Benzododecinium chloride

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

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:

vapour pressure

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From July 02, 2019 to July 18, 2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 104 (Vapour Pressure Curve)

Qualifier:

according to guideline

Guideline:

EU Method A.4 (Vapour Pressure)

GLP compliance:

yes (incl. QA statement)

Type of method:

effusion method: Knudsen cell

Key result

Test no.:

#1

Temp.:

ca. 20 °C

Vapour pressure:

ca. 0 Pa

Remarks on result:

other: Calculated by extrapolation of the measured vapour pressure curve for temperature 20 deg C

Key result

Test no.:

#2

Temp.:

ca. 25 °C

Vapour pressure:

ca. 0 Pa

Remarks on result:

other: Calculated by extrapolation of the measured vapour pressure curve for temperature 25 deg C

Key result

Test no.:

#3

Temp.:

ca. 50 °C

Vapour pressure:

ca. 0 Pa

Remarks on result:

other: Calculated by extrapolation of the measured vapour pressure curve for temperature 50 deg C

Results

Thermal Stability

The DSC run PN18027 is shown in Figure 1 (kindly refer the attached background material section of the IUCLID). In the temperature range of 30 - 50 °C a first endothermic effect can be observed. A second endothermic effect was detected in the temperature range of 170 - 210 °C. The test was terminated at 300 °C.

 

Effusion method: Knudsen cell

The vapour pressure was measured in the temperature range of 100 to 125 °C. The measured vapour pressure values together with the measured temperatures are listed in below table:

Number	Temperature (Deg C)	Vapour pressure (Pa)
1	100	-
2	105	0.025
3	110	0.042
4	115	0.072
5	120	0.12
6	125	0.2

 

Figure 2 shows the vapour pressure as a function of the inverse temperature 1/T (kindly refer the attached background material section of the IUCLID). Segment No. 1 was not considered for the linear regression since water was evaporated from the test substance at the beginning of the examination.

The vapour pressure of the test substance was calculated by extrapolation of the measured vapour pressure curve for the temperatures 20, 25 and 50°C. The vapour pressure of the test substance was determined to be 1.4E-7 Pa, 3.5E-7 Pa and 2.0E-5 Pa at 20°C, 25°C and 50°C respectively.

Conclusions:

Under the study conditions, vapour pressure of the test substance was determined to be 1.4E-7 Pa, 3.5E-7 Pa and 2.0E-5 Pa at 20°C, 25°C and 50°C respectively.

Executive summary:

A study was conducted to determine the vapour pressure of the substance, using Knudsen cell Effusion method according to the OECD Guideline 104 and EU Method A.4, in compliance with GLP. Under the study conditions, vapour pressure of the test substance was determined to be 1.4E-7 Pa, 3.5E-7 Pa and 2.0E-5 Pa at 20°C, 25°C and 50°C respectively (Hartmann, 2019).

Cross-reference 2

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

Endpoint:

particle size distribution (granulometry)

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the substance is marketed or used in a non solid or granular form

Cross-reference 3

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

Endpoint:

skin irritation: in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1975

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Justification for type of information:

Refer to section 13 of IUCLID for details on the read-across justification. The study with the read across substance is considered sufficient to fulfil the information requirements.

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPPTS 870.2500 (Acute Dermal Irritation)

Deviations:

yes

Remarks:

1. In the study, abraded and non abraded skin sites were used; however, the guideline recommends unabraded skin. 2. Exposure period was 24 h; however, guideline recommends 4 h exposure period

GLP compliance:

no

Species:

rabbit

Strain:

not specified

Type of coverage:

occlusive

Preparation of test site:

other: The test substance was applied to both abraded and intact skin

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

Test material
- Amount(s) applied (volume or weight with unit): 0.5 mL

Duration of treatment / exposure:

24h

Observation period:

24 and 72h

Number of animals:

6

Details on study design:

Test site:
- Area of exposure: Back of animal
- Type of wrap if used: The patches consisted of two layers of light gauze cut in squares (2.5 cm on the side). The patches were secured to the test area by thin bands of adhesive tape and the trunk of each animal was wrapped in clear plastic trunk bands after application of the test substance.
- Type of test site: Two areas (intact and abraded) on the back of each animal placed approximately 10 cm apart

Scoring system:
- Skin reactions were scored for erythema and edema, according to Draize Woodland and Calvery scoring system.

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

other: 24h and 72h

Score:

6.29

Max. score:

8

Reversibility:

not fully reversible within: 72h

Remarks on result:

other: Intact and abraded skin site

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 24h and 72h

Score:

3.33

Max. score:

4

Reversibility:

not fully reversible within: 72h

Remarks on result:

other: Intact skin site

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 24h and 72h

Score:

3.5

Max. score:

4

Reversibility:

not fully reversible within: 72h

Remarks on result:

other: Abraded skin site

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 24h and 72h

Score:

2.66

Max. score:

3

Reversibility:

not fully reversible within: 72h

Remarks on result:

other: Intact skin site

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 24h and 72h

Score:

3

Max. score:

3

Reversibility:

not fully reversible within: 72h

Remarks on result:

other: Abraded skin site

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

other: 24/72 h

Score:

ca. 3.5 - ca. 4

Max. score:

4

Reversibility:

not fully reversible within: 72 h

Remarks on result:

positive indication of irritation

Remarks:

(mean erythema score was: 3.5 for intact and 4 for abraded skin)

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

other: 24 / 72 h

Score:

ca. 3 - ca. 3.5

Max. score:

4

Reversibility:

not fully reversible within: 72 h

Remarks on result:

positive indication of irritation

Remarks:

(mean erythema score was: 3 for intact and 3.5 for abraded skin)

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

other: 24 / 72 h

Score:

ca. 3.5

Max. score:

4

Reversibility:

not fully reversible within: 72 h

Remarks on result:

positive indication of irritation

Remarks:

(mean erythema score was: 3.5 for intact and 3.5 for abraded skin)

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

other: 24 / 72 h

Score:

ca. 3.5

Max. score:

4

Reversibility:

not fully reversible within: 72 h

Remarks on result:

positive indication of irritation

Remarks:

(mean erythema score was: 3.5 for intact and 3.5 for abraded skin)

Irritation parameter:

erythema score

Basis:

animal #5

Time point:

other: 24 / 72 h

Score:

ca. 3

Max. score:

4

Reversibility:

not fully reversible within: 72 h

Remarks on result:

positive indication of irritation

Remarks:

(mean erythema score was: 3 for intact and 3 for abraded skin)

Irritation parameter:

erythema score

Basis:

animal #6

Time point:

other: 24 / 72 h

Score:

ca. 3.5 - ca. 4

Max. score:

4

Reversibility:

not fully reversible within: 72 h

Remarks on result:

positive indication of irritation

Remarks:

(mean erythema score was: 4 for intact and 3.5 for abraded skin)

Irritation parameter:

edema score

Basis:

animal #1

Time point:

other: 24 / 72 h

Score:

ca. 2.5 - ca. 3

Max. score:

3

Reversibility:

not fully reversible within: 72 h

Remarks on result:

positive indication of irritation

Remarks:

(mean erythema score was: 2.5 for intact and 3 for abraded skin)

Irritation parameter:

edema score

Basis:

animal #2

Time point:

other: 24 / 72 h

Score:

ca. 2.5 - ca. 3

Max. score:

3

Reversibility:

not fully reversible within: 72 h

Remarks on result:

positive indication of irritation

Remarks:

(mean erythema score was: 2.5 for intact and 3 for abraded skin)

Irritation parameter:

edema score

Basis:

animal #3

Time point:

other: 24/72 h

Score:

ca. 3

Max. score:

3

Reversibility:

not fully reversible within: 72 h

Remarks on result:

positive indication of irritation

Remarks:

(mean erythema score was: 3 for intact and 3 for abraded skin)

Irritation parameter:

edema score

Basis:

animal #4

Time point:

other: 24/72 h

Score:

ca. 2.5 - ca. 3

Max. score:

3

Reversibility:

not fully reversible within: 72 h

Remarks on result:

positive indication of irritation

Remarks:

(mean erythema score was: 2.5 for intact and 3 for abraded skin)

Irritation parameter:

edema score

Basis:

animal #5

Time point:

other: 24/72 h

Score:

ca. 3

Max. score:

3

Reversibility:

not fully reversible within: 72 h

Remarks on result:

positive indication of irritation

Remarks:

(mean erythema score was: 3 for intact and 3 for abraded skin)

Irritation parameter:

edema score

Basis:

animal #6

Time point:

other: 24/72 h

Score:

ca. 2.5 - ca. 3

Max. score:

3

Reversibility:

not fully reversible within: 72 h

Remarks on result:

positive indication of irritation

Remarks:

(mean erythema score was: 2.5 for intact and 3 for abraded skin)

Irritation parameter:

erythema score

Time point:

24/48/72 h

Remarks on result:

other: see below table for details on results

Irritation parameter:

edema score

Time point:

24/48/72 h

Remarks on result:

other: see below table for details on results

Irritant / corrosive response data:

- Severe erythema and edema were observed in animals with abraded and intact skin. See below table for individual animal scores at each time point.

Table 1. Individual animal data on the skin irritation response

Rabbit no.	Reaction	24 h		72 h
		Intact	Abraded	Intact	Abraded
1	Erythema	4	4	3	4
	Edema	2	3	3	3
2	Erythema	3	4	3	3
	Edema	2	3	3	3
3	Erythema	4	4	3	3
	Edema	3	3	3	3
4	Erythema	4	4	3	3
	Edema	2	3	3	3
5	Erythema	3	3	3	3
	Edema	3	3	3	3
6	Erythema	4	4	4	3
	Edema	2	3	3	3

 

Interpretation of results:

other: Category 1B (corrosive) based on CLP criteria

Conclusions:

Based on the results of the read across study, the test substance, C12 ADBAC, can be considered to be corrosive to rabbit skin.

Executive summary:

A study was conducted to determine the skin irritation / corrosion potential of the read across substance, C12 -16 ADBAC (50 -80% active), according to US EPA OPPTS 870.2500. The experiment was performed in rabbits. The undiluted test substance was applied on intact and abraded skin sites using occlusive patches for an exposure period of 24 h. The skin was then observed for erythema and edema formation and the scoring was done according to the Draize, Woodland and Calvery scoring system at 24 and 72 h from the onset of exposure. Severe erythema and edema were observed in all the test animals at both the abraded and intact sites. The mean Primary Irritation Index (PII) of the test substance was calculated to be 6.29 and the mean values of erythema and edema were 3.33 (intact skin site), 3.5 (abraded skin site), 2.66 (intact skin site) and 3 (abraded skin site). Under study conditions, C12 -16 ADBAC is considered to be corrosive to rabbit skin (Wallace, 1975). Based on the results of the read across study, the test substance, C12 ADBAC, can be considered to be corrosive to rabbit skin.

Cross-reference 4

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

Based on the available weight of evidence experimental studies, the test substance, C12 ADBAC, is expected to have a poor absorption potential through oral and dermal routes and to be primarily excreted via faeces. Based on QSAR predictions and data on read across substance, it is likely to undergo aliphatic hydroxylation as the first metabolic reaction. Further, based on its ionic nature, molecular weight and key physico-chemical properties it is likely to have no bioaccumulation potential.

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

ABSORPTION:  

Oral absorption  

Based on physicochemical properties:

According to REACH guidance document R7.C (May 2014), 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).  

The test substance, C12 ADBAC is an alkyl dimethylbenzyl ammonium chloride (ADBAC) is a cationic surfactant, which is a mono-constituent with majorly C12 alkyl chain length and molecular weight of 340 g/mol. The purified form of the substance is a white solid. It has a very good water solubility of >2000 mg/mol (based on CMC) and a low log Kow of 2.63 value, which was determined using estimation method based on solubility ratios. Based on these parameters, a moderate to high absorption potential can be expected.  

However, given the fact that the test substance is highly ionic suggests that the test substance is not likely to be readily absorbed from the gastrointestinal tract.  

Based on QSAR prediction:

The “Lipinski’s rule OASIS”profiler of the OECD QSAR Toolobox v.4.3.1, which describes the molecular properties important for a drug’s pharmacokinetics in the human body, including their absorption, distribution, metabolism, and excretion (”ADME”), predicted the test substance to be ‘bioavailable’.  

Based on experimental data on read across substance:

A study conducted according to EPA OPP 85-1, Sprague-Dawley rats (10 animals per sex per group) were treated with radiolabelled read across substance, C12-16 ADBAC (30% active in water with 99.4% radiolabelled purity). The study was conducted in four phases: a single low dose (10 mg/kg); a single high dose (50 mg/kg); a 14 d repeated dietary exposure with non-radiolabelled read across substance (100 ppm) and single low dose of radiolabelled (14C) read across substance (10 mg/kg); and single intravenous dose (10 mg/kg). Following the single doses or the last dietary dose, urine and faeces were collected for 7 d. A preliminary study had indicated that insignificant 14CO2 was generated. Tissues, urine and faeces were collected and analysed for radioactivity and faeces were analysed by TLC, HPLC and MS for metabolites and parent compound. Following oral administration, radiolabelled read across substance was rapidly absorbed, although in very limited amounts, consistent with its highly ionic nature. Residual 14C in tissues was negligible after administration by gavage both after single and repeated dosing, indicating low potential for bioaccumulation. After i.v. administration a higher amount of radioactivity (30−35%) was found as residue in the tissues. About 6−8% of orally administered read across substance is excreted in the urine whereas, 87−98% was found in the faeces. Since no data on bile duct-cannulated rats are available, it was not possible to conclude if this radioactivity accounts exclusively for unabsorbed read across substance or not. However, the i.v. experiment showed that 20−30% was excreted in the urine and 44-55% in the faeces, suggesting that both the kidney and liver are capable of excreting read across substance once absorbed and that absorption is higher than the % found in the urine after oral administration. Based on the urinary mean value 3-4% (with a single peak value of 8.3%) and biliary excretion values (3.7-4.6%), as well as on the absence of residues in the carcass, as measured at 168 h, it can be expected that the read across substance absorption through the g.i. tract is about 10% (conclusion not included in the study report; as assessed by the Italian Rapporteur Member state in the biocides dossier; ECHA biocides assessment report, 2015). Less than 50% of the orally administered read across substance was found to be metabolised to side-chain oxidation products. In view of the limited absorption of the read across substance, the four major metabolites identified were expected to be at least partially formed in the gut of rats, apparently by microflora. No significant difference in metabolism between male and female rats or among the dosing regimens was observed. Repeated dosing did not alter the uptake, distribution or metabolism of read across substance. Under the conditions of the study, the read across substance was found to have limited absorption (ca. 10%; due to its ionic nature), negligible distribution (no bioaccumulation), and majorly excreted majorly via faeces (87-98%) following oral administration. However, following i.v. administration, it was found to be widely distributed (30-35%) in tissues and excreted both via faeces (40-55%) and urine (20-30%). Four major metabolites were identified, formed via oxidation of the alkyl chain (Selim, 1987). Further, the biocides assessment report concluded that “the oral absorption can be considered to be approximately 10%, based on the 5-8% of the C12-16-ADBAC administered dose eliminated via urine and tissue residues (less than 1% of the administered dose 7 days after single and repeated oral dosing). More than 90% is excreted in the faeces and the pattern did not change after repeated doses. Although it was not possible to discriminate between unabsorbed/absorbed material, based on the chemical nature of the test substance, it can be anticipated that about 90% is present in faeces as unabsorbed material. The majority of C12-16-ADBAC metabolism is expected to be carried out by intestinal flora; the metabolites, which account for less than 60% of the administered dose, include hydroxyl- and hydroxyketo- derivatives of the dodecyl, tetradecyl and hexadecyl chains. No metabolite accounted for more than 10% of the total administered dose”(ECHA biocides assessment report, 2015).  

Assessment from biocides assessment report available on read across substances: 

As indicated above the biocides assessment reports available on the read across substance C12-16 ADBAC indicated that given its ionic nature, C12-16 ADBAC was not expected to be readily absorbed from the gastrointestinal tract or skin. And based on the results from the in vivo studies with rats and in vitro studies with human skin, an oral and dermal absorption value of 10% could be considered at non-corrosive concentrations. Another biocides assessment report by RMS Italy , on the read across substance Coco TMAC, additionally reported two supporting in vivo studies on rats from literature, apart from the studies with C12-16 ADBAC and didecyldimethylammonium chloride (DDAC), which indicated an oral uptake of C16 TMAC of about 3.3 % (1.22 excreted by urine and around 2% in bile; 92% found back in faeces on day 3); and a dermal uptake of about 3.15% (in two days: 1.76% excreted in urine, 0.28% in faeces, organs 1.11%) (ECHA biocides assessment report, 2015, 2016).  

Conclusion:Overall, based on the available weight of evidence information and given the ionic nature, the test substance can be expected to overall have low absorption potential through the oral route. Therefore, in line with the biocide assessment report and as a conservative approach a maximum oral absorption value of 10% 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 a white solid, with an MW exceeding 100 g/mol, good water solubility and a calculated log Kow ranging between 2 and 3, which suggests a moderate absorption potential. However, given the fact that the test substance is highly ionic 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 Jmax data, it can be calculated by multiplying the estimated water solubility (i.e., 22.47 mg/L) from WSKOWWIN v.1.43) with the Kp value (i.e.,0.00171 cm/h) from DERMWIN v2.01 applications of EPI Suite v4.1. The calculated Jmax of the mono-constituent was determined to be 0.038 μg/cm2/h. As per Kroes et al., 2007 and Shen et 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.  

Based on experimental data on read across substances:

An in vitro study was conducted to determine the rate and extent of dermal absorption of the read across substance, C12-16 ADBAC (80.5% active; 81.2% radiolabelled purity), according to OECD Guideline 428, in compliance with GLP. The study was conducted with radiolabelled read across substance at 0.03% and 0.3% concentrations, which was topically applied over split-thickness human skin membranes mounted into flow-through diffusion cells. Receptor fluid was pumped underneath the skin at a flow rate of 1.5 mL/hour. The skin surface temperature was maintained at approximately 32°C. A barrier integrity test using tritiated water was performed and any skin sample exhibiting a permeability coefficient (kp) greater than 2.5 x 10-3 cm/h was excluded from subsequent absorption measurements. The 14C- radiolabelled read across substance was applied at an application rate of 10 mg/cm2. Absorption was assessed by collecting receptor fluid in hourly intervals from 0-6 h post dose and then in 2-hourly intervals from 6-24 h post dose. At 24 h post dose, the exposure was terminated by washing and drying the skin. The stratum corneum was then removed from the skin by 20 successive tape strips. All samples were analysed by liquid scintillation counting. Under the conditions of the study, the mean absorbed dose and mean dermal deliveries were determined to be 0.05% (0.01 ηg equiv. /cm2) and 2.22% (0.07 ηg equivalent/cm2) of the applied dose for the low concentration test preparation, respectively, and 0.03% (0.01 ηg equivalent /cm2) and 2.16% (0.67 ηg equivalent/cm2) of the applied dose for the high concentration test preparation, respectively. The stratum corneum acted as a barrier to absorption, with the mean total unabsorbed doses (recovered in skin wash, tissue swabs, pipette tips, cell wash, stratum corneum and unexposed skin) of 96.80 and 94.68% of the applied dose for the low and high concentration test preparations, respectively. The maximum fluxes for the low and high doses were 0.12 ηg equivalent /cm2/h and 0.74 ηg equivalent /cm2/h, respectively, at 2 h (Roper, 2006). Based on literature evidence, substances with Jmax ≤ 0.1μg/cm2/h, can be expected to have low skin penetration potential and can be assigned a default skin absorption of <10% (Shenet al., 2014). Further, the dermal absorption of the read across substance was concluded in its biocides assessment report (by RMS Italy) to be 8.3%, which was obtained by summing up the radioactivity present in the receptor fluid (0.05%), at the application site (after 20 consecutive tape stripping procedures) and the one present in tape strips (n°6-20) (ECHA biocides assessment report, 2015).  

Assessment from biocides assessment report available on read across substance:

As indicated above the biocides assessment reports available on the read across substance C12-16 ADBAC indicated that given its ionic nature, C12-16 ADBAC was not expected to be readily absorbed from the gastrointestinal tract or skin. And based on the results from the in vivo studies with rats and in vitro studies with human skin, an oral and dermal absorption value of 10% could be considered at non-corrosive concentrations (ECHA biocides assessment report, 2015).  

Conclusion: Overall, based on all the available weight of evidence information, the test substance can be expected to have a low absorption potential absorption through the dermal route. Therefore, as a conservative approach a default value of 10% 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 1.4E-7 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 good 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, together with the highly ionic nature, the test substance can be expected to have moderate absorption potential at the maximum 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 the rat liver S9 metabolism simulator of the OECD QSAR Toolbox v.4.3. The second simulator of the OECD Toolbox (in vivorat metabolism simulator) was not used as it does not consistently perform predictions for salts. According to these simulators, all the major constituents (present at >5%) are primarily predicted to undergo aliphatic hydroxylation as the first or second metabolic reactions. For further details, refer to the Read across justification.  

Based on experimental data on read across substance: 

As discussed in the Selim, 1987 study, less than 50% of the orally administered test substance is metabolised to side-chain oxidation products. In view of the limited absorption of the test substance, the four major metabolites identified may be at least partially formed in the gut of rats, apparently by microflora. The metabolites, which account for less than 60% of the administered dose, include hydroxyl- and hydroxyketo- derivatives of the dodecyl, tetradecyl and hexadecyl chains. No metabolite accounted for more than 10% of the total administered dose. No significant difference in metabolism between male and female rats or among the dosing regimens was observed. Repeated dosing did not alter the uptake, distribution or metabolism of the test substance (Selim, 1987).  

Conclusion:Based on all the available weight of evidence information, the test substance is considered to be primarily metabolised by alkyl chain hydroxylation, which is carried out by the intestinal flora.   

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. Identification of the target organs in repeated dose studies are also indicative of the extent of distribution. 

Given the ionic nature of the test substance, a low or negligible tissue distribution is expected due to low absorption potential. In case of an uptake and tissue distribution to certain extent the test substance will have a low bioaccumulation potential, which is supported by the BCF estimation using the ionic BCF regression-based equation from BCFBAF v. 3.02 program of EPISuiteTM  

Based on experimental data on read across substance:

As discussed above under absorption section, based on the negligible residual 14C in tissues following administration of the read across substance by gavage both after single and repeated dosing, indicated a low potential for bioaccumulation (Selim, 1987).  

Conclusion:Based on all the available weight of evidence information, the test substance is not expected to show significant tissue distribution or bioaccumulation potential.   

EXCRETION:  

Based on physico-chemical 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 that the MW of the test substance exceed 300 g/mol, but has good water solubility, it is likely to be excreted through urine but to a lesser extent.  

Based on experimental data on read across substance:

Based on the evidence from the available oral studies discussed under the absorption section (Selim, 1987), the test substance is primarily expected in faeces (>90%) and less via urine (<10%).  

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

Results and discussion

Clinical signs:

other: