4,4'-Isopropylidenediphenol, polymer with 1-chloro-2,3-epoxypropane, propane-1,2-diol acrylate and succinic anhydride

Endpoint summary

Description of key information

Available weight of evidence information from physico-chemical properties, QSAR predictions and other toxicity studies indicates that, the test substance can be overall expected to have a low absorption potential through oral and dermal routes and high to moderate through inhalation routes (if exposed). Further, based on the estimated BCF value and physico-chemical parameters, it is likely to have low bioaccumulation potential and excreted primarily via faeces. Based on metabolism simulators from OECD Toolbox, the constituents of the test substance are likely to undergo ester hydrolysis as the first metabolic reactions leading to the formation of polar metabolites, which would eventually be excreted via urine.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

There were no studies available in which the toxicokinetic properties of test substance‘4,4’-Isopropylidenediphenol, polymer with 1-chloro-2,3-epoxypropane, propane-1,2-diol acrylate and succinic anhydride’ were investigated. However, as per REACH guidance document R7.C (2017), information on absorption, distribution, metabolism and excretion may be deduced from the physicochemical properties, QSAR modelling and information from other studies.

ABSORPTION

Oral absorption

Based on physico-chemical properties

According to REACH guidance document R7.C, oral absorption is maximal for substances with molecular weights 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 an UVCB, with several constituents having molecular weights (MW) ranging from 130.14 to 1259.37g/mol, with an average MW of 722.43 g/mol. It is a highly viscous liquid with a poor water solubility determined to be <0.007 mg/L and an experimentally determined log Kow ranging from <1.1 to >6.2. Volatility was determined to be low (0.19 Pa).

Based on the R7.C indicative criteria, oral uptake of the test substance is assessed to be low, given their high average molecular weight (exceeding 500), poor water solubility and relatively high log Kow.

 

Based on QSAR predictions:

The Lipinski’s rule OASIS profiler of the OECD QSAR Toolobox v.4.3.1, which describes the molecular properties important for a drug’s pharmacokinetics in the human body, including their absorption, distribution, metabolism, and excretion (”ADME”), predicted‘less bioavailable’for all the constituents except for hydroxypropyl acrylate or tripropylene glycol monoacrylate (i.e., constituent 5).

Based on other toxicity studies:

Some amount of systemic absorption of the test substance via the oral route is confirmed due to presence of clinical signs in an acute toxicity study in rats.

Conclusion:The assessment of oral absorption based on physico-chemical properties as well as Lipinski’s rule of five profiler indicates that, except for the residual constituent 5, which is present at very low amounts, the overall test substance can be expected to have a low absorption potential. However, a maximum of 50% oral absorption has been considered for a conservative risk assessment.

Dermal absorption

Based on physico-chemical 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 to be 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 viscous liquid, with an MW exceeding 100 g/mol, poor water solubility (<1 mg/L) and an experimental log Kow of ≥3 for majority of the constituents. This suggests that the test substance is likely to have a low penetration potential through the skin.

Based on QSAR predictions:

The two well-known parameters often used to characterise percutaneous penetration potential of substances are the dermal permeability coefficient (Kp[1]) and maximum flux (Jmax). Kp reflects the speed with which a chemical penetrates across stratum corneum (SC) and Jmax represents the rate of penetration at steady state of an amount of permeant after application over a given area of SC. Out of the two, although Kp is more widely used in percutaneous absorption studies as a measure of solute penetration into the skin. However, it is not a practical parameter because for a given solute, the value of Kp depends on the vehicle used to deliver the solute. Hence, Jmax i.e., the flux attained at the solubility of the solute in the vehicle is considered as the more useful parameter to assess dermal penetration potential as it is vehicle independent (Robert and Walters, 2007).

In the absence of experimental data, Jmax can be calculated by multiplying the estimated water solubility with the Kp values from DERMWIN v2.01 application of EPI SuiteTMv4.11. The calculated Jmax of the major constituents were found to be very low ranging from 3.1E-14 to 4.4E-06 μg/cm2/h, except for a value of 77 μg/cm2/h calculated for the residual constituent 5 (i.e., hydroxypropyl acrylate), which is present at <3% in the composition. As per Shenet al.2014, the default dermal absorption for substances with Jmax is ≤0.1 μg/cm2/h is less than 10% and for substances with Jmax is >0.1 μg/cm2/h but ≤10 μg/cm2/h, it did not exceed 40%.

The above Jmax based dermal absorption assessment is further supported by the ‘low skin permeability’ categorisation according to the ‘skin permeability (beta)’ profiler from OECD QSAR Toolbox 4.3.1 for all constituents, except for the residual constituent 5.

Therefore, based on these calculations, the test substance is overall predicted to have a low absorption potential except for a moderate potential for the residual constituent 5, via the dermal exposure route.

Based on other toxicity studies:

Some amount of bioavailability of the test substance via the dermal route is confirmed by the positive sensitisation studies indicating that some transfer through the first epidermal layer has taken place.

Further, body weight alterations observed in few animals in the acute dermal toxicity study in rats, indicates some amount of systemic absorption either through dermal route or due to ingestion via grooming.

Conclusion: The assessment of dermal absorption based on physico-chemical properties, QSAR predictions and other toxicity studies indicates that, except for the residual constituent hydroxypropyl acrylate, which is present at very low amounts, the overall test substance can be expected to have a low absorption potential. However, a maximum of 50% dermal absorption has been considered for a conservative risk assessment.

Inhalation absorption

Based on physico-chemical properties:

According to REACH guidance document R7.C, 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 be available for absorption.

The test substance because of its high viscosity and relatively low vapour pressure of 0.19 Pa at 20°C, will not be available as vapour for inhalation under ambient conditions. Also, spray applications (i.e., PROC 7 or 11) are not included in the registration dossier. Therefore, the substance will neither be available for inhalation as vapour nor as aerosols.

Conclusion:Overall based on physico-chemical properties of the test substance, absorption is possible via upper mucosa but is limited by the inhaled amount which is assumed to be low due to the very low vapour pressure. Therefore, a conservative default value of 100% inhalation absorption has been considered for a conservative risk assessment.

METABOLISM:

Based on QSAR predictions:

The predicted metabolism of the test substance was evaluated using the in vivo rat metabolism simulator and the rat liver S9 metabolism simulator of the OECD QSAR Toolbox v.4.3. According to these simulators, the main constituents (present at >5%) are primarily predicted to undergo ester hydrolysis as first metabolic reaction. See table in the CSR for the reaction sites. For further details, refer to the read across justification.

Based on other toxicity studies:

The results of acute, repeated dose and mutagenicity testing suggest that no toxic metabolites are formed when the constituents of test substance are broken down.

DISTRIBUTION:

Based on physico-chemical properties:

The physico-chemical information (high molecular weight, high lipophilicity and low water solubility) indicates that test substance could be distributed to many tissues, once absorbed and bioavailable.

Accumulation potential: Based on the estimated BCF and MW, water solubility values, the bioaccumulation potential of the substance is expected to be low.

EXCRETION:

Based on physico-chemical properties:

Based on the high MW and low water solubility, the test substance as such is expected to be excreted primarily via faeces. Nevertheless, there will be some urinary elimination following formation of water-soluble conjugates via Phase II reactions.

[1]Log Kp = -2.80 + 0.66 log kow – 0.0056 MW