Octadecanoic acid, reaction products with 2-amino-2-methyl-1-propanol

Endpoint summary

Description of key information

Based on the available weight of evidence information, the test substance is expected to be having a low absorption potential through oral, low to moderate absorption potential through dermal and moderate to high absorption potential through inhalation route. Based on QSAR predictions, it is likely to undergo aliphatic hydroxylation as the first metabolic reaction. Further, based on the estimated BCF value, it 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 (May 2014), oral absorption is maximal for substances with a 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, C16-18 AMP, is a UVCB substance with a MW ranging from 327.56-355.61 g/mol for the major constituents. The purified form of the substance is solid (cream-like consistency) witha poor water solubility of <1mg/L at 20°C (based on CMC) and a high estimated log Kow of 6.59.

Based on the R7.C indicative criteria, oral uptake of the test substance constituents is assessed to be low to moderate given average MW not exceeding 500, poorwater solubilityand high log Kow values.

Conclusion:Overall, based on the above information, the test substance can be expected to have a low absorption potential through the oral route. However, 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 a 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 white solid flakes, with an MW exceeding 100 g/mol,poor water solubilityand an estimated log Kow greater than 3. 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 0.01 to 0.11 μg/cm2/h. As per Shenet al.2014, the default dermal absorption for substances with Jmax values >0.1 but ≤10 μg/cm2/h, did not exceed 40% and≤0.1 μg/cm2/h is less than 10%.Based on this, the test substance can be predicted to have low to moderate absorption potential through the dermal route.

Conclusion: Overall, 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. However, 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 are not available for absorption.

Based on experimental and estimated vapour pressure values of 3.7 Pa at 20°C and 9.71E-04 Pa at 25°C respectively, the test substance is considered to have low volatility under ambient conditions. Therefore, the substance is expected neither to be available for inhalation as vapours nor as aerosols. Further, should there be inhalation exposure, considering the poor water solubility of the substance, it is not expected to be retained in the mucus and almost the entire test substance amount is likely to reach the lower respiratory tract followed by absorption into the blood stream.

Conclusion: Based on the above information, if exposure occurs, 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 QSAR modelling:

The predicted metabolism of the test substance was evaluated using rat liver S9 metabolism simulator andin vivorat metabolism simulator of the OECD QSAR Toolbox v.3.4. According to these simulators, all the 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.

BIOACCUMULATION:

Based on low water solubility, a stearic hindrance potential (due to long alkyl chain) and the estimated BCF value, both uptake and bioaccumulation potential are expected to be low.

EXCRETION:

Based on molecular weight and physico-chemical information, the main excretion pathway of the test substance is expected to be via urine.