[No public or meaningful name is available]

Endpoint summary

Description of key information

Based on the available weight of evidence information, the test substance is expected to be having moderate absorption potential through oral route and inhalation routes and a low absorption potential via, dermal route. Based on QSAR predictions, the different constituents are likely to undergo aliphatic hydroxylation and the phosphate esters and alkyl esters are likely to undergo ester hydrolysis in addition. This leads to formation of more polar metabolites and likely excretion via urine. Further, based on the log Kow or estimated BCF values, the test substance is likely 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 (ECHA, 2017), 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 UVCB substance, having an MW of ranging from 242.45 to 546.86 g/mol for the major constituents (average: 417.61 g/mol). The substance is a solid, with high water solubility of 2270 mg/L at 20°C (based on CMC) and a moderate log Kow of 0.85 (calculated based on individual solubility ratio).

Based on the above R7.C indicative criteria, and considering that the test substance is anionic, therefore it is expected not to be readily absorbed from the gastrointestinal tract.

Conclusion:Overall, based on the above information, the test substance can be expected to overall have a moderate absorption potential through the oral route. Therefore, a 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 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 solid, with an MW exceeding 100 g/mol, high water solubility (>100 mg/L) and a moderate calculated log Kow of 0.85 (below the favourable range). This suggests that the test substance is likely to have a low 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 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 Suite v4.11. The calculated Jmax of the major constituents were found to range from 1.65E-03 to1.47E-01 μg/cm2/h leading to a weighted average value of 6.82E-02 μg/cm2/h. As per Shenet al.2014, the default dermal absorption for substances with Jmax is ≤0.1 μg/cm2/h is less than 10%. Based on these calculations, the test substance is predicted to be poorly absorbed via the dermal exposure route.

Conclusion: Overall, based on all the available weight of evidence information together with ionic nature, the test substance can be expected to have a low absorption potential absorption through the dermal route. However, as a conservative approach a 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.

Based on the fact that the test substance is a solid (in the form of white pellets) with a low experimental vapour pressure value of 0.0079 Pa at 25°C, it is likely to have low exposure potential through the inhalation route. Further, if at all there is any inhalation exposure during the use conditions, considering the high-water solubility of the substance, it is expected to be retained in the mucus and a lesser amount will reach the lower respiratory tract. In addition, retained substance 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 to be similar to the oral route.  

Conclusion: Based on the above information, and considering that the test substance is ionic therefore, it is expected not to be readily absorbed from the respiratory tract if exposed. Nevertheless, as a conservative approach, a default value of 100% has been considered for the risk assessment.

METABOLISM:

Based on identified literature:

Anin vivometabolic transformation study following oral or intraperitoneal administration of 14C-labelled shorter chain trialkyl ester phosphate, 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 predicted metabolism of the test substance was evaluated using rat liver S9 metabolism andin vivorat metabolism simulators of the OECD QSAR Toolbox v.3.4. According to these simulators, all the major constituents (present at >5%), are primarily predicted to undergo ω or ω-1aliphatic hydroxylation reactions. The phosphate esters and the alkyl ester in addition were predicted to undergo ester hydrolysis. See table in CSR for the reaction sites. For further details, refer to the read across justification.  

 

Major constituents	Rat liver S9 metabolism simulator/in vivorat metabolism simulator
mono- C16 PSE, K+ and mono-C16 PSE	ω-1 Aliphatic hydroxylation and ester hydrolysis
di- C16 PSE, K+ and di- C16 PSE	ω-1 Aliphatic hydroxylation and ester hydrolysis
Cetyl alcohol	ω-1 Aliphatic hydroxylation
Isostearyl alcohol	ω Aliphatic hydroxylation
Stearic acid/potassium stearate	ω-1 Aliphatic hydroxylation
Cetyl stearate	ω-1 Aliphatic hydroxylation and ester hydrolysis
Cetyl Isostearate	ω Aliphatic hydroxylation and ester hydrolysis
Isostearyl Isostearate	ω Aliphatic hydroxylation and ester hydrolysis
Isostearyl stearate	ω Aliphatic hydroxylation and ester hydrolysis

 

DISTRIBUTION     

Based on physico-chemical properties:   

According to REACH guidance document R7.C (ECHA, 2017), the smaller the molecule, the wider the distribution. Small water-soluble molecules and ions will diffuse through aqueous channels and pores, although the rate of diffusion for very hydrophilic molecules will be limited. Further, if the molecule is lipophilic (log P >0), it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. 

Considering that the test substance is an anionic combined with its physico-chemical information (i.e., MW, moderate lipophilicity and high water solubility) suggests that test substance could be distributed to highly perfused organs/tissues (e.., liver, kidney), once absorbed and bioavailable. 

However, based on the log Kow <4.5 and predicted BCF values ranging from 0.89 to 591 L/kg ww using the Arnot Gobas method from the the BCFBAF v3.02 model of EPI Suite^TMv.4.11 (see Annex 3), the bioaccumulation potential of the substance is expected to be low. 

Conclusion:Based on all the available weight of evidence information, the test substance is likely to be distributed if absorbed, but with a low bioaccumulation potential.  

EXCRETION:     

Based on physicochemical properties:   

According to REACH guidance document R7.C (ECHA, 2017), the characteristics favourable for urinary excretion are low molecular weight (below 300 in the rat), good water solubility, and ionization of the molecule at the pH of urine (4.5 to 8). 

Given the physicochemical properties of the test substance and MW, the test substance is likely to be excreted via both faeces and urine. Further, there will be also urinary elimination following formation of water-soluble conjugates or metabolites via Phase II reactions. 

Conclusion:Based on all the available weight of evidence information, the test substance is expected to be primarily excreted via urine and faeces.   

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