Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
Toxicokinetic assessment of the substance based on the available data
Type of information:
other: expert statement
Adequacy of study:
key study
Study period:
Not applicable
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: since this is a theoretical assessment, the Klimisch value cannot be 1.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report Date:
2018

Materials and methods

Objective of study:
other: Toxicokinetic assessment of the substance based on the available data
Test guideline
Qualifier:
according to
Guideline:
other: Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. European Chemical Agency, Version 6.0
Version / remarks:
November 2016
Deviations:
no
GLP compliance:
no

Results and discussion

Main ADME results
Type:
absorption
Results:
The absorption factors for risk assessment purposes are derived to be 50% (oral), 100% (inhalation) and 100% (dermal).

Any other information on results incl. tables

Toxicokinetic assessment

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 uptake via these three routes will be addressed individually.

After oral administration, in general, a compound needs to be dissolved before it can be taken up from the gastrointestinal tract. Although the water solubility of Ethanol, 2,2’-[(3-methylphenyl)imino]bis- is moderate with 9.33 g/L at 20°C, the substance will dissolve to some extent into the gastrointestinal fluids and become available for uptake. Based on its molecular weight (approx. 195), uptake via passive diffusion (passage of small water-soluble molecules through aqueous pores or carriage across membranes with the bulk passage of water) is possible. Ethanol, 2,2’-[(3-methylphenyl)imino]bis- has a moderate partition coefficient (log Pow = 1.9), which implies that this substance will dissolve in lipids and can thus cross epithelia by passive diffusion. The substance has two ionisable groups, the hydroxyl groups. No information is available on its dissociation constant, so at this point it cannot be determined if the substance is present in an ionized form along the gastro-intestinal tract. Presence in ionized form could potentially hamper uptake. For risk assessment purposes oral absorption of Ethanol, 2,2’-[(3-methylphenyl)imino]bis- is set at 50%, based on its water solubility, its low molecular weight and its moderate log Pow and presence of ionisable groups. The oral toxicity data do not provide reason to deviate from the proposed oral absorption factor.

Once absorbed, distribution of the substance throughout the body is expected to some extent based on its limited water solubility and moderate molecular weight. Absorbed Ethanol, 2,2’-[(3-methylphenyl)imino]bis- is expected to be excreted via urine. Based on its moderate partition coefficient (log Pow = 1.9), it is unlikely that Ethanol, 2,2’-[(3-methylphenyl)imino]bis- will accumulate significantly in adipose tissue.

Ethanol, 2,2’-[(3-methylphenyl)imino]bis- is expected to have a very low vapour pressure (calculated as 2.23E-04 Pa at 25°C), which indicates that exposure via air can be considered to be very limited. This is further supported by the fact that Ethanol, 2,2’-[(3-methylphenyl)imino]bis- is a paste (at room temperature), so no potentially inhalable particles of the substance are present that need to be considered. If however, theoretically, particles reach the tracheobronchial region, Ethanol, 2,2’-[(3-methylphenyl)imino]bis- is likely to dissolve in the mucus lining of the respiratory tract and to get absorbed. Although its ability to dissolve in water is limited, Ethanol, 2,2’-[(3-methylphenyl)imino]bis- can dissolve in lipids and is therefore able to cross biological membranes. Furthermore, the substance has irritating properties, therefore interference with the epithelium lining of the respiratory tract can be expected. Such interference is expected to significantly enhance uptake of a substance, therefore it is concluded that for risk assessment purposes as worst case the inhalation absorption of Ethanol, 2,2’-[(3-methylphenyl)imino]bis- should be set at 100%.

As Ethanol, 2,2’-[(3-methylphenyl)imino]bis- is a solid, uptake through the skin is unlikely to occur unless it is dissolved in a body fluid (sweat). The water solubility of Ethanol, 2,2’-[(3-methylphenyl)imino]bis- is moderate, and considered sufficient to partition from the stratum corneum into the epidermis. Its ability to dissolve in lipids will furthermore favour easy crossing of epidermal barriers. Its moderate molecular size is expected to facilitate uptake through dermal epithelium. According to the criteria given in the REACH Guidance, 10% dermal absorption will be considered in case MW >500 and log Pow <-1 or >4, otherwise 100% dermal absorption should be used. As the physical/chemical properties of Ethanol, 2,2’-[(3-methylphenyl)imino]bis- do not meet the criteria for limited dermal absorption (MW 195.26; log Pow = 1.9), for risk assessment purposes dermal absorption should be set at 100%. This is supported by the fact that the substance has skin irritating properties, thus the substance is expected to interfere with dermal epithelia. After the skin surface is damaged, Ethanol, 2,2’-[(3-methylphenyl)imino]bis- will be absorbed easily due to its low molecular weight and moderate water solubility. Based on the above data, for risk assessment purposes the dermal absorption of Ethanol, 2,2’-[(3-methylphenyl)imino]bis- is set at 100%.

Applicant's summary and conclusion

Conclusions:
A toxicokinetic assessment was performed based on the available data of Ethanol, 2,2’-[(3-methylphenyl)imino]bis-. Based on the physical/chemical properties and the toxicity data of the substance, the following absorption factors are derived for risk assessment purposes: 50% (oral), 100% (inhalation) and 100% (dermal). The bioaccumulation potential is expected to be low.