Reactive Orange 143

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics

Type of information:

other: assessment based on available information

Adequacy of study:

key study

Study period:

20 December 2012

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Objective of study:

other: toxicokinetic assessment

Qualifier:

no guideline required

GLP compliance:

no

Radiolabelling:

no

Route of administration:

other: oral, dermal and inhalation

Details on exposure:

see assessment

Type:

other:

Results:

proposed factor for oral, dermal and inhalation absorption for risk assessment purposes

The hydrophilic character of FAT 40854/A (log Pow <-1.8) will limit this passive diffusion and although the water solubility is >500 g/L, the large molecular weight (ca 950 g/mol) will prevent passage through the aqueous pores. Furthermore, the ionization of FAT 40854/A will impair the uptake since compounds need to pass the lipid membranes in the gastrointestinal wall (1). It is therefore unlikely that FAT 40854/A will be absorbed to a high extent from the gastro-intestinal tract. For risk assessment purposes the oral absorption of FAT 40854/A is set at 10 %. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor, as red staining of the faeces is observed while reddish discolouration of organs was restricted to the glandular mucosa of the stomach and Peyer’s patches of high dose animals. Once absorbed, the relatively high molecular weight of FAT40854/A is not favourable for wide distribution. Also, the absence of coloured organs in the repeated-dose toxicity study is indicative for a low potential for accumulation within the body. Based on the hydrophilic properties (log Pow <-1.8), the extracellular concentration may be higher than the intracellular concentration. There are no data available providing direct information on respiratory absorption. The low vapour pressure <1.5 x 10-3 Pa) indicates that FAT40854/A is not available for inhalation as a vapour. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract. The particle size distribution for FAT40854/A indicates, that the particles of FAT40854/A have the potential to be inhaled (<100 µm), of which a significant part may reach the thoracic region (<50 µm) and about 10 % may reach the alveolar region (<15 µm) of the respiratory tract. Based on the high water solubility, FAT40854/A has the potential to diffuse readily into the mucus lining of the respiratory tract. Log Pow, molecular weight and ionization lower the potential for absorption. Therefore, for risk assessment purposes inhalatory absorption is expected to be less than the standard 100 % and is set at 50 %. A solid has to dissolve into the surface moisture of the skin before uptake can begin. Although the water solubility for FAT40854/A is high (>500 g/L ), the hydrophilic property (log Pow<-1.8) of FAT40854/A is not favourable for penetration into the stratum corneum. According to the criteria given in the REACH guidance (2) 10 % dermal absorption will be considered in case MW >500 and log Pow <-1 and >4, otherwise 100 % dermal absorption should be used (1). As FAT40854/A meets these criteria for restricted dermal absorption, 10 % dermal absorption is used for risk assessment purposes.

 

  REFERENCES

 

1.    Martinez, Amidon GL. Mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 2002; 42: 620-43.

2.    Guidance for the implementation of REACH. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. European Chemical Agency, May 2008.

3.    A. Parkinson. In: Casarett and Doull’s Toxicology, The basic science of poisons. Sixth edition. Ed. C.D. Klaassen. Chapter 6: Biotransformation of xenobiotics.,, 2001.

Conclusions:

For risk assessment purposes, the oral and dermal absorption for FAT 40854/A TE is set at 10%, and the absorption via inhalation is set at 50%.

Executive summary:

The hydrophilic character of FAT 40854/A TE (log Pow <-1.8) will limit this passive diffusion and although the water solubility is>500 g/L, the large molecular weight (ca 950 g/mol) will prevent passage through the aqueous pores. Furthermore, the ionization of FAT 40854/A TE will impair the uptake since compounds need to pass the lipid membranes in the gastrointestinal wall (1). It is therefore unlikely that FAT 40854/A TE will be absorbed to a high extent from the gastro-intestinal tract. For risk assessment purposes the oral absorption of FAT 40854/A TE is set at 10%. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor, as red staining of the faeces is observed while reddish discolouration of organs was restricted to the glandular mucosa of the stomach and Peyer’s patches of high dose animals.

Once absorbed, the relatively high molecular weight of FAT40854/A TE is not favorable for wide distribution. Also, the absence of coloured organs in the repeated dose toxicity study is indicative for a low potential for accumulation within the body. Based on the hydrophilic properties (log Pow <-1.8), the extracellular concentration may be higher than the intracellular concentration.

There are no data available providing direct information on respiratory absorption. The low vapour pressure <1.5 x 10-3 Pa) indicates that FAT40854/A TE is not available for inhalation as a vapour. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract. The particle size distribution for FAT40854/A TE indicates, that the particles of FAT40854/A TE have the potential to be inhaled (<100 µm), of which a significant part may reach the thoracic region (<50 µm) and about 10% may reach the alveolar region (<15 µm) of the respiratory tract. Based on the high water solubility, FAT40854/A TE has the potential to diffuse readily into the mucus lining of the respiratory tract. Log Pow, molecular weight and ionization lower the potential for absorption. Therefore, for risk assessment purposes inhalatory absorption is expected to be less than the standard 100% and is set at 50%.

A solid has to dissolve into the surface moisture of the skin before uptake can begin. Although the water solubility for FAT40854/A TE is high (>500 g/L ), the hydrophilic property (log Pow<-1.8) of FAT40854/A TE is not favourable for penetration into the stratum corneum. According to the criteria given in the REACH guidance (2) 10% dermal absorption will be considered in case MW>500 and log Pow <-1 and >4, otherwise 100% dermal absorption should be used (1). As FAT40854/A TE meets these criteria for restricted dermal absorption, 10% dermal absorption is used for risk assessment purposes.

A toxicokinetic risk assessment for FAT 40854/A TE was made based on available physico-chemical properties of the substance, together with relevant toxicological information. based on all information available, for risk assessment purposes the oral and dermal absorption for FAT 40854 are set at 10%, and the absorption via inhalation is set at 50%. FAT 40854A/TE is considered to have low bioaccumulation potential.

Description of key information

The assessment is based on physico-chemical properties of FAT 40854/A and the available and relevant toxicological data.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

50

Additional information

The hydrophilic character of FAT 40854/A (log Pow <-1.8) will limit this passive diffusion and although the water solubility is >500 g/L, thelarge molecular weight (ca. 950 g/mol) will prevent passage through the aqueous pores. Furthermore, the ionization of FAT 40854/A will impair the uptake since compounds need to pass the lipid membranes in the gastrointestinal wall (1). It is therefore unlikely that FAT 40854/A will be absorbed to a high extent from the gastro-intestinal tract. For risk assessment purposes the oral absorption of FAT 40854/A is set at 10 %. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor, as red staining of the faeces is observed while reddish discolouration of organs was restricted to the glandular mucosa of the stomach and Peyer’s patches of high dose animals. Once absorbed, the relatively high molecular weight of FAT40854/A is not favourable for wide distribution. Also, the absence of coloured organs in the repeated-dose toxicity study is indicative for a low potential for accumulation within the body. Based on the hydrophilic properties (log Pow <-1.8), the extracellular concentration may be higher than the intracellular concentration (1). There are no data available providing direct information on respiratory absorption. The low vapour pressure <1.5 x 10-3 Pa) indicates that FAT40854/A is not available for inhalation as a vapour. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract. The particle size distribution for FAT40854/A indicates, that the particles of FAT40854/A have the potential to be inhaled (<100 µm), of which a significant part may reach the thoracic region (<50 µm) and about 10 % may reach the alveolar region (<15 µm) of the respiratory tract. Based on the high water solubility, FAT40854/A has the potential to diffuse readily into the mucus lining of the respiratory tract. Log Pow, molecular weight and ionization lower the potential for absorption. Therefore, for risk assessment purposes inhalatory absorption is expected to be less than the standard 100 % and is set at 50 %. A solid has to dissolve into the surface moisture of the skin before uptake can begin. Although the water solubility for FAT40854/A is high (>500 g/L ), the hydrophilic property (log Pow<-1.8) of FAT40854/A is not favourable for penetration into the stratum corneum. According to the criteria given in the REACH guidance (2) 10 % dermal absorption will be considered in case MW >500 and log Pow <-1 and >4, otherwise 100 % dermal absorption should be used (1). As FAT40854/A meets these criteria for restricted dermal absorption, 10 % dermal absorption is used for risk assessment purposes.