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EC number: 205-351-5 | CAS number: 139-07-1
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
![](https://echa.europa.eu./o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Endpoint summary
Administrative data
Link to relevant study record(s)
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1987
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Objective of study:
- absorption
- distribution
- excretion
- metabolism
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 85-1 (Metabolism and Pharmacokinetics)
- GLP compliance:
- yes
- Specific details on test material used for the study:
- - Analytical purity: 30% aqueous solution
- Lot/batch No.: Non-radiolabelled: 05-6K
- Radiochemical purity (if radiolabelling): 99.4%
- Locations of the label (if radiolabelling): 14C-ADBAC - Radiolabelling:
- yes
- Remarks:
- 14C-labelled test substance
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Test animals:
- Source: Charles River
- Age at study initiation: 6 weeks
- Weight at study initiation: Average body weight: 268.6 g (male) and 167.0 g (female) - Details on exposure:
- Preparation of dosing solutions:
Preliminary experiments: Oral gavage – single low dose
Experiment 1: Oral gavage – single low dose
Experiment 2: Dietary – repeated low dose
Experiment 3: Oral gavage – single high dose
Experiment 4: Intravenous
Vehicle:
Distilled water (Preliminary experiments and Experiments 1, 3 and 4)
Rodent diet/distilled water (Experiment 2)
Concentration in vehicle:
Preliminary experiments and Experiment 1: 1.0 mg/mL
Experiment 2: 100 ppm in diet for 14 d/1 mg/mL in water single oral dose
Experiment 3: 5.0 mg/mL
Experiment 4: 4 mg/mL
Homogeneicity and stability of the test material: Stable - Duration and frequency of treatment / exposure:
- Preliminary experiments: Oral gavage – single low dose
Experiment 1: Oral gavage – single low dose
Experiment 2: Dietary – repeated low dose for 14 d
Experiment 3: Oral gavage – single high dose
Experiment 4: Intravenous - Dose / conc.:
- 10 mg/kg bw/day
- Remarks:
- Preliminary experiments and Experiment 1 and Experiment 4
- Dose / conc.:
- 100 ppm
- Remarks:
- Experiment 2: 100 ppm non-radiolabelled substance for 14 d, followed by 10 mg/kg radiolabelled.
- Dose / conc.:
- 50 mg/kg bw/day
- Remarks:
- Experiment 3
- No. of animals per sex per dose / concentration:
- Preliminary experiments: 2 per sex per group (Total 8 animals)
Main experiments:5 per sex per group (Total 40 animals) - Control animals:
- no
- Details on dosing and sampling:
- Pharmacokinetic study (Absorption, distribution, excretion):
- Tissues and body fluids sampled: urine, faeces, blood, plasma, cage washes
- Time and frequency of sampling: Urine, faeces and urine/feces separator washing samples were collected at the following time intervals: 0-4, 4-8, 8-12, 12-24, 24-36, 36-48, 48-72, 72-96, 96-120, 120-144 and 144-168 h.
Metabolite characterisation studies:
- Tissues, urine and faeces were collected and analysed for radioactivity and faeces were analysed by TLC, HPLC and MS for metabolites and parent compound. - Preliminary studies:
- Results in preliminary studies indicated that negligible amounts of 14CO2 (0.020%) were found in expired air, demonstrating that radiolabel was localized in a stable portion of the molecule
- Details on absorption:
- Following oral administration, 14C-ADBAC was rapidly absorbed, although in very limited amount as indicated by the low blood levels (<0.003% of the administered dose/ml) attained starting from 15 min after dosing and peaking between 3 and 8 h. Blood concentration declined to approximately 25% of the peak value within 24 h.
Based on data on urine excretion and tissue residues after oral administration, and indication from i.v. experiment, it can be expected that the test subsatnce absorption through the g.i. tract is about 20% (conclusion not included in the study report; as assessed by the Italian Rapporteur Member state in the biocide dossier). - Details on distribution in tissues:
- Residual 14C in tissues was negligible (<1%) after administration of radiolabelled test substance 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.
- Details on excretion:
- Percent Recovery:
Experiment 1:
Males: 5.77% urine; 98.61% faeces
Female: 6.88% urine; 91.20% faeces
Total Recovery: 104.54 ± 5.29% - males; 98.11 ± 3.25% females
Experiment 2:
Males: 4.76% urine; 95.12% faeces
Female: 5.80% urine; 97.22% faeces
Total Recovery: 100.19 ± 4.94% - males; 103.1 ± 5.18% females
Experiment 3:
Males: 7.75 % urine; 90.03% faeces
Female: 6.95% urine; 87.48% faeces
Total Recovery: 98.36 ± 2.42% - males; 94.58 ± 7.57% females
Experiment 4:
Males: 30.63% urine; 44.44% faeces
Female: 20.58% urine; 55.09% faeces
Total Recovery: 108.43 ± 5.56% - males; 111.45 ± 3.96% females
Remarks:
- About 6−8% of orally administered test 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 is not possible to conclude if this radioactivity accounts exclusively for unabsorbed test 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 test substance once absorbed and that absorption is higher than the % found in the urine after oral administration.
- Little or no gender or dose-dependent differences were observed in the excretion patterns nor in rats receiving a single or repeated dose.
- Based on the 5-8% of the test substance administered dose eliminated via urine and tissue residues (less than 1% of the administered dose 7 days after single and repeated oral dosing), it can be expected that the test substance absorption through the g.i. tract is about 10% (ECHA biocides assessment report, 2015).
- 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 (ECHA biocides assessment report, 2015) - Metabolites identified:
- yes
- Details on metabolites:
- Over 50% of the faecal radioactivity was unchanged parent compound. Four major metabolites were identified, as oxidation products of the two decyl side chains to hydroxy and hydroxyketo derivatives. The only metabolism which occurred involved oxidation of the two decyl side chains to hydroxy and hydroxyketo derivatives. All were more polar and presumed less toxic than the parent compound. It is predicted that there is no major metabolite greater than 10% of the dosed radioactivity.
- Conclusions:
- Under the conditions of the study, the test substance was found to have limited absorption (ca. 10%), 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 Repeated dosing did not alter the uptake, distribution or metabolism of test substance.
- Executive summary:
A study was conducted to determine the basic toxicokinetics of the raadiolabelled test substance, C12-16 ADBAC (30% active in water with 99.4% radiolabelled purity), according to EPA OPP 85-1, in compliance with GLP. Sprague-Dawley rats (10 animals per sex per group) were treated with radiolabelled test substance. 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 test substance (100 ppm) and single low dose of radiolabelled (14C) test 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 test 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 test 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 test 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 test 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 test 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 test substance was found to be metabolised to side-chain oxidation products. In view of the limited absorption of the test 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 test substance. Under the conditions of the study, the test 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).
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 1987
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- KL2 due to RA
- 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
- Objective of study:
- other: Absorption, distribution, metabolism and excretion
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 85-1 (Metabolism and Pharmacokinetics)
- GLP compliance:
- yes
- Radiolabelling:
- yes
- Remarks:
- 14C-labelled test substance
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Test animals:
- Source: Charles River
- Age at study initiation: 6 weeks
- Weight at study initiation: Average body weight: 268.6 g (male) and 167.0 g (female) - Details on exposure:
- Preparation of dosing solutions:
Preliminary experiments: Oral gavage – single low dose
Experiment 1: Oral gavage – single low dose
Experiment 2: Dietary – repeated low dose
Experiment 3: Oral gavage – single high dose
Experiment 4: Intravenous
Vehicle:
Distilled water (Preliminary experiments and Experiments 1, 3 and 4)
Rodent diet/distilled water (Experiment 2)
Concentration in vehicle:
Preliminary experiments and Experiment 1: 1.0 mg/mL
Experiment 2: 100 ppm in diet for 14 d/1 mg/mL in water single oral dose
Experiment 3: 5.0 mg/mL
Experiment 4: 4 mg/mL
Homogeneicity and stability of the test material: Stable - Duration and frequency of treatment / exposure:
- Preliminary experiments: Oral gavage – single low dose
Experiment 1: Oral gavage – single low dose
Experiment 2: Dietary – repeated low dose for 14 d
Experiment 3: Oral gavage – single high dose
Experiment 4: Intravenous - Dose / conc.:
- 10 other:
- Remarks:
- Doses / Concentrations:
Preliminary experiments and Experiment 1: 10 mg/kg
Experiment 2: 100 ppm non-radiolabelled substance for 14 d, followed by 10 mg/kg radiolabelled.
Experiment 3: 50 mg/kg
Experiment 4: 10 mg/kg - No. of animals per sex per dose / concentration:
- Preliminary experiments: 2 per sex per group (Total 8 animals)
Main experiments:5 per sex per group (Total 40 animals) - Control animals:
- no
- Details on dosing and sampling:
- Pharmacokinetic study (Absorption, distribution, excretion):
- Tissues and body fluids sampled: urine, faeces, blood, plasma, cage washes
- Time and frequency of sampling: Urine, faeces and urine/feces separator washing samples were collected at the following time intervals: 0-4, 4-8, 8-12, 12-24, 24-36, 36-48, 48-72, 72-96, 96-120, 120-144 and 144-168 h.
Metabolite characterisation studies:
- Tissues, urine and faeces were collected and analysed for radioactivity and faeces were analysed by TLC, HPLC and MS for metabolites and parent compound. - Preliminary studies:
- Results in preliminary studies indicated that negligible amounts of 14CO2 (0.020%) were found in expired air, demonstrating that radiolabel was localized in a stable portion of the molecule
- Details on absorption:
- Following oral administration, 14C-ADBAC was rapidly absorbed, although in very limited amount as indicated by the low blood levels (<0.003% of the administered dose/ml) attained starting from 15 min after dosing and peaking between 3 and 8 h. Blood concentration declined to approximately 25% of the peak value within 24 h.
Based on data on urine excretion and tissue residues after oral administration, and indication from i.v. experiment, it can be expected that the test subsatnce absorption through the g.i. tract is about 20% (conclusion not included in the study report; as assessed by the Italian Rapporteur Member state in the biocide dossier). - Details on distribution in tissues:
- Residual 14C in tissues was negligible (<1%) after administration of radiolabelled test substance 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.
- Details on excretion:
- Percent Recovery:
Experiment 1:
Males: 5.77% urine; 98.61% faeces
Female: 6.88% urine; 91.20% faeces
Total Recovery: 104.54 ± 5.29% - males; 98.11 ± 3.25% females
Experiment 2:
Males: 4.76% urine; 95.12% faeces
Female: 5.80% urine; 97.22% faeces
Total Recovery: 100.19 ± 4.94% - males; 103.1 ± 5.18% females
Experiment 3:
Males: 7.75 % urine; 90.03% faeces
Female: 6.95% urine; 87.48% faeces
Total Recovery: 98.36 ± 2.42% - males; 94.58 ± 7.57% females
Experiment 4:
Males: 30.63% urine; 44.44% faeces
Female: 20.58% urine; 55.09% faeces
Total Recovery: 108.43 ± 5.56% - males; 111.45 ± 3.96% females
Remarks:
- About 6−8% of orally administered test 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 is not possible to conclude if this radioactivity accounts exclusively for unabsorbed test 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 test substance once absorbed and that absorption is higher than the % found in the urine after oral administration.
- Little or no gender or dose-dependent differences were observed in the excretion patterns nor in rats receiving a single or repeated dose.
- Based on the 5-8% of the test substance administered dose eliminated via urine and tissue residues (less than 1% of the administered dose 7 days after single and repeated oral dosing), it can be expected that the test substance absorption through the g.i. tract is about 10% (ECHA biocides assessment report, 2015).
- 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 (ECHA biocides assessment report, 2015) - Metabolites identified:
- yes
- Details on metabolites:
- Over 50% of the faecal radioactivity was unchanged parent compound. Four major metabolites were identified, as oxidation products of the two decyl side chains to hydroxy and hydroxyketo derivatives. The only metabolism which occurred involved oxidation of the two decyl side chains to hydroxy and hydroxyketo derivatives. All were more polar and presumed less toxic than the parent compound. It is predicted that there is no major metabolite greater than 10% of the dosed radioactivity.
- Conclusions:
- 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%).
- Executive summary:
A study was conducted to determine the basic toxicokinetics of the radiolabelled read across substance, C12-16 ADBAC (30% active in water with 99.4% radiolabelled purity), according to EPA OPP 85-1, in compliance with GLP. Sprague-Dawley rats (10 animals per sex per group) were treated with radiolabelled read across substance. 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). Based on the results of the read across study, a similar toxicokinetic profile can be expected for the test substance.
- Endpoint:
- dermal absorption in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From August 18, 2005 to August 17, 2006
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 428 (Skin Absorption: In Vitro Method)
- Deviations:
- no
- GLP compliance:
- yes
- Specific details on test material used for the study:
- - Name of test material: Alkyl(C12-C16)dimethylbenzylammonium chloride (non-radiolabelled ADBAC) and [14C]-ADBAC (radiolabelled ADBAC)
- Analytical purity: non-radiolabelled: 80.5% pure; radiolabelled: 99.7%
- Composition of test material, percentage of components:
- Lot/batch No.: radiolabelled: 990930; non-radiolabelled: J2220459
- Radiochemical purity (if radiolabelling): 99.7%
- Specific activity (if radiolabelling): 25 mCi/mmol; total radioactivity: 1 mCi/mL in etanol
- Storage condition of test material: non-radiolabelled: ambient temperature in dark - Radiolabelling:
- yes
- Species:
- human
- Details on test animals or test system and environmental conditions:
- Human skin membranes, in vitro
- Type of coverage:
- other: Automated flow-through diffusion cell system
- Vehicle:
- water
- Doses:
- 0.03% (w/w) and 0.3% (w/w), in water
- No. of animals per group:
- In vitro study
- Details on in vitro test system (if applicable):
- Skin preparation:
- Source of skin: Eight samples from Plastic Surgery unit, St. Johns Hospital, West Lothian NHS Trust, Livingston, UK
- Ethical approval if human skin: Yes
- Type of skin: Full-thickness human skin (1 upper arm, 2 abdomen and 5 breast)
- Preparative technique: Skin was transferred to Charles River Laboratories on ice and cleaned of subcutaneous fat and connective tissue using scalpel. Skin was washed in cold running tap water and dried using tissue paper. Each sample was then cut into smaller pieces, wrapped in aluminium foil, put into self sealing plastic bags and stored at -20°C until required. Split-thickness membranes were prepared by pinning the full thickness skin, stratum corneum uppermost, onto a raised cork board and cutting at a setting equivalent to 200-400 µm depth using a Zimmer electric dermatome.
Principles of assay:
- Diffusion cell: Automated flow-through diffusion cell system (Scott/Dick, University of Newcastle-upon-Tyne, UK)
- Receptor fluid: Tissue culture medium containing approximately 5% (w/v) bovine serum albumin, 1% (w/v) streptomycin (approximately 0.1 mg/mL), and penicillin G (approximately 100 units/mL)
- Solubility of test substance in receptor fluid:
- Flow-through system: Automated
- Test temperature: The mean temperature 19°C (SD=0.8°C)
- Humidity: The mean relative humidity 35% (SD=0.6%) - Total recovery:
- Refer to Table-1
- Key result
- Dose:
- 0.03%
- Parameter:
- percentage
- Absorption:
- 0.05 %
- Remarks on result:
- other: 24 h
- Remarks:
- 96.80% was not absorbed
- Key result
- Dose:
- 0.3%
- Parameter:
- percentage
- Absorption:
- 0.03 %
- Remarks on result:
- other: 24 h
- Remarks:
- 94.68% was not absorbed
- Conclusions:
- Under the conditions of the study, the mean absorbed dose and mean dermal deliveries were determined to be 0.05% and 2.22% of the applied dose for the low concentration test preparation and 0.03% and 2.16% of the applied dose for the high concentration test preparation, 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, indicating low absorption potential.
- Executive summary:
An in vitro study was conducted to determine the rate and extent of dermal absorption of the test 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 test 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 test 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).
- Endpoint:
- dermal absorption in vitro / ex vivo
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- From August 18, 2005 to August 17, 2006
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- KL2 due to RA
- 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:
- according to guideline
- Guideline:
- OECD Guideline 428 (Skin Absorption: In Vitro Method)
- Deviations:
- no
- GLP compliance:
- yes
- Radiolabelling:
- yes
- Species:
- human
- Details on test animals or test system and environmental conditions:
- Human skin membranes, in vitro
- Type of coverage:
- other: Automated flow-through diffusion cell system
- Vehicle:
- water
- Doses:
- 0.03% (w/w) and 0.3% (w/w), in water
- No. of animals per group:
- In vitro study
- Details on in vitro test system (if applicable):
- Skin preparation:
- Source of skin: Eight samples from Plastic Surgery unit, St. Johns Hospital, West Lothian NHS Trust, Livingston, UK
- Ethical approval if human skin: Yes
- Type of skin: Full-thickness human skin (1 upper arm, 2 abdomen and 5 breast)
- Preparative technique: Skin was transferred to Charles River Laboratories on ice and cleaned of subcutaneous fat and connective tissue using scalpel. Skin was washed in cold running tap water and dried using tissue paper. Each sample was then cut into smaller pieces, wrapped in aluminium foil, put into self sealing plastic bags and stored at -20°C until required. Split-thickness membranes were prepared by pinning the full thickness skin, stratum corneum uppermost, onto a raised cork board and cutting at a setting equivalent to 200-400 µm depth using a Zimmer electric dermatome.
Principles of assay:
- Diffusion cell: Automated flow-through diffusion cell system (Scott/Dick, University of Newcastle-upon-Tyne, UK)
- Receptor fluid: Tissue culture medium containing approximately 5% (w/v) bovine serum albumin, 1% (w/v) streptomycin (approximately 0.1 mg/mL), and penicillin G (approximately 100 units/mL)
- Solubility of test substance in receptor fluid:
- Flow-through system: Automated
- Test temperature: The mean temperature 19°C (SD=0.8°C)
- Humidity: The mean relative humidity 35% (SD=0.6%) - Total recovery:
- Refer to Table-1
- Key result
- Dose:
- 0.03%
- Parameter:
- percentage
- Absorption:
- 0.05 %
- Remarks on result:
- other: 24 h
- Remarks:
- 96.80% was not absorbed
- Key result
- Dose:
- 0.3%
- Parameter:
- percentage
- Absorption:
- 0.03 %
- Remarks on result:
- other: 24 h
- Remarks:
- 94.68% was not absorbed
- Conclusions:
- Based on the results of the read across study, a similar low absorption potential through dermal route can be expected for the test substance.
- Executive summary:
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 the results of the read across study, a similar low absorption potential through dermal route can be expected for the test substance.
Referenceopen allclose all
All rats receiving the test substance i.v. experienced clear signs of toxicity, including death, and all but one showed red urine during the first 4 h after the treatment.
All rats receiving the test substance i.v. experienced clear signs of toxicity, including death, and all but one showed red urine during the first 4 h after the treatment.
- Low dose (0.030%):
The mean mass balance was 99.03% of the applied dose (3.09 μg equiv./cm2). The mean dislodgeable dose was 60.53% of the applied dose (1.89 μg equiv./cm2). The mean total unabsorbed dose was 96.80% of the applied dose (3.02 μg equiv./cm2). This consisted of the dislodgeable dose, unexposed skin (0.02%) and the radioactivity associated with the stratum corneum (36.25%). The stratum corneum acted as a good barrier to the test substance as the bulk of the radioactivity (30.26%) was recovered in the outermost 5 tape strips (tape strips 1-5). Considerably less radioactivity was recovered with each of the subsequent 3 groups of tape strips (3.20%, 1.82% and 0.97% in tape strips 6-10, 11-15 and 16-20 respectively), suggesting that the test substance would be sloughed off with the skin in the future. The absorbed dose (0.05%, or <0.01 μg equiv./cm2) was the sum of the receptor fluid (0.05%) and the receptor rinse (<0.01%). Dermal delivery (2.22%, or 0.07 μg equiv./cm2) was the sum of the absorbed dose and the exposed skin (2.18%). There was no apparent lag time and the fluxes ranges from 0.03 to 0.12 ng equiv./cm2/h over the 1 to 24-h exposure period.
- High dose (0.300%):
The mean mass balance was 96.84% of the applied dose (29.91 μg equiv./cm2). The dislodgeable dose was 77.87% of the applied dose (24.05 μg equiv./cm2). The mean total unabsorbed dose was 94.68% of the applied dose (29.24 μg equiv./cm2). This consisted of the dislodgeable dose, unexposed skin (0.17%) and the radioactivity associated with the stratum corneum (16.64%). The stratum corneum acted as a good barrier to the test item as the bulk of the radioactivity (10.86%) was recovered in the outermost 5 tape strips (tape strips 1-5). Considerably less radioactivity was recovered with each of the subsequent 3 groups of tape strips (3.11%, 1.71% and 0.96% in tape strips 6-10, 11-15 and 16-20, respectively), again suggesting that the test item would be sloughed off with the skin in the future. The absorbed dose (0.03%, or 0.01 μg equiv./cm2) was the sum of the receptor fluid (0.03%) and the receptor rinse (<0.01%). Dermal delivery (2.16%, or 0.67 μg equiv./cm2) was the sum of the absorbed dose and the exposed skin (2.13%). There was no apparent lag time. There was no apparent lag time and the fluxes ranges from 0.22 to 0.74 ng equiv./cm2/h over the 1 to 24-h exposure period.
Table 1. Summary of recoveries after 24h
Test Preparation |
Low Concentration |
High Concentration |
Target test substance concentration (%, w/w) |
0.03 |
0.30 |
Test substance concentration by Radioactivity (%, w/w) |
0.031 |
0.306 |
Test preparation application rate (mg/cm2)a |
10.01 |
10.09 |
Test substance application Rate (μg equiv./cm2) |
3.12 |
30.87 |
Dislodgeable Dose (% Applied Dose) |
60.53 |
77.87 |
Unabsorbed Dose (% Applied Dose) |
96.80 |
94.68 |
Absorbed Dose (% Applied Dose) |
0.05 |
0.03 |
Dermal Delivery (% Applied Dose) |
2.22 |
2.16 |
Mass Balance (% Applied Dose) |
99.03 |
96.84 |
Dislodgeable Dose (μg equiv./cm2) |
1.89 |
24.05 |
Unabsorbed Dose (μg equiv./cm2) |
3.02 |
29.24 |
Absorbed Dose (μg equiv./cm2) |
<0.01 |
0.01 |
Dermal Delivery (μg equiv./cm2) |
0.07 |
0.67 |
Mass Balance (μg equiv./cm2) |
3.09 |
29.91 |
a mg of test preparation per cm of skin
- Low dose (0.030%):
The mean mass balance was 99.03% of the applied dose (3.09 μg equiv./cm2). The mean dislodgeable dose was 60.53% of the applied dose (1.89 μg equiv./cm2). The mean total unabsorbed dose was 96.80% of the applied dose (3.02 μg equiv./cm2). This consisted of the dislodgeable dose, unexposed skin (0.02%) and the radioactivity associated with the stratum corneum (36.25%). The stratum corneum acted as a good barrier to the test substance as the bulk of the radioactivity (30.26%) was recovered in the outermost 5 tape strips (tape strips 1-5). Considerably less radioactivity was recovered with each of the subsequent 3 groups of tape strips (3.20%, 1.82% and 0.97% in tape strips 6-10, 11-15 and 16-20 respectively), suggesting that the test substance would be sloughed off with the skin in the future. The absorbed dose (0.05%, or <0.01 μg equiv./cm2) was the sum of the receptor fluid (0.05%) and the receptor rinse (<0.01%). Dermal delivery (2.22%, or 0.07 μg equiv./cm2) was the sum of the absorbed dose and the exposed skin (2.18%). There was no apparent lag time and the fluxes ranges from 0.03 to 0.12 ng equiv./cm2/h over the 1 to 24-h exposure period.
- High dose (0.300%):
The mean mass balance was 96.84% of the applied dose (29.91 μg equiv./cm2). The dislodgeable dose was 77.87% of the applied dose (24.05 μg equiv./cm2). The mean total unabsorbed dose was 94.68% of the applied dose (29.24 μg equiv./cm2). This consisted of the dislodgeable dose, unexposed skin (0.17%) and the radioactivity associated with the stratum corneum (16.64%). The stratum corneum acted as a good barrier to the test item as the bulk of the radioactivity (10.86%) was recovered in the outermost 5 tape strips (tape strips 1-5). Considerably less radioactivity was recovered with each of the subsequent 3 groups of tape strips (3.11%, 1.71% and 0.96% in tape strips 6-10, 11-15 and 16-20, respectively), again suggesting that the test item would be sloughed off with the skin in the future. The absorbed dose (0.03%, or 0.01 μg equiv./cm2) was the sum of the receptor fluid (0.03%) and the receptor rinse (<0.01%). Dermal delivery (2.16%, or 0.67 μg equiv./cm2) was the sum of the absorbed dose and the exposed skin (2.13%). There was no apparent lag time. There was no apparent lag time and the fluxes ranges from 0.22 to 0.74 ng equiv./cm2/h over the 1 to 24-h exposure period.
Table 1. Summary of recoveries after 24h
Test Preparation |
Low Concentration |
High Concentration |
Target test substance concentration (%, w/w) |
0.03 |
0.30 |
Test substance concentration by Radioactivity (%, w/w) |
0.031 |
0.306 |
Test preparation application rate (mg/cm2)a |
10.01 |
10.09 |
Test substance application Rate (μg equiv./cm2) |
3.12 |
30.87 |
Dislodgeable Dose (% Applied Dose) |
60.53 |
77.87 |
Unabsorbed Dose (% Applied Dose) |
96.80 |
94.68 |
Absorbed Dose (% Applied Dose) |
0.05 |
0.03 |
Dermal Delivery (% Applied Dose) |
2.22 |
2.16 |
Mass Balance (% Applied Dose) |
99.03 |
96.84 |
Dislodgeable Dose (μg equiv./cm2) |
1.89 |
24.05 |
Unabsorbed Dose (μg equiv./cm2) |
3.02 |
29.24 |
Absorbed Dose (μg equiv./cm2) |
<0.01 |
0.01 |
Dermal Delivery (μg equiv./cm2) |
0.07 |
0.67 |
Mass Balance (μg equiv./cm2) |
3.09 |
29.91 |
a mg of test preparation per cm of skin
Description of key information
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.
Key value for chemical safety assessment
- Bioaccumulation potential:
- low bioaccumulation potential
- Absorption rate - oral (%):
- 10
- Absorption rate - dermal (%):
- 10
- 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 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.
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