Hexanamide, N-(2-hydroxyethyl)-3,5,5-trimethyl-

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

experimental study

Adequacy of study:

key study

Study period:

24 Sep 2012 to 30 Jan 2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Compliant with current guidelines and GLP compliant.

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: 8-9 weeks
- Weight at study initiation: Males: 303-372g: Females: 215-265g
- Fasting period before study: None
- Housing: 2 or 3 per sex per cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23C
- Humidity (%): 40-70%
- Air changes (per hr): Minimum of 10
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 24 Sep 2012 To: 16 Nov 2013

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Test item is miscible with corn oil but not with water or other vehicles.
- Concentration in vehicle: 10-100 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg
- Lot/batch no. (if required): Not applicable
- Purity: Not applicable

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Achieved concentration and homogeneity determined to be within acceptance criteria at Weeks 1 and 4 of study.

Duration of treatment / exposure:

Once daily oral gavage adminsitration as follows:
Males: 28 days
Females: between 42 and 46 days (dependent upon dates of mating and parturition)

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
Doses: 0, 30, 75 and 125 mg/kg/day
Basis:

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:The dose levels were agreed with the Sponsor following evaluation of existing relevant toxicological data, including a 7-day dose range finding study (Charles River Study No. 496177).
- Rationale for animal assignment (if not random): Not applicable- random allocation
- Rationale for selecting satellite groups: Not applicable
- Post-exposure recovery period in satellite groups: Not applicable
- Section schedule rationale (if not random): Not applicable

Positive control:

Not applicable

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals checked hourly up to 4 hours post dose on each day of dosing
- Cage side observations: Twice daily mortaility checks (am/pm)

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Once during pre-trial and then daily throughout the treatment period.

FOOD CONSUMPTION
- Food consumption: Weekly prior to pairing for mating. No further food consumption for the males, however food consumption measured for females on Days 0-7, 7-14 and 14-20 of gestation and 0-4 of lactation.

WATER CONSUMPTION Yes
- Time schedule for examinations: Water consumption was monitored regularly by visual inspection of water bottles however no data was recorded.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Pre-trial, Week 4 (males) and prior to sacrifice (females in early lactation).
- Dose groups that were examined: All

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Week 4 (males), ~ Day 4 of lactation (females)
- Anaesthetic used for blood collection: No
- Animals fasted: No
- How many animals: 5 animals per sex per dose group
- Parameters examined:

Red blood cell count
Haemoglobin
Haematocrit
Mean cell volume
Red blood cell distribution width
Mean cell haemoglobin concentration
Mean cell haemoglobin
Reticulocyte count
Platelet count
White blood cell count
Neutrophil count
Lymphocyte count
Monocyte count
Eosinophil count
Basophil count
Large unclassified cells
Activated partial thromboplastin time
Fibrinogen
Prothrombin time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Week 4 (males), ~ Day 4 of lactation (females)
- Animals fasted: No
- How many animals: 5 animals per sex per dose group
- Parameters examined:

Urea
Glucose
Aspartate aminotransferase
Alanine aminotransferase
Alkaline phosphatase
Creatine phosphokinase
Lactate dehydrogenase
Sodium
Potassium
Chloride
Total protein
Albumin
Globulin
Albumin/globulin ratio
Cholesterol
Creatinine
Total bilirubin
Calcium
Phosphate

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Weekly
- Dose groups that were examined: All
- Battery of functions tested:
Cageside and standardised arena observations (Weekly)
Grip strength, pain perception, landing foot splay and motor activity (Males (all): Week 4: Females (5 animals per group): Day 3 of lactation)

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

Reproductive endpoints included in separate IUCLID summary.

Statistics:

Where required to assist with interpretation, tests were applied to determine the statistical significance of observed differences between Control and groups receiving test item. All statistical tests were two-sided and performed at the 5% significance level using in house software. Pairwise comparisons were only performed against the control group.

Body weight and food consumption (prior to mating), haematology, coagulation, clinical chemistry and selected FOB and motor activity data was analysed for homogeneity of variance using the ‘F Max' test. If the group variances appeared homogeneous, a parametric ANOVA was used and pairwise comparisons were made using Fisher’s F protected LSD method via Student's t test ie pairwise comparisons were made only if the overall F test was significant. If the variances were heterogeneous, log or square root transformations were used in an attempt to stabilise the variances. If the variances remained heterogeneous, then a Kruskal-Wallis non-parametric ANOVA was used and pairwise comparisons were made using chi squared protection (via z tests, the non-parametric equivalent of Student's t test).

Organ weight data was analysed as above, and by analysis of covariance (ANCOVA) using terminal body weight as the covariate.

Clinical signs:

no effects observed

Description (incidence and severity):

9 female animals were found dead/prematurely euthanised either in late gestation/early lactation; the distribution had no assocaiation to dose level and they were not considered test-item related. Excess salivation noted post dose in test animals.

Mortality:

no mortality observed

Description (incidence):

9 female animals were found dead/prematurely euthanised either in late gestation/early lactation; the distribution had no assocaiation to dose level and they were not considered test-item related. Excess salivation noted post dose in test animals.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Description (incidence and severity):

No inter-group differences were noted during the study, however there was no positive data recorded

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Mean liver weights were higher than Control in males at all dose levels and slightly higer at 75 and 125 mg/kg/day in females. Mean kidney weights were higher than Control in males at all dose levels (no effects in females).

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Liver: centrilobular hypertrophy (males and females at 125 mg/kg/day: only dose level examined). Kidneys (males at 125 mg/kg/day only): intraepithelial hyaline droplets, single cell necrosis, foci of basophilic (regenerating) tubules, granular casts.

Histopathological findings: neoplastic:

no effects observed

Details on results:

Mortaility:

There were 9 female animals found dead or prematurely euthanised either in late gestation or early lactation (between Day 22 of gestation and Day 2 of lactation). Although a definitive cause of death could not be established for many of these animals, the distribution of the deaths; 2/10, 4/10, 1/10 and 2/10 (0, 30, 75 and 125 mg/kg/day, respectively) indicated that they were not related to the test item.

Clincal Signs:

Excess salivation was noted post dose in animals receiving the test item. This sign was transient and was considered not to be adverse.

Organ Weights:

Absolute mean liver weights were higher than Control in males at all dose levels (1.11X, 1.06X and 1.13X Control mean, at 30, 75 and 125 mg/kg/day, respectively. In females, absolute mean liver weights were slightly higher than Control at 75 and 125 mg/kg/day (1.06X and 1.08X Control mean, respectively).

Absolute mean kidney weights were higher than Control in males at all dose levels (1.08X, 1.08X and 1.19X Control mean, at 30, 75 and 125 mg/kg/day, respectively). There were no clear differences between the kidney weights of females receiving the test item and Control females.

Histopathology:

In the liver minimal or mild centrilobular hypertrophy of hepatocytes was present in 4/5 males and 5/5 females at 125 mg/kg/day.

In comparison to Control there was a moderate or marked increase in intraepithelial hyaline droplets in the cortical tubules in the kidneys of males at125 mg/kg/day. Associated with the droplets were minimal single cell necrosis of the tubular epithelium, an increase in the incidence and severity of foci of basophilic (regenerating) tubules and, in 2/5 animals, granular casts at the cortico-medullary junction. These findings were considered to be consistent with a diagnosis of ‘hyaline-droplet nephropathy’ caused by an overload of the male rat specific protein alpha-2-microglobulin.

Dose descriptor:

NOAEL

Effect level:

125 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects considered adverse or relevant to humans were observed after 28 or more days of exposure. The highest dose administered was established as the NOAEL

Critical effects observed:

not specified

Conclusions:

Under the conditions of this study, and based on the lack of human relevance of findings in the male kidneys at the high dose, the systemic or parental NOAEL was considered to be 125 mg/kg bw/day.

Executive summary:

A combined repeated dose toxicity study with the reproduction / developmental toxicity screening test was conducted to determine the toxicity to reproduction and/or development of test substance, according to OECD Guideline 422, in compliance with GLP. Sprague-Dawley rats were randomised into 3 test groups and one Control group, each containing 10 males and 10 females. Males were treated by oral gavage at doses from 30, 75 and 125 mg/kg bw/day for 2 weeks prior to mating, then through mating, until the day prior to necropsy (4 weeks of treatment). Females were treated with the same doses for 2 weeks prior to mating, then through mating, gestation and until at least Day 4 of lactation (ca. 6 weeks of treatment). The following parameters and end points were evaluated in this study: clinical signs, body weights, food consumption, ophthalmology, detailed functional tests and observations, reproductive parameters (mating and pregnancy performance, fertility, maternal care and pup performance), clinical pathology parameters (haematology, coagulation and clinical chemistry), organ weights, and gross and microscopic pathological examinations. There were no test substance related effects on body weights, body weight changes, food consumption, ophthalmology, detailed functional tests and observations, clinical pathology parameters (haematology, coagulation and clinical chemistry) or gross necropsy findings. Excess salivation noted transiently post dose in animals receiving the test substance may have been a consequence of an unpleasant taste associated the test substance; it was nevertheless considered not to be adverse. The distribution of the 9 female animals found dead or prematurely euthanised (2/10, 4/10, 1/10 and 2/10 at 0, 30, 75 and 125 mg/kg bw/day, respectively) either in late gestation or early lactation (between Day 22 of gestation and Day 2 of lactation) indicated no clear relationship to the test substance. Furthermore, these animals were not observed to be suffering from clinical signs that were considered to be test substance-related; indeed other than the salivation noted above, there were no clinical signs in the animals surviving to the end of the study that were considered to be test substance related. Similarly, test substance related histopathological findings were not observed to a greater degree/severity in the premature decedents relative to the animals surviving to terminal sacrifice. There were no test substance-related effects on mating, pregnancy performance, fertility or maternal care and pup performance (litter survival and pup weights). It should be noted that there were high absolute numbers of litter losses (2/8, 2/6, 1/9 and 3/9 of surviving females at 0, 30, 75 and 125 mg/kg bw/day, respectively) and low viability rates (66%, 74%, 87% and 63% at 0, 30, 75 and 125 mg/kg bw/day, respectively); however the distribution of these findings indicated no clear relationship to the test substance. The minimal or mild centrilobular hypertrophy of hepatocytes in the livers of animals at 125 mg/kg bw/day, correlated with high liver weights in animals receiving the test substance. Whilst this finding was considered to be test substance related, it was not associated with any changes in clinical chemistry parameters and was considered to be an adaptive response and not adverse. The histopathological findings in the kidneys of males at 125 mg/kg bw/day were consistent with a diagnosis of ‘hyaline-droplet nephropathy’, which correlated with high kidney weights in males receiving the test substance. The findings were considered to be caused by an accumulation of complexes of the male rat specific protein alpha-2-microgloblin and the test substance that were resistant to degradation. As little or no alpha-2-microgloblin protein is present in man, Greaves (2007), these findings were considered not to be relevant to man. Therefore, under the conditions of this study, and based on the lack of human relevance of findings, the parental, reproductive and neonatal NOAEL was considered to be 125 mg/kg bw/day (Wallace, 2013).

Cross-reference 2

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

Based on the available weight of evidence experimental studies, the test substance is expected to be have a low to moderate absorption potential through oral and dermal route and moderate to high absorption potential through the inhalation route. Following absorption, the test substance can be expected to under amide hydrolysis or hydroxylation as first metabolic reactions, distributed into different organs with a low bioaccumulation potential. Further, it is likely to be excreted both via faces and urine.

Bioaccumulation potential:

low bioaccumulation potential

ABSORPTION:

Oral absorption

Based on physicochemical properties:

According to REACH guidance document R.7C (May 2017), oral absorption is maximal for substances with molecular weight (MW) below 500.For gastrointestinal absorption by passive diffusion across biological membranes which consist of both aqueous and lipid layers both water and lipid solubility are necessary.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 substance3,5,5-trimethyl C6 MEA is a non-ionic surfactant which belongs to a monoethanolamine (MEA) derived fatty acid alkanolamide category. It is a mono-constituent with majorly branched C9 alkyl chain length and molecular weight of 201.31g/mol. The purified form of the substance appears as brown liquid. It is considered to have low water solubility based on an experimental water solubility of 40 mg/L at andhigh lipophilicity based onlog Kow of 4.4. Given its high lipophilicity it is likely to have limited solubility in gastrointestinal fluids. Further, the low water solubility of the substance indicates that absorption may occur via facilitated diffusion, active transport or pinocytosis, processes requiring energy.

 

Therefore, overall based on the R7.C indicative criteria, and the fact that non-ionic surfactants have a low permeating potential, the test substance can be expected to have a low to moderate absorption potential from the gastrointestinal tract.

 

Based on (Q)SAR predictions:  

The “Lipinski’s rule OASIS” profiler of the OECD QSAR Toolbox v.4.4.1, which describes the molecular properties important for a drug’s pharmacokinetics in the human body, predicted the main constituents to be ‘bioavailable’. Therefore, the test substance can be overall considered to have a bioavailability potential.

 

Based on ‘other toxicity’ studies:

According to REACH guidance document R7.C (ECHA, 2017), other toxicity studies can be helpful to get information on occurrence of absorption without any specification of the extent or amount. For example: if signs of systemic toxicity are present in acute or repeated dose studies, then absorption has occurred. Also colored urine and/or internal organs can provide evidence that a colored substance has been absorbed.

A 7-day dose-range finding study and an OECD 422 screening study available with the test substance, showed signs of systemic toxicity at dose of 125 mg/kg bw/day, suggesting a likelihood of absorption to a certain extent (See Section 5.6 of the CSR).

 

Conclusion :Overall, based on the available weight of evidence information, the test substance can be expected to overall have a low to moderate absorption potential through the oral route.Therefore, as a conservative approach, a maximum value of 50% has been considered for the risk assessment.

Dermal absorption

Based on physicochemical properties:  

According to REACH guidance document R.7C (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 Kow 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 a liquid, with a MW exceeding 100 g/mol, low water solubility and high log Kow exceeding 3, all of which suggest a likelihood of low absorption potential through the dermal route. However, given that the test substance is a non-ionic surfactant, which have a better permeating potential through skin due to their lower CMC, higher solubilisation capability (Ullahet al., 2019; Somet al., 2012) compared to other types of surfactants, the test substance can be considered to have a low to moderate absorption potential at best.

Based on (Q)SAR 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 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 v2.02 application of EPI SuiteTM v4.11. The calculated Jmax value for the test substance including its impurities ranged from 0.0013 to 0.15 μg/cm2/h. As per Kroeset al.,2004 and Shenet al. 2014, the default dermal absorption for substances with Jmax between >0.1 to ≤10 μg/cm2/h can be considered to be less than 40% while Jmax ≤0.1 μg/cm2/h is less than 10%. Based on the predicted Jmax value, which is just above 0.1 μg/cm2/h limit, the test substance can be considered to have overall a low absorption potential through the dermal route.  

Based on ‘other toxicity’ studies:

According to REACH guidance document R7.C (ECHA, 2017), other toxicity studies can be helpful to get information on occurrence of absorption without any specification of the extent or amount. For example: if signs of systemic toxicity in dermal studies indicate that absorption has occurred. Also, if the substance has been identified as a skin sensitizer then, provided the challenge application was to intact skin, some uptake must have occurred although it may only have been a small fraction of the applied dose.

Acute dermal toxicity study conducted with test substance in rat did not show any clinical signs throughout the observation period. Similar absence of clinical signs and sensitisation response was also observed in a skin sensitisation study available with test substance in mice (see Section 5.5 of the CSR). Based on this information, the test substance is expected to have low absorption potential.

 

Conclusion :Overall, based on the available weight of evidence information, the test substance can be expected to overall have a low to moderate absorption potential through the dermal route. Therefore, as a conservative approach, a maximum 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 liquid physical state and relatively low vapour pressure of 1.9E-4 Pa at 20 °C, will not be available as particles or vapours for inhalation under ambient conditions. In case of spraying applications, only coarse droplets would be an exposure potential resulting in very low respiratory fraction. Of the inhalable fraction, due to the low water solubility, the test substance will not be retained in the mucus and hence is more likely to reach the deeper lungs for absorption, whereabsorption via passive diffusion will be favoured given its high log Kow.On the other hand, the larger deposited droplets 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.

Based on ‘other toxicity’ studies:

According to REACH guidance document R7.C (ECHA, 2017), if signs of systemic toxicity are present in an oral toxicity study or there are other data to indicate the potential for absorption following ingestion it is likely the substance will also be absorbed if it is inhaled.

No inhalation studies were available with the test substance or its structural analogue. However, the presence of signs of systemic effects in the 7 day and an OECD 422 screening studyconducted with the test substance, suggests a likelihood of absorption to a certain extent also through the inhalation route.

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 (Q)SAR predictions:  

Q)SAR modelling tools such as the OECD Toolbox v 4.4.1 allow the identification and prioritisation of Phase I metabolic pathways, which in turn allow in relative terms an assessment whether chemically similar substances follow similar or different metabolic pathways.

The OECD Toolbox was used to predict the first metabolic reaction, as two metabolic simulators (in vivorat metabolism simulator and rat liver S9 metabolism simulator) take into account amide hydrolysis as a Phase I metabolic reaction.Based on predictions from the two simulators of the OECD Toolbox and expert judgement, amide hydrolysis and the hydroxylation are expected to be the first metabolic reactions for the test substance (see below Table).

Composition	Rat liver S9 metabolism simulator/in vivorat metabolism simulator
Main constituent: N-(2-hydroxyethyl)-3,5,5-trimethylhexanamide	Amide hydrolysisandhydroxylation

Based on ‘other toxicity’ studies:

The results of acute toxicity or mutagenicity study with the test substance or the OECD 422 screening study, suggest that no toxic metabolites are likely to be formed when the constituents of test substance are broken down.

 

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, which is a surfactant has a higher permeating potential due to its non-ionic nature, combined with its physico-chemical information (i.e., MW, high lipophilicity and low 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 3-372 L/kg ww using BCFBAF v3.02 of EPI Suite^TM v.4.11, the bioaccumulation potential of the substance is expected to be low.

Based on ‘other toxicity’ studies:

According to REACH guidance document R7.C (ECHA, 2017), identification of the target organs in repeated dose studies can be indicative of the extent of distribution.  

The OECD 422 screening study showed effects on liver and kidneys which suggests a distribution potential to these organs (see section 5.6 of the CSR for further details).

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 andfaeces.  

 

References:

ECHA (European Chemical Agency), 2017. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance Version 3.0 June 2017.

Kroes R et al., 2007. Application of the threshold of toxicological concern (TTC) to the safety evaluation of cosmetic ingredients. Food and Chemical Toxicology, 45(12), pp.2533-2562.

OECD, 2020. The OECD QSAR toolbox for grouping chemicals into categories, version 4.4.1., http://toolbox.oasis-lmc.org/?section=download (accessed March 2020).

Roberts MS and Walters KA, 2007. Dermal absorption and toxicity assessment. CRC Press; 2007 December 14.

Shen J, Kromidas L, Schultz T, Bhatia S 2014. An in-silico skin absorption model for fragrance materials. Food and chemical toxicology, 74:164-76.

Som I, Bhatia K, Yasir M. Status of surfactants as penetration enhancers in transdermal drug delivery. Journal of pharmacy & bioallied sciences. 2012 Jan;4(1):2.

Ullah I, Baloch MK, Niaz S, Sultan A, Ullah I. Solubilizing potential of ionic, zwitterionic and nonionic surfactants towards water insoluble drug flurbiprofen. Journal of Solution Chemistry. 2019 Dec 1;48(11-12):1603-16.​

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