route. Observations from the repeated dose study conducted on a structural analogue substance show that the dye is eliminated in the faeces of rats. This route of excretion is available to reduce the substance in the body.

There are references that sulphonated azo dyes are poorly absorbed from the intestine after oral intake, but the substance will be degraded at gastro-intestinaI pH 1-4 and won’t be eliminated as such, but in the form of relatively smaller aromatic amine metabolites. The metabolites are absorbed, modified by the liver and excreted in the bile and urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

30

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

50