Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: expert statement
Adequacy of study:
key study
Study period:
2010
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Expert statement comprising all available data on toxicokinetics

Data source

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

Materials and methods

Objective of study:
other: Assessment of toxicokinetic behaviour
Test guideline
Qualifier:
no guideline required
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
455-600-9
EC Name:
-
Cas Number:
790240-84-5
Molecular formula:
CAS formula: C34 H46 N12 O5 S . C3 H6 O3
IUPAC Name:
2-hydroxypropanoic acid; 7-{[4,6-bis({[3-(diethylamino)propyl]amino})-1,3,5-triazin-2-yl]amino}-4-hydroxy-3-[(1E)-2-(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl)diazen-1-yl]naphthalene-2-sulfonic acid

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 is made.  

2        Available studies with relevant information

A toxicokinetic study of the substanceis 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 / boiling point RCC Ltd. 857550 Vapour pressure RCC Ltd. 857552 Partition coefficient n-octanol / water RCC Ltd. 857555 Water solubility RCC Ltd. 857555 Particle size distribution RCC Ltd. 857560 Hydrolysis at different pH RCC Ltd. 857581 Acute oral toxicity study in rats RCC Ltd. 857561 Acute dermal toxicity study in rats RCC Ltd. 857562 Acute skin irritation study in rabbits RCC Ltd. 857563 Acute eye irritation study in rabbits RCC Ltd. 857564 Skin sensitisation test (LLNA) RCC Ltd. 857565 28-day oral toxicity study in rats RCC Ltd. 857566  
3        Discussion

3.1       Physico-chemical properties

The substance is a solid with high water solubility (188.8 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. However, the estimated low log POW indicates a certain polarity of the substance. Therefore, only limited enteral resorption of the test item may be assumed. The substance has a molecular weight of >700 g/mol, which may hamper enteral absorption and influence the mechanism of excretion, as substances with a molecular weight > approximately 400 g/mol are also excreted into the intestine via the bile.  

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. Also in a subacute 28 day oral gavage toxicity study, the substance was administered at dose levels of 50, 200 and 1000 mg/ kg body weight daily to rats. No mortality occurred during the study period. No test item related findings of toxicological relevance were noted at any dose level during week 1-3 of treatment. No changes in clinical appearance or behaviour were noted during the observation period that were considered to represent a clear sign of toxicity. The assessment of haematology and clinical biochemistry data indicated no changes of toxicological significance at termination of the treatment. Urinalysis, however, showed yellow-brown to red-brown discoloration of the urine in animals treated with 1000 mg/kg/day. This was considered to be a passive effect of the test item that was excreted via the kidneys. Therefore, it can be concluded that the substance 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, red discoloration of the skin, persisting until day 5-6 of the observation period was noted, indicating a low tendency for adsorption on skin. The substance has 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. The sensitizing potential of the substance has been investigated by a Local Lymph Node Assay (LLNA). It is not considered to be a skin sensitizer when tested up to the highest applicable concentration. Thus, bioavailability via the dermal route cannot be confirmed by the available data.  

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 range of 49-157°C and the very low vapour pressure of 5×10-24Pa 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 0.3 to 90 µm with a mass median diameter (MMD) of 3.9 µm. As half of the particles have a size smaller than 4 µm, a potential for respiration of the substance is clearly given. However, the registration substance is only manufactured and marketed as aqueous solution at a maximum of 20% (w/w). The solid form of the registration substance is generated solely for registration purposes.

3.3       Distribution in tissues Repeated dose studies on rats revealed yellow-brown to red-brown discoloration of the urine after oral application of the test item. It can therefore be concluded 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.  

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 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, red discoloration of feces (in the 200 and 1000 mg/kg bw/day study groups) and yellow-brown to red-brown discoloration of the urine (in the 1000 mg/kg bw/day study group) were noted. 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. 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, based on the available studies. 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 yellow-brown to red-brown 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.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
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, based on the available studies. 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 yellow-brown to red-brown 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.
Executive summary:

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 is 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 / boiling point

RCC Ltd.

857550

Vapour pressure

RCC Ltd.

857552

Partition coefficient n-octanol / water

RCC Ltd.

857555

Water solubility

RCC Ltd.

857555

Particle size distribution

RCC Ltd.

857560

Hydrolysis at different pH

RCC Ltd.

857581

Acute oral toxicity study in rats

RCC Ltd.

857561

Acute dermal toxicity study in rats

RCC Ltd.

857562

Acute skin irritation study in rabbits

RCC Ltd.

857563

Acute eye irritation study in rabbits

RCC Ltd.

857564

Skin sensitisation test (LLNA)

RCC Ltd.

857565

28-day oral toxicity study in rats

RCC Ltd.

857566

 


3        Discussion

3.1       Physico-chemical properties

The substance is a solid with high water solubility (188.8 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. However, the estimated low log POW indicates a certain polarity of the substance. Therefore, only limited enteral resorption of the test item may be assumed.

The substance has a molecular weight of >700 g/mol, which may hamper enteral absorption and influence the mechanism of excretion, as substances with a molecular weight > approximately 400 g/mol are also excreted into the intestine via the bile.

 

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.

Also in a subacute 28 day oral gavage toxicity study, the substance was administered at dose levels of 50, 200 and 1000 mg/ kg body weight daily to rats. No mortality occurred during the study period. No test item related findings of toxicological relevance were noted at any dose level during week 1-3 of treatment. No changes in clinical appearance or behaviour were noted during the observation period that were considered to represent a clear sign of toxicity. The assessment of haematology and clinical biochemistry data indicated no changes of toxicological significance at termination of the treatment.

Urinalysis, however, showed yellow-brown to red-brown discoloration of the urine in animals treated with 1000 mg/kg/day. This was considered to be a passive effect of the test item that was excreted via the kidneys.

Therefore, it can be concluded that the test substance 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, red discoloration of the skin, persisting until day 5-6 of the observation period was noted, indicating a low tendency for adsorption on skin.

The substance has 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.

The sensitizing potential of the substance has been investigated by a Local Lymph Node Assay (LLNA). It is not considered to be a skin sensitizer when tested up to the highest applicable concentration.

Thus, bioavailability via the dermal route cannot be confirmed by the available data.

 

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 range of 49-157°C and the very low vapour pressure of 5×10-24 Pa 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 0.3 to 90 µm with a mass median diameter (MMD) of 3.9 µm. As half of the particles have a size smaller than 4 µm, a potential for respiration of the substance is clearly given.

 

3.3       Distribution in tissues

Repeated dose studies on rats revealed yellow-brown to red-brown discoloration of the urine after oral application of the test item. It can therefore be concluded 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.

 

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 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, red discoloration of feces (in the 200 and 1000 mg/kg bw/day study groups) and yellow-brown to red-brown discoloration of the urine (in the 1000 mg/kg bw/day study group) were noted.

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.

 


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, based on the available studies. The level of inhalation exposure is negligible due to the low vapour pressure, but inhalation of dust of the substance may be possible.

Observation ofyellow-brown to red-brown 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.