Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: expert statement
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Theoretical assessment taking all currrently available relevant information into account, based on the REACH Guidance: Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance. Since this is a theoretical assessment, the Klimisch value cannot be 1.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report Date:
2017

Materials and methods

Objective of study:
absorption
Test guideline
Qualifier:
according to
Guideline:
other: Guidance for the implementation of REACH. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. European Chemical Agency
Version / remarks:
Version 3.0 June 2017
Deviations:
not applicable
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Main ADME results
Type:
absorption
Results:
For risk assessment purposes, % is used for oral, dermal and inhalation absorption

Any other information on results incl. tables

After exposure, a substance can enter the body via the lungs, the gastrointestinal tract, and the skin. Since different parameters are relevant for absorption via the different routes of exposure, the 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 Sakura salicylate is limited with 0.267 g/L at 20°C, the substance will dissolve to some extent into the gastrointestinal

fluids. As its molecular weight (appr. 224.25 Da) is low, uptake via passive diffusion (passage of small water-soluble molecules through aqueous pores or carriage across membranes with the bulk passage of water) is expected. Sakura salicylate has a moderate partition coefficient (log Pow = 3.25), which implies that this substance is favourable for absorption directly across the epithelium by passive diffusion. Sakura salicylate contains one ionisable group, the hydroxyl-group attached to the benzene ring

in the structure. No data are available on the dissociation constant(s) of this substance. Phenol is known to weakly acidic and is only present in ionized form at high pHs. In parallel, this is expected for Sakura salicylate. Under physiological circumstances (in the stomach or intestinal tracts) only low pH circumstances are present, therefore Sakura salicylate is expected to be present only in the non-ionised form, which will not interfere with absorption. Taken all data together, there are no indications that uptake of Sakura salicylate is hampered. Therefore, for risk assessment purposes oral absorption of Sakura salicylate is set at 100%. The oral toxicity data do not provide reason to deviate from the proposed oral absorption factor. Once absorbed, wide distribution of the test substance throughout the body is expected based on its limited water solubility and low molecular weight. Absorbed Sakura salicylate is expected to be excreted via urine. Based on its moderate partition coefficient (3.25), it is unlikely that Sakura salicylate will accumulate to a high extent in adipose tissue. Sakura salicylate has a low vapour pressure (0.297 Pa at 25ºC), which indicates that it unlikely that exposure to the substance as a vapour will occur. Since Sakura salicylate is a liquid, aerosols may reach the respiratory tract. If these aerosols reach the tracheobronchial region, Sakura salicylate is likely to dissolve in the mucus lining the respiratory tract and to get absorbed due to its water solubility and low molecular weight. Sakura salicylate has been shown not to have irritating properties, therefore interference with the epithelium lining the respiratory tract is not expected. Taken the above data into consideration, it is concluded that for risk

assessment purposes as worst case the inhalation absorption of Sakura salicylate is set at 100%. Sakura salicylate is a liquid, as a consequence, uptake through the skin is likely to occur, especially when the substance has log P value between 1 and 4. Also the molecular size of Sakura salicylate (< 500) favours uptake through dermal epithelium. As discussed above, when exposed to the skin, the substance is expected to be present in non-ionised form, which will not affect uptake. The water solubility of Sakura salicylate is moderate, which is sufficient to partition from the stratum corneum into the epidermis. According to the criteria given in the REACH Guidance, the dermal absorption should be set at 100% for risk assessment purposes. As this value can overestimate the actual dermal adsorption, this parameter was determined with the skin absorption model (SAM) calculator developed by the Research Institute for Fragrance Materials (RIFM). This model was developed for “fragrance-like” materials, with a molecular weight ranging from

30 to 330 Da, a log Kow from -1 to 9, and log S from -9 to 1. This implies that Sakura salicylate falls within the application domain (MW = appr. 224.25

Da; log Kow = 3.25; log S = -0.57), and the calculation can be used for this substance. The dermal adsorption was calculated to be ≤ 40%, this value will be used for risk assessment purposes. The results of the toxicity studies do not provide reasons to deviate from this proposed dermal absorption factor.

Applicant's summary and conclusion

Conclusions:
A toxicokinetic assessment was performed based on the available data of Sakura salicylate. Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 100% (oral), 100% (inhalation) and 40% (dermal) for risk assessment purposes. The bioaccumulation potential is expected to be low.