Phosphoric acid, mono- and di-isotridecyl esters, compd. with 2,2'-iminobis[ethanol]

Endpoint summary

Description of key information

There were no studies available in which the toxicokinetic properties of the test substance were investigated. However, as per REACH guidance document R7. C (ECHA, 2017), information on absorption, distribution, metabolism and excretion may be deduced from the physicochemical properties. Based on the physicochemical properties, QSAR predictions/modelling as well as the available toxicological data, the test substance is expected to have higher absorption potential via the oral and inhalation route compared to the dermal route. It is likely to be metabolised via aliphatic hydroxylation in Phase I metabolism. Overall, the substance is expected to have low bioaccumulation potential.

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

ABSORPTION:

Oral absorption

Based on physicochemical properties:

According to REACH guidance document R.7C (May 2014), oral absorption is high for substances with molecular weights (MW) lower than 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 vales (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 substance is a UVCB with mono- and di- phosphate ester constituents of carbon chain length as C12 -13, having a MW ranging from 413 -645 g/mol and a molecular weight of 523 on dry matter basis. It is a light yellow paste, with moderate water solubility of 600 mg/L at 20°C (based on CMC) and a log Kow of 3.56, calculated based on solubility in octanol and water.

Based on the R.7C indicative criteria, the oral uptake of the constituents of the substance is assessed to be moderate, given the average MW of 523, moderate water solubility and Kow values. This is supported by the presence of systemic effects due to repeated dosing of the substance in a combined reproductive-repeated dose toxicity study in rats.

Conclusion: Based on the available weight of evidence information, the substance can be expected to be moderately absorbed through the oral route. Therefore, as a conservative approach a default value of 50% has been considered for the risk assessment.

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 a 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. 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 stratum corneum into the epidermis.

The substance is a yellow paste, with an average MW weight exceeding 100 g/mol, moderate water solubility and a predicted log Kow of 3.56. This suggests that, the test substance is likely to have moderate to high penetration potential through the skin.

Conclusion: Based on all the available weight of evidence information, the test substance can be expected to have a moderate to high absorption potential absorption through the dermal route. Therefore, as a conservative approach a default value of 50% has been considered for the risk assessment

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, because of its relatively low vapour pressure of 15 Pa at 20°C will not be available as vapours for inhalation under ambient conditions. Therefore, the substance will neither be available for inhalation as vapours nor as aerosols. Further, if at all there is any inhalation exposure, considering the moderate water solubility of the substance, it is expected to be retained in the mucus and only very little may reach the lower respiratory tract. The absorption fate of the deposited material thereafter is expected to be similar to the oral route/gastrointestinal tract.

Conclusion: Based on all the available weight of evidence information, the test substance can be expected to have moderate to high absorption through the inhalation route. Therefore, as a conservative approach, a default value of 100% has been considered for the risk assessment.

METABOLISM:

Based on identified literature:

In vivo metabolic transformation study following oral or intraperitoneal administration of 14C-labelled shorter chain trialkyl phosphate ester, tributyl phosphate (TBP), revealed oxidation as the first stage metabolic process, catalysed by cytochrome P-450-dependent mono-oxygenase, at the ω or ω-1 position on the butyl chains. The hydroxyl groups generated at the ω or ω-1 position were further oxidized to produce carboxylic acids and ketones, respectively (Suzuki et al., 1984a). Following these oxidations, the oxidized alkyl moieties were removed as glutathione conjugates, which were then excreted as N–acetyl cysteine derivatives in urine (Suzuki et al., 1984b).

Based on QSAR modelling:

The predicted metabolism of the test substance was evaluated using rat liver S9 metabolism simulator of the OECD QSAR Toolbox v.3.4. According to these simulators, all the 7 major constituents (present at >5%) are primarily predicted to undergo aliphatic hydroxylation as first metabolic reaction. See table in the CSR for the reaction sites. For further details, refer to the read across justification.

BIOACCUMULATION:

Based on the MW and physicochemical information (log Kow and water solubility) and metabolism prediction, the bioaccumulation potential of the substance is expected low.

EXCRETION:

Based on the average MW and moderate water solubility and related moderate to high systemic availability upon inhalation, oral or dermal exposure, the test substance as such is expected to be excreted via urine.