Phosphoric acid, mono- and di-isotridecyl esters, potassium salts

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 relatively higher absorption potential via the oral and inhalation route compared to the dermal route. It is likely to be metabolised via aliphatic hydroxylation phase-I reaction. 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 R7.C (May 2014), oral absorption is maximal for substances with molecular weights (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 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 test substance is a UVCB with mono- and di- phosphate ester constituents of varying carbon chain length (C12, 13, 14), having an average MW of 415.56 g/mol. It is a white paste like solid, with moderate water solubility of 600 mg/L at 20°C and a low log Kow of 2.95, calculated based on solubility in octanol and water.

Based on the R7.C indicative criteria, the oral uptake of the constituents of the test substance is assessed to be moderate to high, given the average molecular weight not exceeding 500, moderate water solubility and low log Kow values of the test substance. This is supported by the presence of systemic effects in the 14-day range finding study conducted with the read across substance, phosphoric acid, dodecyl ester, potassium salt (C12 PSE, K+) in rats.

Based on QSAR prediction:

Human intestinal absorption (HIA) can also be predicted for the constituents of the test substance using the Multicase model v.3.45 of the OECD QSAR Toolbox v.3.4. HIA is expressed as a percentage of the oral dose absorbed from the gastrointestinal tract. Substances with HIA values of 80% are considered well absorbed and with 90% values are extensively and almost completely absorbed. For those compounds for which the absorption was reported as being poor, the value is 5%.

The HIA of the test substance could not be estimated as the structures of the constituents were out of domain of the QSAR model.

Conclusion:Based on the available weight of evidence information, the test substance can be expected to have moderate to high absorption 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 test substance white paste like solid, with an average MW weight of 415.56 g/mol, moderate water solubility and an experimental log Kow less than 3. This suggests that, the test substance will have a low to moderate penetration potential through the skin.

Based on QSAR prediction:

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 EPISuite v4.1. The calculated Jmax of the constituents were found to range from 1E-06 μg/cm2/h to 3.90E-02 μg/cm2/h leading to a weighted average value of 4.05E-02 μg/cm2/h. As per Shenet al. 2014, the default dermal absorption for substances with Jmax is ≤0.1 μg/cm2/h can be considered to be less than 10%. Based on this, the test substance can be predicted to have low absorption potential through the dermal route.

Conclusion: Based on all the available weight of evidence information, the test substance can be expected to have a low to moderate 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 140 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 vivometabolic 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 (Suzukiet 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 (Suzukiet al., 1984b).

Based on QSAR modelling:

The above evidence is supported by the predicted metabolism for the test substance 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 CSR for the reaction sites. For further details, refer to the RA justification.

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

BIOACCUMULATION:

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

EXCRETION:

Based on the average MW and moderate water solubility, the test substance as such is expected to be excreted via urine.