Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: expert statement
Adequacy of study:
key study
Study period:
2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study. Expert statement based on all available data on toxicokinetics for the substance registered.

Data source

Reference
Reference Type:
other: expert statement
Title:
Unnamed
Year:
2010
Report date:
2010

Materials and methods

Test guideline
Qualifier:
no guideline required
Deviations:
not applicable
Principles of method if other than guideline:
The Toxicokinetic Assessment is meant to fulfil the requirement as defined in the REGULATION (EC) No 1907/2006 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 18 December 2006 requests in Annex VIII, point 8.8.1:
"Assessment of the toxicokinetic behaviour of the substance to the extent that can be derived from the relevant available information."
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Tris(2-hydroxyethyl)ammonium 7-{4-[4-(2-cyanoamino-4-hydroxy-6-oxidopyrimidin-5-ylazo)benzamido]-2-ethoxy-phenylazo}naphthalene-1,3-disulfonate
EC Number:
421-440-3
EC Name:
Tris(2-hydroxyethyl)ammonium 7-{4-[4-(2-cyanoamino-4-hydroxy-6-oxidopyrimidin-5-ylazo)benzamido]-2-ethoxy-phenylazo}naphthalene-1,3-disulfonate
Cas Number:
778583-04-3
Molecular formula:
Hill formula: C47 H66 N12 O19 S2 CAS formula: C29 H21 N9 O10 S2 x 3 C6 H15 NO3
IUPAC Name:
tris(tris(2-hydroxyethyl)azanium) 2-(cyanoamino)-5-{2-[4-({4-[2-(6,8-disulfonaphthalen-2-yl)diazen-1-yl]-2-methoxyphenyl}carbamoyl)phenyl]diazen-1-yl}-6-hydroxypyrimidin-4-olate

Results and discussion

Any other information on results incl. tables

1        Introduction

The substance is a dye intended to be registered under REACH Regulation (Regulation (EC) 1907/2006). Thus, an assessment of the toxicokinetic behaviour of the substance to the extent that can be derived from the relevant available information shall be made.

 

2        Available studies with relevant information

A toxicokinetic study of the substance is not available.

 

The following studies are available and were identified to contain relevant information for the estimation of toxicokinetic properties:

 

Study type

Test Laboratory

Report No.

Melting point

RCC Ltd.

632013

Vapour pressure

RCC Ltd.

632035

Partition coefficient n-octanol / water

RCC Ltd.

632068

Water solubility

RCC Ltd.

632057

Particle size distribution

RCC Ltd.

632125

Hydrolysis at different pH

RCC Ltd.

632103

Acute oral toxicity study in rats

RCC Ltd.

632136

Acute dermal toxicity study in rats

RCC Ltd.

632147

Acute skin irritation study in rabbits

RCC Ltd.

632158

Acute eye irritation study in rabbits

RCC Ltd.

632160

Skin sensitisation test (GPMT)

RCC Ltd.

632171

28-day oral toxicity study in rats

RCC Ltd.

632182

 


3        Discussion

3.1       Physico-chemical properties

The substance is a solid with high water solubility (>176 g/L at 20°C) and a low log POW of <-3 (estimated from the respective solubility in water and in n-octanol).

The substance is hydrolytically stable in water at pH 4-9 and at temperatures up to 50 °C.

Regarding the high water solubility it can be expected that the substance is likely to be bioavailable, at least by the oral route. The estimated low log POW indicates a low potential for accumulation in fatty tissues but also a certain polarity of the substance. Therefore, only limited enteral resorption of the test item may be assumed.

 

3.2       Uptake

Available toxicity studies with the substance did not include plasma level measurements of the test substance. Therefore, there is no direct data to clarify the extent of systemic availability of the parent molecule.

 

3.2.1       Oral route

No evident systemic toxicity was observed in the acute oral study in rat.

However, deep yellow discoloration of the urine, slight changes in several hematological and biochemical parameters as well as higher kidney weights and coloration of the gastrointestinal tract were noted in the 28 day subacute toxicity study. All these findings were observed at dose levels of 200 and/or 1000 mg/kg.

These findings give rise to the assumption that the test item is absorbed in the gastrointestinal tract after oral application but gives no indication of the amount absorbed.

 

3.2.2       Dermal route

In the acute dermal study in rats, no signs of systemic toxicity were observed. However, yellow discoloration of the skin at the application site was evident in all animals after the removal of the dressing on test day 2 and persisted until study termination (day 15). This clearly shows that the substance at least adsorbed in the upper part of the skin but gives no indication on dermal absorption.

The substance has also been tested for irritating effects on skin; it was considered not to be irritant, showing mean erythema and edema scores of 0 for all time points, neither caused it systemic effects in the treated animals.

The sensitizing potential of the substance has been investigated by a guinea pig maximisation test. The test item was not considered to be a skin sensitizer when tested up to the highest applicable concentration.

Using the available data, no clear statement on dermal bioavailability can be made.

 

3.2.3       Inhalational route

No toxicity study after pulmonary uptake of the substance is available to date. When taking into account the determined melting point of >220°C and the very low vapour pressure of 2×10-22Pa at 25°C, evaporation of the substance into air is not likely to happen.

Inhalation of dust may be another route of exposure via inhalation. Analysis of particle size distribution shows a range from 0.5 to >100 µm with a mass median diameter (MMD) of 11.5 µm. As approximately 25% of the particles have a size smaller than 4 µm, dust of the substance may be bioavailable via inhalation. However, the registration substance is of low toxicity after acute and repeated oral application.

 

3.3       Distribution in tissues

The subacute repeated dose study on rats revealed yellow of the urine after oral application of the test item. It is therefore highly likely that the substance, after uptake in the gastrointestinal tract, is transferred to the liver via the portal vein and then distributed in the body by blood circulation.

No direct plasma measurements have been performed in either toxicity study.

 

3.4       Metabolism

No specific metabolism studies have been performed with the substance.

Based on the present data, it is not possible to reason about the metabolisation of the substance in the body.

 

3.5       Excretion

No test item or metabolite analysis was performed on urine or feces in either available study.

In the subacute 28 day toxicity study, orange discoloration of feces and deep yellow discoloration of urine were noted in the 200 and 1000 mg/kg bw/day study groups.

Due to its stability and the absence of adverse effects of toxicological relevance regarding cage site observations and urinanalysis data it can be expected, according to the results of the present toxicity studies that, after oral exposure, the substance would not tend to accumulate in the organism, but to be excreted via urine and faeces.

No other signs of substance resorption or excretion were seen in any available toxicity study.

 


4        Summary

Results from oral toxicity studies in rats up to 28 days indicated that there is systemic availability of the substance or metabolites at a high oral dosage. Direct evidence in the form of plasma data is not available. No evidence of dermal bioavailability is given, although adsorption of the dyestuff was noted in the acute dermal toxicity study. The level of inhalation exposure is negligible due to the low vapour pressure, but inhalation of dust of the substance may be possible.

Observation of dark yellow discoloration of the urine after repeated oral administration indirectly shows a certain distribution of the substance in the body. The estimated low log POW indicates a low potential for accumulation in fatty tissues.

Excretion of the substance in the form of discoloration is observed in urine and feces; direct evidence in the form of analytical data is not available.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results

Based on the available data, there is no indication of critical bioaccumulation potential of the registration substance.
Executive summary:

1        Introduction

The substance is a dyeintended to be registered under REACH Regulation (Regulation (EC) 1907/2006). Thus, an assessment of the toxicokinetic behaviour of the substance to the extent that can be derived from the relevant available information shall be made.

 

2        Available studies with relevant information

A toxicokinetic study of the substance is not available.

 

The following studies are available and were identified to contain relevant information for the estimation of toxicokinetic properties:

 

Study type

Test Laboratory

Report No.

Melting point

RCC Ltd.

632013

Vapour pressure

RCC Ltd.

632035

Partition coefficient n-octanol / water

RCC Ltd.

632068

Water solubility

RCC Ltd.

632057

Particle size distribution

RCC Ltd.

632125

Hydrolysis at different pH

RCC Ltd.

632103

Acute oral toxicity study in rats

RCC Ltd.

632136

Acute dermal toxicity study in rats

RCC Ltd.

632147

Acute skin irritation study in rabbits

RCC Ltd.

632158

Acute eye irritation study in rabbits

RCC Ltd.

632160

Skin sensitisation test (GPMT)

RCC Ltd.

632171

28-day oral toxicity study in rats

RCC Ltd.

632182

 


3        Discussion

3.1       Physico-chemical properties

The substance is a solid with high water solubility (>176 g/L at 20°C) and a low log POWof <-3 (estimated from the respective solubility in water and in n-octanol).

The substance is hydrolytically stable in water at pH 4-9 and at temperatures up to 50°C.

Regarding the high water solubility it can be expected that the substance is likely to be bioavailable, at least by the oral route. The estimated low log POWindicates a low potential for accumulation in fatty tissues but also a certain polarity of the substance. Therefore, only limited enteral resorption of the test item may be assumed.

 

3.2       Uptake

Available toxicity studies with the substance did not include plasma level measurements of the test substance. Therefore, there is no direct data to clarify the extent of systemic availability of the parent molecule.

 

3.2.1       Oral route

No evident systemic toxicity was observed in the acute oral study in rat.

However, deep yellow discoloration of the urine, slight changes in several hematological and biochemical parameters as well as higher kidney weights and coloration of the gastrointestinal tract were noted in the 28 day subacute toxicity study. All these findings were observed at dose levels of 200 and/or 1000 mg/kg.

These findings give rise to the assumption that the test item is absorbed in the gastrointestinal tract after oral application but gives no indication of the amount absorbed.

 

3.2.2       Dermal route

In the acute dermal study in rats, no signs of systemic toxicity were observed. However, yellow discoloration of the skin at the application site was evident in all animals after the removal of the dressing on test day 2 and persisted until study termination (day 15). This clearly shows that the substance at least adsorbed in the upper part of the skin but gives no indication on dermal absorption.

The substance has also been tested for irritating effects on skin; it was considered not to be irritant, showing mean erythema and edema scores of 0 for all time points, neither caused it systemic effects in the treated animals.

The sensitizing potential of the substance has been investigated by a guinea pig maximisation test. The test item was not considered to be a skin sensitizer when tested up to the highest applicable concentration.

Using the available data, no clear statement on dermal bioavailability can be made.

 

3.2.3       Inhalational route

No toxicity study after pulmonary uptake of the substance is available to date. When taking into account the determined melting point of >220°C and the very low vapour pressure of 2×10-22Pa at 25°C, evaporation of the substance into air is not likely to happen.

Inhalation of dust may be another route of exposure via inhalation. Analysis of particle size distribution shows a range from 0.5 to >100 µm with a mass median diameter (MMD) of 11.5 µm. As approximately 25% of the particles have a size smaller than 4 µm, dust of the substance may be bioavailable via inhalation. However, the registration substance is of low toxicity after acute and repeated oral application.

 

3.3       Distribution in tissues

The subacute repeated dose study on rats revealed yellow of the urine after oral application of the test item. It is therefore highly likely that the substance, after uptake in the gastrointestinal tract, is transferred to the liver via the portal vein and then distributed in the body by blood circulation.

No direct plasma measurements have been performed in either toxicity study.

 

3.4       Metabolism

No specific metabolism studies have been performed with the substance.

Based on the present data, it is not possible to reason about the metabolisation of the substance in the body.

 

3.5       Excretion

No test item or metabolite analysis was performed on urine or feces in either available study.

In the subacute 28 day toxicity study, orange discoloration of feces and deep yellow discoloration of urine were noted in the 200 and 1000 mg/kg bw/day study groups.

Due to its stability and the absence of adverse effects of toxicological relevance regarding cage site observations and urinanalysis data it can be expected, according to the results of the present toxicity studies that, after oral exposure, the substance would not tend to accumulate in the organism, but to be excreted via urine and faeces.

No other signs of substance resorption or excretion were seen in any available toxicity study.

 

4        Summary

Results from oral toxicity studies in rats up to 28 days indicated that there is systemic availability of the substance or metabolites at a high oral dosage. Direct evidence in the form of plasma data is not available. No evidence of dermal bioavailability is given, although adsorption of the dyestuff was noted in the acute dermal toxicity study. The level of inhalation exposure is negligible due to the low vapour pressure, but inhalation of dust of the substance may be possible.

Observation of dark yellow discoloration of the urine after repeated oral administration indirectly shows a certain distribution of the substance in the body. The estimated low log POWindicates a low potential for accumulation in fatty tissues.

Excretion of the substance in the form of discoloration is observed in urine and feces; direct evidence in the form of analytical data is not available.