Didecyldimethylammonium chloride

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

GLP study, fully complying to OECD 417. No deviations. Criteria radiochemical purity and total radiation recovery were generally met. Recovery rates for dermal dose groups were slightly low. Some deviations from study plan occurred which are not considered to have compromised the validity or integrity of the study. Due to subsequent oral uptake of dermal applied dose, no information can be derived on quantitative dermal uptake from this study.

Objective of study:

toxicokinetics

Qualifier:

according to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

GLP compliance:

yes (incl. QA statement)

Radiolabelling:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

-Source: Charles River Laboratories France, L’Arbresle, France. Caesarean Obtained, Barrier Sustained-Virus Antibody Free (COBS-VAF®).
-Sex: 60 males and 60 females.
-Age/weight at study initiation: Young adults approx. 7 weeks old; for the bile collection group, animals were around 10 weeks old.
-Number of animals per group: Kinetics (5 groups): 9 males & 9 females (3 /group/time/sex)
-Excretion balance: (3 groups): 5 males & 5 females
-Bile collection (1 group): 4 males & 4 females
-Control animals: Yes: For the purposes of pre-dose sample analysis, plasma, blood and tissues will be collected from at least one untreated supplementary animal/sex using the above mentioned procedures.

Route of administration:

other: Gavage and topical

Vehicle:

water

Details on exposure:

Refer to study design

Duration and frequency of treatment / exposure:

6 hour(s)

Remarks:

Doses / Concentrations:
Males: oral 50 or 200; dermal 1.5 or 15 mg/kg bw/day
Females: oral 50 or 200; dermal 1.5 or 15 mg/kg bw/day

No. of animals per sex per dose / concentration:

Males: 64; Females: 64

Control animals:

no

Positive control reference chemical:

Not applicable

Details on study design:

The blood and plasma pharmacokinetics, tissue distribution and mass balance of total radioactivity of [14C] DDAC were evaluated following single dermal administration (at 1.5 and 15 mg/kg, as 6-hour exposure over 10% of the body surface) and single (at 50 and 200 mg/kg) and repeated (at 50 mg/kg/day) oral gavage administrations to male and female Sprague-Dawley rats. In addition, the elimination of radioactivity in bile after single oral administration at 50 mg/kg was investigated. Investigations included blood and plasma pharmacokinetics, tissue distribution and mass balance of total radioactivity.

The animals were divided into 9 groups; groups 1 to 5 (each of 9 animals/sex) for plasma/blood pharmacokinetics of radioactivity and tissue distribution, groups 6 to 8 (each of 5 animals/sex) principally for excretion balance and group 9 (4 animals/sex) for bile collection. 

 The animals wore an Elizabethan collar to prevent ingestion of the test item. At the end of the exposure period, the collar was removed and kept with the swabs for analysis. After 6 hours, the treated areas were washed using dampened cotton swabs with diluted hand soap followed by two dry swabs to remove all traces of the test item.

Details on dosing and sampling:

Animals of groups 1 to 4 and 6 and 7 were treated once with the radiolabelled test item. Animals of groups 5 and 8 were treated once per day for 6 days with the unlabelled test item, followed by a single administration of the radiolabelled test item on the seventh day. All oral dosages applied 2.2 MBq/kg for radioactive dose-levels, and 3.7 MBq/kg for dermal applications. Dermal dosages were applied on clipped skin approx. 10% of the total body surface area, over the interscapular/upper back region.

Blood and plasma sampling:
Oral group: 0.5, 1, 2, 4, 8, 24, 48, 72 and 96 hours  
Dermal group: 3 and 6 (i.e. during the exposure period), 7, 8, 10, 16, 24, 48 and 72 hours.

Following the final blood sampling/animal (i.e. at 24, 48 and 72/96 hours), each sampled animal was sacrificed by cervical dislocation, under isoflurane anesthesia. The carcass were weighed and the following tissues dissected out and weighed: Adrenals, Gastro intestinal tract (complete), Lymph nodes (mesenteric and mandibular), Brain, Heart, Muscle (right leg adductor), Eyes, Kidneys, Pancreas, Fat (abdominal), Liver, Skin (lower back), Femur (right with marrow), Lungs, Spleen. In addition, for the dermal treated animals, the application site will be dissected out and weighed. Thereafter, the application site and the skin from the lower back will be each stripped completely (using tape) 13 times. No macroscopic examination was performed on the prematurely sacrificed animals or those found dead. 

Excreta: Urine and faeces were collected from the groups 6 to 8 animals for the radioactive treatments at the following times:
- during a period of 24 hours before radioactive dosing on day 1 (groups 6 and 7), or day 7 (group 8),
- and then during the periods 0-24, 24-48, 48-72, 72-96, 96-120, 120-144 and 144-168 hours after the radioactive gavage/dermal application.

After each collection of faeces, the cages and trays were carefully rinsed with not more than 20 mL of water (cage wash) (except for last collection; approximately 100 mL were used). Expired CO2 was not collected as earlier studies with DDAC showed no radioactivity in the expired air. Any measurement of radioactivity lower then two times the blank was reported as BLQ (below the limit of quantification).

Statistics:

Not reported

Type:

other: Absorption, distribution and excretion

Results:

Low dermal and oral absorption. The actual minimal fraction of the oral dose absorbed was 0.93 to 3.16%; this was eliminated rapidly, essentially within a 48 hour period.

Details on absorption:

Oral:
Following single and/or repeated oral gavage at 50 and 200 mg/kg/day, the plasma and blood radioactivity levels were non-quantifiable indicating a low oral bioavailability. The actual minimal fraction of the oral dose absorbed was 0.93 to 3.16%; this was eliminated rapidly, essentially within a 48-hour period. The vast majority of the oral dose was excreted rapidly in the faeces.

Dermal:
Following single dermal application at 1.5 and 15 mg/kg, the plasma and blood radioactivity levels were non-quantifiable at all time-points. For the 1.5 mg/kg group, around 1% and 50% of the dose was eliminated in the urine and faeces, respectively, mostly within a 48-hour period, suggesting that the dermal dose was highly absorbed via the skin. However, as the test site was not protected with an Elizabethan collar during the main part of the collection period (the collar was worn during the exposure period only), this may have been due to the animal licking the test site. This is also supported with the finding that after oral dosing only 1-2.5% was excreted via bile back to intestines, and 2-3% excreted via urine. If similar routes of excretion are expected for dermal absorbed doses, it would not be possible to find levels of 50% of applied doses in intestines with only 1% excreted via urine. This indicates that about 50% of the dermal applied dose was taken up orally after all.

Details on distribution in tissues:

Oral:
At the high oral dose-level only, quantifiable levels of radioactivity were found in some central organs at 24 hours post-dosing (intestines, liver., kidney) ; otherwise, the vast majority of the dose was confined to the intestines and levels decreased over time. 

Dermal:
At 24 hours post-dosing, most of the radioactivity was in the "stripped" skin (dermis and epidermis) application site (6.07 to 21.6% of the dose) and intestines for both dose-levels, though some radioactivity was in the skin adjacent to the application site (most likely from cross-contamination due to grooming) and minor traces were in the eyes and other organs. At 72/168 hours, levels in the application site were 1.06 to 2.82% of the radioactive dose, suggesting the skin acted as a drug reservoir. In the stratum corneum of the application site, the levels of radioactivity were of similar magnitude in the different layers at each time point. For all tissues/organs, the radioactivity levels essentially decreased over time. All data showed generally a low inter-animal variability. In addition, there was no evidence of gender differences.

Details on excretion:

Oral:
Only 2.57/1.14% (males/females) of the oral dose was eliminated in the bile in a 24-hour period.  No metabolites or parent drug were found in urine.

Dermal:
For the 1.5 mg/kg group, around 1% and 50% of the dose was eliminated in the urine and faeces, respectively, mostly within a 48-hour period.

Metabolites identified:

not measured

Conclusion: 

Low dermal and oral absorption. The actual minimal fraction of the oral dose absorbed was 0.93 to 3.16%; this was eliminated rapidly, essentially within a 48 -hour period.

Conclusions:

Low oral and probably negligible dermal absorption. The total oral absorption value was roughly in the range around 3-7%, based on urinary (0.93 - 3.16%) and bile (1.8-4.0%) excretion; elimination was rapidly, essentially within a 48 hour period.

Executive summary:

The blood and plasma pharmacokinetics, tissue distribution and mass balance of total radioactivity of [14C] DDAC were evaluated following single dermal administration (at 1.5 and 15 mg/kg, as 6-hour exposure over 10% of the body surface) and single (at 50 and 200 mg/kg) and repeated (at 50 mg/kg/day) oral gavage administrations to male and female Sprague-Dawley rats. In addition, the elimination of radioactivity in bile after single oral administration at 50 mg/kg was investigated. Investigations included blood and plasma pharmacokinetics, tissue distribution and mass balance of total radioactivity.

Conclusion

Low oral and probably negligible dermal absorption. The total oral absorption value was roughly in the range around 3-7%, based on urinary (0.93 - 3.16%) and bile (1.8-4.0%) excretion; elimination was rapidly, essentially within a 48 hour period.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

toxicokinetics

Principles of method if other than guideline:

The dermal study part is like OECD 421 Skin absorption

GLP compliance:

no

Radiolabelling:

yes

Remarks:

Didecyldimethylammonium iodide was [3H] labeled using [3H]methyliodide for the quaternisation of didecylmethylamine).

Species:

rat

Strain:

other: Iva:SIV 50

Sex:

female

Details on test animals or test system and environmental conditions:

Species: Female rats (strain Iva:SIV 50), approx. 200-300 grams, individually housed in metabolic cages for at least 72 hrs.

Route of administration:

other: dermal & oral intubation

Vehicle:

not specified

Details on exposure:

Refer to details on dosing

Duration and frequency of treatment / exposure:

72 hours

Remarks:

Doses / Concentrations:
Refer to details on dosing

No. of animals per sex per dose / concentration:

Number of animals: 4 animals dermal and 4 animals oral

Control animals:

no

Positive control reference chemical:

Not applicable

Details on study design:

Refer to details on dosing and sampling

Details on dosing and sampling:

Dosage: 

Dermal: 100 or 200 µL over approx 2 cm2 of shaved skin, under plaster for 72 hr. The application volumes were 100 µL or 200 µL. The solvent was carefully dried off with a hair drier. To prevent the animals from licking the test compound a Poro Plast ophthalmologic plaster provided with an elevated plastic window was placed in position over the application site with adhesive tape during the exposure time of at least 72 h.

Oral: intubation of 200 µL

Liver, kidney, spleen, heart, lung and muscle were removed, deep-frozen and stored until preparation for scintillation counting.

Statistics:

No data

Preliminary studies:

Not applicable

Type:

excretion

Results:

Total urinary excretion amounted to only 1.3 and 1.4% of the administered dose after dermal and oral treatment, respectively

Details on absorption:

Dermal and gastrointestinal absorption are very poor.

Details on distribution in tissues:

The amount of [3H] activity measured in the organs was also similar in both groups. No target organ was found.

Details on excretion:

Total urinary excretion amounted to only 1.3% and 1.4% of the administered dose after dermal and oral treatment respectively. 

Metabolites identified:

yes

Details on metabolites:

Urinary Metabolites: The consecutive extractions of the urine of orally dosed animals before and after enzymatic and hydrolytic cleavage revealed that approximately 20% of the excreted radioactivity was eliminated as the parent compound whereas the remaining obviously did undergo metabolic alteration. Approximately 4% of the urinary [3H] activity was extractable after treatment with glucuronidase/sulfatase, another 20% after strong hydrolytic treatment, most probably resulting in the cleavage of other conjugates. No further attempts were made to identify the metabolites. The studies on the radioactivity extracted from urine revealed that part of the metabolism most probably proceeds by oxidation and conjugation reactions analogous to the degradation of the fatty acids by beta oxidation.

The above findings indicate that the test compound does not readily penetrate cell membranes and that it is very stable. It also does not undergo considerable degradation in the skin or in the stomach. The studies on the radioactivity extracted from urine revealed that part of the metabolism, most probably, proceeds by oxidation and conjugation reactions analogous to the degradation of the fatty acids by B-oxidation. A similar pattern of radiolabelled urinary metabolites was found by Isomaa (1975) who studied the gastrointestinal absorption of [1 -14C] cetyl trimethylammonium bromide in rats. No 14CO2 was discovered in the expired air thus complete oxidation and N-dealkylation of the cetyl group is not expected to take place.

Conclusions:

Dermal and gastrointestinal absorption are very poor. Total urinary excretion amounted to only 1.3% and 1.4% of the administered dose after dermal and oral treatment respectively. The amount of [3H] activity measured in the organs was also similar in both groups. No target organ was found.

Executive summary:

Dermal and gastrointestinal absorption are very poor. Total urinary excretion amounted to only 1.3% and 1.4% of the administered dose after dermal and oral treatment respectively. The amount of [³H] activity measured in the organs was also similar in both groups. No target organ was found.

Urinary Metabolites:

The The consecutive extractions of the urine of orally dosed animals before and after enzymatic and hydrolytic cleavage revealed that approximately 20% of the excreted radioactivity was eliminated as the parent compound whereas the remaining obviously did undergo metabolic alteration. Approximately 4% of the urinary [3H] activity was extractable after treatment with glucuronidase/sulfatase, another 20% after strong hydrolytic treatment, most probably resulting in the cleavage of other conjugates. No further attempts were made to identify the metabolites. The studies on the radioactivity extracted from urine revealed that part of the metabolism most probably proceeds by oxidation and conjugation reactions analogous to the degradation of the fatty acids by beta oxidation. A similar pattern of radiolabelled urinary metabolites was found by Isomaa 1975 who studied the gastrointestinal absorption of [1-¹⁴C] cetyl-trimethyl-ammonium bromide in rats. No ¹⁴CO₂was discovered in the expired air thus complete oxidation and N-dealkylation of the cetyl group is not expected to occur.

Findings indicate that DDAC does not readily penetrate cell membranes, that it is very stable and does not undergo considerable degradation on the skin or in the stomach. The similar metabolism pattern between cetyl-trimethyl ammonium and didecyl-dimethyl ammonium also indicate that metabolism is likely to be similar for the various substances in the DDAC group.

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient for assessment

Reason / purpose for cross-reference:

reference to other study

Objective of study:

toxicokinetics

Qualifier:

no guideline followed

GLP compliance:

not specified

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data

Route of administration:

other: gavage, repeat: diet

Vehicle:

not specified

Details on exposure:

The study involved administration of 5 mg or 50 mg 14C-labelled DDAC, using 5 male and 5 female rats each. Rats in the repeat low dose group received 34 ppm DDAC in diet for 14 days prior to the single dose of 5 mg/kg 14C-DDAC.

Duration and frequency of treatment / exposure:

Refer to details on exposure

Remarks:

Doses / Concentrations:
Males- single: 5 mg or 50 mg DDAC, repeat: 34 ppm DDAC in diet for 14 days.
Females -single: 5 mg or 50 mg DDAC, repeat: 34 ppm DDAC in diet for 14 days

No. of animals per sex per dose / concentration:

Refer to details on exposure

Control animals:

no

Positive control reference chemical:

Not applicable

Details on study design:

Refer to details on exposure

Details on dosing and sampling:

Refer to details on exposure

For all groups urine and faeces were collected, and after 7 days rats were euthanised and selected tissue and organs were analysed for radioactivity.

Statistics:

No data

Preliminary studies:

Not applicable

Type:

other: Absorption, metabolism and excretion

Details on absorption:

Evidence indicated that DDAC is not well absorbed from the gastro-intestinal tract, and only not well absorbed from the gastro-intestinal tract, and only a negligible amount (0.003 -0.675%) remained in the body after 7 days.

Details on distribution in tissues:

Not studied

Details on excretion:

No radioactivity was excreted as 14CO2 indicating that the label was in a stable portion of the molecule. In the faeces, 89 -99% of the radioactive material was recovered, and less than 2.5% was found in the urine.

Metabolites identified:

yes

Details on metabolites:

A dose-dependent metabolism was observed in females: more parent compound was metabolised in the single low oral dose than in the single high oral dose. The metabolic process for DDAC in the rat was found to involve oxidation of the decyl side chain to a variety of oxidative products. Evidence seems to favour initial hydroxylation of the carbon next to the terminal carbon, followed by formation of a hydroxyketone. The four major metabolites in this study were more polar and presumed to be less toxic than the parent compound, although their chemical structures were not definitively identified.

None

Conclusions:

The test substance does not have bioaccumulation potential based on the study results.

Executive summary:

Three large-scale pharmacokinetic studies have beenperformed to determine absorption, distribution, metabolism and excretion following administration of 5 mg or 50 mg 14C-labelled DDAC, using 5 male and 5 female rats each. Rats in the repeat low dose group received 34 ppm DDAC in diet for 14 days prior to the single dose of 5 mg/kg 14C-DDAC. For all groups urine and faeces were collected, and after 7 days rats were euthanised and selected tissue and organs were analysed for radioactivity. From this study, DDAC is not well absorbed from the gastro-intestinal tract, and only not well absorbed from the gastro-intestinal tract, and only a negligible amount (0.003 -0.675%) remained in the body after 7 days. No radioactivity was excreted as 14CO2 indicating that the label was in a stable portion of the molecule. In the faeces, 89 -99% of the radioactive material was recovered, and less than 2.5% was found in the urine. A further study to evaluate the metabolic profile of the labelled 14 -C residues in the faeces, indicated a similar pattern of excretion between the sexes, although a dose-dependent metabolism was observed in females: more parent compound was metabolized in the single low oral dose than in the single high oral dose. The metabolic process for DDAC in the rat found to involve oxidation of the decyl side-chain to a variety of oxidative products. Evidence seems to favour initial hydroxylation of the carbon next to the terminal carbon, followed by formation of a hydroxyketone. The four major metabolites found in this study were more polar and presumed to be less toxic than the parent compound, although their chemical structures were not definitively identified.

Description of key information

Based on the available weight of evidence and the cationic nature, DDAC, is expected to have a low absorption potential followed by excretion primarily via feces. 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 or very bioaccumulation potential.  

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

50

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). If signs of systemic toxicity are seen after oral administration (other than those indicative of discomfort or lack of palatability of the test substance), then absorption has occurred.  

DDAC is a di-alkyl dimethyl ammonium chloride type of cationic surfactant, which is a mono-constituent with majorly C10 alkyl chain length. Its molecular weight is ca. 362.1 g/mol. The purified form of the substance is a solid clump-building powder. It has a moderate solubility of 650 mg/L at 25 °C (based on CMC) and a low log Kow of 2.8 value, which was determined based on solubility ratio method.  

Based on the R7.C indicative criteria, together with the fact that the test substance is cationic with a strong adherence potential to the negatively charged surfaces of the membranes, suggests that the it is not expected to easily pass biological membranes.    

Based on experimental data on read across substances:      

A study was conducted to determine the absorption, distribution and excretion patterns following the administration of test substance, DDAI (radiolabelled - purity not specified) the oral route in rats. The gastrointestinal absorption was very poor. Total urinary excretion amounted to only 1.4% of the administered dose. The amount of [3H] activity measured in the organs was low and no target organ was found. The consecutive extractions of the urine of orally dosed animals before and after enzymatic and hydrolytic cleavage revealed that approximately 20% of the excreted radioactivity were eliminated as the parent compound whereas the remaining obviously did undergo metabolic alteration most probably by oxidation and conjugation reactions.  Approximately 4% of the urinary [3H] activity was extractable after treatment with glucuronidase/sulfatase, another 20% after strong hydrolytic treatment, most probably resulting in the cleavage of other conjugates. No further attempts were made to identify the metabolites. These findings indicate that the test substance does not readily penetrate cell membranes and that it was very stable and did not undergo considerable degradation in the stomach. The studies on the radioactivity extracted from urine revealed that part of the metabolism most probably proceeded by oxidation and conjugation reactions analogous to the degradation of the fatty acids by β-oxidation. Under the study conditions, the total absorption, excretion of radioactivity in the urine and the amounts found in the tissues were very low after the administration of test substance by the oral route in rats (Bosshard & Schlatter, 1982).    

One preliminary and three large scale pharmacokinetic experiments were conducted to determine the absorption, distribution, metabolism and excretion patterns following the administration of 14-C radiolabeled test substance, DDAC (purity not specified). The preliminary experiment collected data on the amount of 14C eliminated in the expired air following acute oral administration of 14C-DDAC. The results showed that little or no radioactivity (0.041- 0.054% of dose) was excreted as14CO2, during the 24 h following oral administration of 14C -DDAC. This indicated that the 14C radiolabel was in a stable portion of the DDAC molecule. Three large-scale pharmacokinetic studies were performed to determine absorption, distribution, metabolism and excretion following administration of 5 mg or 50 mg 14C- labelled DDAC, using 5 male and 5 female rats each. Animals were dosed with either 5 mg 14C-labelled test substance (low dose groups), or with 50 mg/kg bw (high dose group). Rats in the third experiment were repeatedly administered low oral dose of 5 mg/kg 14-C labelled test substance. For all groups urine and faeces were collected for analysis and after 7days, rats were euthanised for analysis of selected tissue and organs for radioactivity. From this study, the test substance was found to be not well absorbed from the gastro-intestinal tract, and only a negligible amount (0.003-0.675%) remained in the body after 7 days. No radioactivity was excreted as 14CO2 indicating that the label was in a stable portion of the molecule. In the faeces 89-99% of the radioactive material was recovered, and less than 2.5% was found in the urine. Under the study conditions, the test substance had low absorption (ca. 2.5%) after oral administration which was primarily excreted in the urine and faeces. Only a negligible amount (0.003-0.675%) retained in the body after 1 week (Henderson, 1992). 

A study was conducted to determine the basic toxicokinetics of the test substance, DDAC (non-radiolabellled: 40.5% active, radiolabelled: 98% active), according to OECD Guideline 417, in compliance with GLP. In this study, Sprague-Dawley rats were treated with single and repeated oral doses (50 or 200 mg/kg bw) as well as a single dermal dose (1.5 or 15 mg/kg bw for 6 h) of the radiolabelled test substance. Following single and/or repeated oral doses, the plasma, blood and organ radioactivity levels were essentially non-quantifiable, indicating a low oral bioavailability. The actual minimal fraction of the oral dose absorbed was 0.93 to 3.16%; this was eliminated rapidly, essentially within a 48 -h period. The vast majority of the oral dose was excreted rapidly in the faeces. At the high oral dose level only, quantifiable levels of radioactivity were found in some central organs at 8 h post-dosing (intestines, liver. kidney); otherwise, the vast majority of the dose was confined to the intestines, where their levels decreased over time. Only2.57/1.14% (males/females) and 3.16/1.75% (males/females) of the oral dose was eliminated in the bile and urine in a 24-h period. This indicates that, after intestinal absorption, excretion via bile and urine are of similar magnitude. The total oral absorption value therefore was roughly in the range around 3-7%, based on urinary (0.93 - 3.16%) and bile (1.8-4.0%) excretion. The total oral absorption value therefore was roughly in the range around 3-7%, based on urinary (0.93 - 3.16%) and bile (1.8-4.0%) excretion. Under the conditions of the study and following oral administration the test substance was found to have limited absorption (ca. 3-7%), low distribution (limited to low amounts in intestines, liver. Kidney) and majorly excreted via faeces (ca. >80%) (Appelqvist, 2006).  

Further, the DDAC assessment report for Product Type 8 conducted under Directive 98/8/EC (evaluating Competent Authority: Italy, June 2015, attached in Section 13 of the IUCLID dataset), which reported the above study stated that“Based on the urinary excretion (3-4%), biliary excretion values (2.6%), the absence of residues in the carcass, and 85-90% recovery of radioactivity in faeces as unabsorbed material the actual absorbed fraction is approximately 10% of the orally administered dose, at non-corrosive concentrations.”An additional toxicokinetics study with DDAC was reported in rats, where the majority (>90%) of orally administered DDAC was excreted, very likely unabsorbed, via the faeces. Based on data on urine excretion (ca. 3%) and tissue residues (<1%), and on the 90% recovery of radioactivity obtained in the available toxicokinetic study, it was expected that the oral absorption was limited to ca. 10% at non corrosive concentration).  

Conclusion:Overall, based on the available weight of evidence information, DDAC can be expected to overall have low absorption potential through the oral route. In line with the biocide assessment report a maximum oral absorption value of 10% can be considered for risk assessment.     

Dermal absorption    

Based on physicochemical properties:   

According to REACH guidance document R7.C (ECHA, 2017a), 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 solid clump-building powder, with an MW exceeding 100 g/mol, moderate water solubility and an estimated log Kow below 3.This together with the fact that the test substance is cationic with a strong adherence potential to the negatively charged surfaces, suggests that the test substance at non-corrosive concentrations is likely to have a low penetration potential through the skin.  

At higher corrosive concentrations although there is a likelihood of exposure to the test substance due to disruption of the barrier properties of the skin, the likelihood of occurrence of these cases is expected to be minimal due to the required risk management measures and self-limiting nature of the hazard. Therefore, this scenario has not been considered further for toxicokinetic assessment. 

Based on (Q)SAR prediction:     

The two well-known parameters often used to characterise percutaneous penetration potential of substances are the dermal permeability coefficient (Kp[1][1]) and maximum flux (Jmax). Kp reflects the speed with which a chemical penetrates across SC and Jmax represents the rate of penetration at steady state of an amount of permeant after application over a given area of SC. Out of the two, although Kp is more widely used in percutaneous absorption studies as a measure of solute penetration into the skin. However, it is not a practical parameter because for a given solute, the value of Kp depends on the vehicle used to deliver the solute. Hence, Jmax i.e., the flux attained at the solubility of the solute in the vehicle is considered as the more useful parameter to assess dermal penetration potential as it is vehicle independent (Robert and Walters, 2007).    

In the absence of experimental data, Jmax can be calculated by multiplying the estimated water solubility (using WATERNT v.1.02) with the Kp values from DERMWIN v2.02 application of EPI Suite v4.11. The calculated Jmax value for the C10 alkyl chain was3.93E-06 μg/cm2/h. As per Kroeset al., 2004 and Shenet al. 2014, the default dermal absorption for substances with Jmax ≤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:    

A study was conducted to determine the absorption, distribution and excretion patterns following the administration of test substance, DDAI (radiolabelled - purity not specified) by the dermal route in rats. Dermal absorption were very poor. Total urinary excretion amounted to only 1.3% of the administered dose. The amount of [3H] activity measured in the organs was low and no target organ was found. Under the study conditions, the total absorption, excretion of radioactivity in the urine and the amounts found in the tissues were very low after the administration of test substance by the dermal route in rats (Bosshard & Schlatter, 1982). 

Further, following a single dermal application of the test substance, DDAC in the Appelqvist (2006) study, the plasma and blood radioactivity levels were non-quantifiable at all time-points. For the 1.5 mg/kg bw group, around 1 and 53% of the dose was eliminated in the urine and faeces, respectively, mostly within a 48-h period, suggesting that the dermal dose was highly absorbed via the skin. However, this apparent high absorption via the skin may have been due to the animal licking the test site. This was also supported with the finding that, after oral dosing, only about 1-2.5%% was excreted via bile back to the intestine and 2-3% excreted via urine. If similar routes of excretion are expected for dermally absorbed doses, it would not be possible to find levels of 53% of applied doses in intestine with only 1% excreted via urine. This indicates that about 53% of the dermally applied dose was taken up orally after all. Excretion in bile (1%) and urine (1%) following dermal exposure was similar to that following oral exposure. Further information that can be derived is related to the presence of radioactivity in the tape-stripped skin at the application site. This indicates that the radioactivity present in the dermis-epidermis fraction of the skin is bioavailable with time, since the radioactivity levels decreased from 16-20% (24 h after application) to 1.47-2.39% 168 h after the treatment. However, as the actual dermal absorbed dose must have been very small, it is more likely that de decrease of radioactivity is due to the continuous oral uptake from grooming of the dermal application site (Appelqvist, 2006).

Further, the DDAC assessment report for Product Type 8 conducted under Directive 98/8/EC (evaluating Competent Authority: Italy, June 2015, attached in Section 13 of the IUCLID dataset), which reported the above study stated that:“The available data do not allow a clear quantification of DDAC percutaneous absorption, although they indicate that there are not marked differences between the oral and the dermal bioavailability. Therefore, it is expected that DDAC dermal absorption is limited to ca.10% at non corrosive concentration (as maximum value).”An additionalin vitrodermal absorption study was reported, where following application of 0.1% aqueous concentration of DDAC, the mean total absorbable amount was 9.41% (rounded to 10% at non corrosive concentrations) including the radioactivity present in the dermis and epidermis at the dose site.  

Conclusion: Overall, based on the available weight of evidence information DDAC can be expected to overall have low absorption potential through the dermal route. In line with the biocide assessment report and as a conservative approach a maximum oral absorption value of 10% can be considered for risk assessment. 

Inhalation absorption    

Based on physicochemical properties:   

According to REACH guidance document R7.C (ECHA, 2017a), 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 0.006 Pa at 25 °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. In case of spraying applications, only coarse droplets would be an exposure potential resulting in very low respiratory fraction.Of the inhalable fraction, due to the droplet size and the moderate water solubility almost all droplets are likely to be retained in the mucus and not be available to reach the deeper lungs. The deposited droplets in the upper respiratory tract are expected to be absorbed at a relatively slower rate compared to the deeper lungs due to differences in vascularity. Some of these deposited droplets are also expected to be transported to the pharynx and swallowed via the ciliary-mucosal escalator. Therefore, the systemic uptake of the test substance via respiratory route can be considered to be similar to oral route.

Conclusion: Overall, based on the available weight of evidence information and the higher vascularity of the respiratory tract in general, the test substance can be expected to have low to moderate absorption potential through the inhalation route. Therefore, a maximum value 50% can be considered for the risk assessment as a conservative approach.        

METABOLISM:    

Based on experimental data with read across substance:     

As discussed in the Bosshard & Schlatter, 1982, the analysis of urine metabolites revealed that the test substance DDAI metabolism probably proceed by oxidation and conjugation reactions analogous to the degradation of the fatty acids by β-oxidation. No 14CO2 was detected in expired air, thus complete oxidation and N-dealkylation of the decyl group is not expected to occur. 

A further study to evaluate the metabolic profile of the labelled 14C-residues showed a dose-dependent metabolism in females: more parent compound was metabolized in the single low oral dose than in the single high oral dose. The metabolic process for the test substance in the rat was found to involve oxidation of the decyl side-chain to a variety of oxidative products. Evidence seems to favour initial hydroxylation of the carbon next to the terminal carbon, followed by formation of a hydroxyketone. The four major metabolites found in this study were more polar and presumed to be less toxic than the parent compound, although their chemical structures were not definitively identified. Under the study conditions, the test substance was considered to be metabolized via hydroxylation/oxidation to form polar metabolites (Henderson, 1992).  

Based on (Q)SAR modelling:  

The OECD QSAR Toolbox was used to predict the first metabolic reaction, using the rat liver S9 metabolism simulator and thein vivorat metabolism simulator. As shown in the below table, the OECD QSAR Toolbox v.4.4.1 predicted hydroxylation of the penultimate or ultimate position of the alkyl chain to a carboxylic acid group and subsequent break-down of the alkyl chain for the main constituents of the target substance. 

Representative constituents	Rat liver S9 metabolism simulator /in vivorat metabolism
C10-10 DAQ	ω or ω-1 aliphatic hydroxylation

 

 

Conclusion:Based on all the available weight of evidence information, the test substance is considered to be metabolized by oxidation and conjugation reactions.  

DISTRIBUTION   

Based on physico-chemical properties:  

According to REACH guidance document R7.C (ECHA, 2017a), 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.  

Generally given the ionic nature of the test substance, the test substance is not likely to readily partition across the blood membranes into the different organs, leading to an overall low distribution potential. Moreover, even if the test substance distributes to a certain extent, it is not expected to bioaccumulate based on the experimental BCF value (see section 4.3 of the CSR).  

Based on experimental data on read across substances:  

As discussed above, in the Appelqvist, 2006 study, quantifiable levels of radioactivity were found in some central organs at 8 h post-dosing (intestines, liver. kidney); otherwise, the majority of the dose was confined to the intestines, where levels decreased over time.  

Conclusion:Based on all the available weight of evidence information, the test substance is expected to have a low distribution and bioaccumulation potential.    

EXCRETION:   

Based on physicochemical properties:  

Given the expected low absorption potential of the test substance due to its ionic nature and physico-chemical properties, it can be expected to be primarily excreted through faeces.  

Based on experimental data on read across substances:  

Based on the evidence from the available oral studies (Bosshard & Schlatter, 1982, Henderson, 1992,Appelqvist, 2006), the test substance is primarily expected in faeces (>90%) and less via urine (<10%).Further, in these studies no radioactivity was found in the expired CO2, thus indicating absence of complete oxidation of the alkyl chains.   

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

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