2-hydroxy-1-[4-[4-(2-hydroxy-2-methylpropanoyl)phenoxy]phenyl]-2-methylpropan-1-one

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

50

Additional information

Oral absorption

Based on physicochemical properties:

According to REACH guidance document R7.C (May 2014), oral absorption is maximal for substances with molecular weight (MW) below 500. Water-soluble substances will readily dissolve into the gastrointestinal fluids; however, absorption of hydrophilic substances via passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid. Further, absorption by passive diffusion is higher at moderate log Kow values (between -1 and 4). If signs of systemic toxicity are seen after oral administration (other than those indicative of discomfort or lack of palatability of the test substance), then absorption has occurred.

The test substance is a mono-constituent with a molecular weight of 342.39 g/mol. It has a water solubility of 23.12 mg/L (at 20°C) and a log Kow of 2.39.

Based on the R7.C indicative criteria, the test substance can be expected to have a high absorption potential from the gastrointestinal tract.

Based on ‘other toxicity’ studies:

According to REACH guidance document R7.C (ECHA, 2017), other toxicity studies can be helpful to get information on occurrence of absorption without any specification of the extent or amount. For example, if signs of systemic toxicity are present in acute or repeated dose studies, then absorption has occurred.

An acute toxicity study with the test substance in SD rats revealed clinical signs such as piloerection in all animals at 2000 mg/kg bw (Baudet, 2004). A 2 -day repeated dose study in Hsd rats showed effects on food consumption, body weight and histopathology at 150 mg/kg bw/day (Bioservice, 2007).

Based on these observed effects, the test substance can be expected to be absorbed to a certain extent.

Conclusion:

Overall, based on the available weight of evidence, the test substance can be expected to have a high absorption potential through the oral route. Therefore, the default value of 50% has been considered for risk assessment purposes.

Dermal absorption

Based on physicochemical properties:  

According to REACH guidance document R7.C (ECHA, 2017), dermal absorption is maximal for substances having MW below 100 together with log Kow values ranging between 2 and 3 and water solubility in the range of 100-10,000 mg/L. Substances with MW above 500 are considered too large to penetrate skin. Further, dermal uptake is likely to be low for substances with log P values <0 or <-1, as they are not likely to be sufficiently lipophilic to cross the stratum corneum (SC). Similarly, substances with water solubility below 1 mg/L are also likely to have low dermal uptake, as the substances must be sufficiently soluble in water to partition from the SC into the epidermis. 

The test substance is a solid, with a MW exceeding 100 g/mol, moderate water solubility and log Kow of 2.39, suggesting a low to moderate dermal absorption potential. 

Based on ‘other toxicity’ studies:

According to REACH guidance document R7.C (ECHA, 2017), other toxicity studies can be helpful to get information on occurrence of absorption without any specification of the extent or amount, for example, if signs of systemic toxicity in dermal studies indicate that absorption has occurred. Also, if the substance has beenidentified as a skin sensitiser, then, provided the challenge application was to intact skin, some uptake must have occurred although it may only have been a small fraction of the applied dose.

No acute toxicity dermal studies are available but the test substance, did not elicit a positive response in skin sensitization testing in guinea pigs (Brummer, 2005).

The absence of effects in this study supports the assessment of a low absorption potential via the dermal route.

Conclusion:

Overall, based on the available weight of evidence, the test substance can be expected to overall have a low absorption potential through the dermal route. Therefore, a value of 10% has been considered for risk assessment purposes.

Inhalation absorption

Based on physicochemical properties:   

According to REACH guidance document R7.C (ECHA, 2017), inhalation absorption is maximal for substances with VP >25 KPa, particle size (<100 μm), low water solubility and moderate log Kow values (between -1 and 4). Very hydrophilic substances may be retained within the mucus and not available for absorption. 

The test substance is a solid under ambient conditions and exhibits a low vapour pressure of 1.44E-9 Pa at 20°C. Therefore, the substance will neither be available for inhalation as vapours nor as aerosols under ambient conditions. In case of spraying applications, only coarse droplets would be an exposure potential resulting in very low respiratory fraction. Of the inhalable fraction, due to the moderate water solubility, the test substance will not be retained in the mucus and hence will reach the deeper lungs for absorption. The larger deposited droplets from the upper respiratory tract will be subsequently transported to the pharynx and swallowed via the ciliary-mucosal escalator. The absorption potential of this fraction of the test substance can be considered similar to the oral route.

The test substance is a solid, with a low vapour pressure of 1.44E-9 Pa at 20°C, a particle size < 100 µm (D50 = 12.5 µm),moderate water solubility and log Kow of 2.39, suggesting a low to moderate inhalation absorption potential.

Conclusion:

Based on all the available weight of evidence information, the test substance can be expected to have low to moderate absorption through the inhalation route. Therefore, a value of 50%, similar to oral absorption, has been considered for risk assessment purposes.