Didecyldimethylammonium chloride

Repeated dose toxicity: dermal

Administrative data

Endpoint:

sub-chronic toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

Toxic effect type:

concentration-driven

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

10 mg/kg bw/day

Study duration:

chronic

Species:

dog

Quality of whole database:

Good quality. In line with the data presented in the DDAC assessment report for Product Type 8 conducted under Directive 98/8/EC (evaluating Competent Authority: Italy, June 2015

Organ:

other: Target organs: Only local effects; no true systemic effects

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

12 mg/kg bw/day

Quality of whole database:

Data published in the DDAC assessment report for Product Type 8 conducted under Directive 98/8/EC (evaluating Competent Authority: Italy, June 2015

Endpoint conclusion:

no study available

Oral, rats

A repeated dose 28 day oral toxicity study in rats was conducted according to laboratory internal methodology (Huntingdon Life Sciences). The following dose levels of DDAC were administered by gavage: 2.5, 28 and 50 mg/kg bw/day. Diarrhoea, lethargy, gasping and waddling were noted in all the animals at the mid dose. Abdominal distension, dyspnoea, epitaxis and brown-red staining around the mouth and anal region were also recorded at the high dose. The following effects were also related to high dose treatment: ulceration/erosion, epithelial hyperplasia and hyperkeratosis of the non-glandular epithelium associated with subepithelial oedema and inflammation. Under the study conditions, the LOAEL was determined to be 55 mg/kg bw/day and the NOAEL was 2.5 mg/kg bw/day (HRC, 1989).

In a study compliant with OECD Guideline 408 and EU Method B.26, DDAC (40% a.i.) was given by dietary admixture to Sprague-Dawley rats for 13 weeks at concentrations of 1500, 3000 or 6000 ppm test substance (corresponding to 42, 84 or 175 mg a.i./kg bw/day for males and 49, 96 or 201 mg a.i./kg bw/day for females). At 6000 ppm, main treatment-related findings were soft feces, body weight loss (Week 1), lower body weight gain and food consumption, perturbation of haematological and blood biochemical parameters, distension of the cecum/colon with feces in all animals, histiocytosis, mastocytosis and sinusal haemorrhage in the mesenteric lymph node, consistent with a continued action of a mild irritant. At 3000 ppm, body weight gain and food consumption were affected, changes at clinical pathology were noted, the cecum was distended with feces in about third of the animals, and histiocytosis and mastocytosis in the mesenteric lymph node were seen at histopathology. At 1500 ppm, changes in haematological and blood biochemical parameters were recorded and possibly a marginal increase in histiocytosis and mastocytosis in the mesenteric lymph node which all did not immediately seem to be of toxicological significance. A NOAEL of 1500 ppm of the test substance (corresponding to 46 mg a.i./kg bw/day combined male/female) was established. The corresponding LOAEL was 3000 ppm (corresponding to 90 mg a.i./kg bw/day combined male/female) (CIT, 2004).

A study was conducted in accordance with OECD Guideline 453 and OPPTS Guideline 870.3700 to evaluate the chronic toxicity of the test substance (40% a.i.). The test substance was administered daily to Sprague-Dawley rats by dietary admixture at the concentrations of 700, 1500, and 3000 ppm of for 52 weeks (toxicology sub-group) or for 104 weeks. The test substance did not induce any treatment-related mortality or clinical signs when administered daily for 52 or 104 weeks. At 3000 ppm, the mean body weight and mean body weight gain of the carcinogenicity subgroup animals were slightly lower than in controls (-26%), correlating in females with slightly lower mean food consumption during the first 13 weeks. There were no significant differences in hematological, biochemical and/or urinalysis parameters at any treated dose-level for animals of either sub-group, compared with controls. There were no macroscopic findings attributable to the test item at any of the tested dose-levels. The non-neoplastic histopathological findings confined to the mesenteric lymph nodes and Peyer’s patches were consistent with the continued action of a mild irritant and are considered to be of limited toxicological significance. There were no treatment-related neoplastic findings at histologic al examination. Consequently, the LOAEL for toxicity was considered to be 3000 ppm (equivalent to 62 mg/kg bw/day combined male/female) and the NOAEL 1500 ppm (equivalent to 31 mg a.i./kg bw/day, combined male/female). The test substance was not found to be carcinogenic under the conditions of this study (CIT, 2008).  

Oral, dogs  

A study was conducted to determine the toxicity of the test substance (40% a.i.) administered by dietary admixture to Beagle dogs for 4 weeks at concentrations of 500, 1000 and 2000 ppm (i.e. 202.5, 405 and 810 ppm a.i.) in accordance with OECD Guideline 409. The animals were checked daily for mortality and clinical signs. Bodyweight was recorded weekly and food consumption was measured daily during the pre-dose period and throughout the treatment period. Achieved dosage was calculated daily. Haematological and blood biochemical investigations were performed from the beginning and at the end of the treatment period. At study end, the animals were killed and submitted to a full macroscopic examination. Designated organs were weighed and tissue specimens were preserved. A microscopic examination was performed on selected tissues from animals in the control and high dose groups. At 500 and 1000 ppm, no overt signs of toxicity were noted. At 2000 ppm, emaciated appearance was recorded in 1/2 males and 1/2 females. Lower bodyweight gain in males and bodyweight loss in females was associated with lower food consumption, probably due to low palatability of the test substance. No treatment-related laboratory or histopathological changes were noted. Under the study conditions, the NOAEL was probably higher than 2000 ppm (i.e. 24 and 23 mg a.i./kg bw/day in males and females, respectively) (CIT, 2007).

 

The repeated dose toxicity of the test substance (40% a.i.) in dogs was evaluated in a study performed according to OECD Guideline 409, EEC Method B.27 and US EPA OPPTS Guideline 870.3150. The substance was administered at 0, 300, 600 and 1200 ppm (corresponding to 121.5, 243 or 486 ppm a.i.) in diet for 13 weeks to 4 males and 4 female Beagle dogs per dose group. Food consumption was measured daily. The dose levels were based on a 4-week preliminary study. The mean achieved dosages of DDAC remained stable during the study in all groups and increased in a dose-proportional manner. Based on food consumption and body weight information, the actual ingested dose levels for 0, 300, 600 or 1200 ppm of test substance were as follows: males: 0, 4, 8 and 15 mg a.i./kg bw/day and females: 0, 4, 9 and 18 mg a.i./kg bw/day. No unscheduled deaths occurred during the study. No treatment-related clinical signs were observed. There was no direct effect of treatment on body weight. No treatment-related ophthalmological findings, no treatment-related relevant differences in haematology and blood biochemistry, no urinary findings among qualitative or quantitative parameters, no effects of toxicological importance on organ weights, necropsy findings or microscopic findings were observed in any of the groups. The NOAEL was established at 1200 ppm, corresponding to 15 mg a.i./kg bw/day in males and 18 mg a.i./kg bw/day in females(CIT, 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) reported additional repeated dose toxicity studies with DDAC, which are summarised below: 

The subchronic oral NOAELs were 107-134 mg/kg bw/day in male and female mice and 61-74 mg/kg bw/day in male and female rats mainly based on aspecific effects, such as decreased body weights, considered to be secondary to local effects on gut mucosa and intestinal microflora. No organ specific toxicity was evidenced. With both rodent species high mortality (80% and 96% of treated rats and mice) occurred in animals given DDAC fortified diets at the highest dose tested; death was attributed to gastrointestinal alterations resulting in dehydration and wasting. The exposure to the immediately lower dose caused only minimal body weight effects (10-15% decrease). The steepness of the dose-response curve (from no effects to high % mortality caused by 3-fold higher dose) is also indicative of the mechanism of action through irritation/corrosive properties of DDAC (US ISC; cited in the ECHA biocides assessment report, 2015).  

In a 1-year oral gavage study in dogs with DDAC, the two highest doses (10 and 20 mg/kg bw/day) resulted in G.I. related complications including emesis and abnormal faeces. The clinical signs observed in all the animals treated at 10 mg/kg bw/day (emesis, salivation, soft/loose faeces) persisted for the entire study duration; taking into account that the treatment dosage is reached with 2 different administrations within the day (lowering the entity of the bolus dose achievable with a single administration-possibly giving rise to more severe effects) this dosage cannot be considered as the NOAEL derived from the study. The NO(A)EL should be fixed equal to 3 mg/kg bw/day, related to local effects on gut mucosa. The clinical signs reported at 10 mg/kg bw/day, on which the NOAEL derivation is based, are consistent with the irritation/corrosive properties of the test item: only a small amount of DDAC becomes systemically available, without giving rise to any significant systemic effects. The systemic effects (10-15% decrease in body weight), were seen at 20/30 mg/kg bw/day, although secondary to effects in the gut. In this context, the AEL cannot be regarded as a “true” systemic threshold and therefore, at WGII2015 it has been agreed that the AEL approach should not be performed. Consequently, only a qualitative local risk assessment (including exposure assessment) have to be considered from the use of DDAC (US ISC; cited in the ECHA biocides assessment report, 2015).  

The NOAELs for non-neoplastic effects after chronic dietary DDAC administration were 32-41 mg/kg bw/day for rats and 76 – 93 mg/kg bw/day for mice. NOAELs values derivation was mainly based on unspecific effects, such as decreased body weights, considered to be secondary to local effects on gut mucosa and intestinal microflora. No organ specific toxicity was evidenced. In line with the fact that the main outcome directly derives from the irritative/corrosive properties of the active substance, the subchronic and chronic NOAELs are similar in rodents, and little difference is expected between the 2-exposure scenario (US ISC; cited in the ECHA biocides assessment report, 2015).  

The RMS further concluded the NOAEL for local effects and systemic effects at 3 and 10 mg/kg bw/day, based on sub-chronic studies of US ISC in dogs and the non-neoplastic NOAEL at 27 mg/kg bw/day based on the long-term study in rats (EQC).

 

Dermal 

 

Due to the direct corrosive effect and limited dermal absorption, effects will be characterised by local tissue damage rather than systemic toxicity. Available information on dermal absorption makes a route-to-route approach possible. 

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) reported a subchronic repeated dose dermal study with DDAC, where no systemic effects were seen at the highest dose that could be applied without excessive skin irritation. Therefore, the systemic NOAEL was 12 mg/kg bw/day (highest dose tested) and the local NOAEL was 2 mg/kg bw/day (US ISC; cited in the ECHA biocides assessment report, 2015).

Inhalation 

The test substance has low vapour pressure and therefore will be present in air only at negligible concentrations under normal and foreseeable use conditions. Further inhalation testing in animals was therefore not considered necessary. Moreover, since the substance is classified as corrosive, testing would be excessively harmful to the animals. 

 

Overall assessment

When evaluating all available studies, it becomes clear that the effects are characterised by local gastro-intestinal irritation rather than by systemic toxicity. The effects that are seen at the LOAEL consist of decreased bodyweight gain and food consumption, with or without clinical symptoms. There are no signs of haematological, biochemical or histopathological nature that would indicate systemic or organ toxicity. This is the case in dietary as well as in gavage studies. The NOAELs do not change with increasing duration of the study (especially on the basis of concentration in the diet what compensated for allometric scaling and metabolic changes with age). This lack of increased toxicity with duration represents a further indication for a lack of systemic toxicity. 

Based on the results from the repeated dose oral studies, the test substance does not warrant a classification for STOT REaccording to EU CLP (Regulation EC/1272/2008) criteria. 

Cross-reference 2

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

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.  

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

50

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 

Cross-reference 3

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

Based on the results from thein vivoirritation studies, DDAC is considered to be corrosive to skin as well as eyes. 

Endpoint conclusion:

adverse effect observed (corrosive)

Endpoint conclusion:

adverse effect observed (irreversible damage)

Endpoint conclusion:

no study available

Skin irritation/corrosion

In an OECD Guideline 404 compliant study, 0.5 mL of test substance was applied under occlusive patches on the clipped dorsal area of a total of six New Zealand White rabbits per group. The animals were left for an exposure period of 3 min for three animals and 1 h for the other three animals. The residual test material was removed by gentle swabbing with cotton wool soaked in 3% (v/v) aqueous acetic acid followed by cotton wool soaked in distilled water. Approximately one h following removal of the patches, and 24, 48, 72 h and 7 and 14 days later, the test sites were examined for evidence of primary irritation and scored according to Draize (1959). In this study, no adverse skin reactions were noted at any treated skin site in the 3 min exposure group except slight erythema and oedema at the treated sites up to the 72 h observation period. However, after 1 h exposure, a light brown discoloration of the epidermis and slight haemorrhage of the dermal capillaries were noted at all treated skin sites one h after the removal of the patches. Eschar had developed at all treated skin sites at the 24 h observation period and continued to be present at the 48 and 72 h and day seven observation. Blanching and moderate erythema were also noted at all the treated skin sites during this period. On Day 14, sunken eschar was noted at all the treated skin sites. Based on the study results, the test substance is considered to be corrosive to skin (Safepharm, 1987).  

In a further OECD Guideline and EU Method compliant study, under GLP conditions, dorsal hair was removed by clipping in 6 animals and the neat test substance was applied to the skin under a semi-occlusive bandage. The animals were divided into two groups according to the exposure period: 3 min and 4 h. After removal of the patches, the skin is observed for signs of irritation. In this study, the 4 h exposure produced severe erythema and severe edema up to the 72 h observation period and the skin appeared rough, dry, scabbed with discoloration. The 3 min exposure produced slight erythema, slight to severe oedema up to 7 days and at end of 14 day observation period, the skin appeared dry, rough and leather-like. The mean score for oedema and erythema was 4 up to the observation period of 72 h. Based on the study results, the test substance was found to be corrosive (Hoechst, 1991).  

Further, DDAC is anticipated to be severely damaging to human skin based on its corrosive nature. The maximum concentration that is likely not produce irritating effect on intact skin is 0.1%. Irritation becomes manifest at concentrations of 1% and higher (Cutler and Drobeck, 1970).    

 

Eye irritation

The test substance is classified as corrosive to skin. Hence, for animal welfare reasons, testing for eye irritation has not been conducted and DDAC is considered to cause severe eye damage.  

Further, the substance is expected to be severely damaging to eyes based on its corrosive nature. Concentrations as low as 0.1 to 0.5% are often irritating to conjunctivae and mucous membranes (Cutler and Drobeck, 1970).  

Studies conducted in rabbit demonstrate that the test substance is corrosive to skin and warrants classification as Skin Corr. 1B - H314 (Causes severe skin burns and eye damage) according to EU CLP (Regulation EC/1272/2008) criteria. Testing for eye irritation was not conducted since the substance is proposed for classification as corrosive; severe eye irritation responses along with irreversible eye damage are expected.

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Didecyldimethylammonium chloride

EC Number:

230-525-2

EC Name:

Didecyldimethylammonium chloride

Cas Number:

7173-51-5

Molecular formula:

C22H48N Cl

IUPAC Name:

didecyldimethylammonium chloride

Results and discussion

Target system / organ toxicity

Critical effects observed:

not specified