Didecyldimethylammonium chloride

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

other:

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

The vapour pressure of the test substance was measured according to the isothermal thermo gravimetric effusion method of OECD Guideline 104, EU Method A.4 and US EPA OPPTS 830.7950 (Brekelmans, 2012).

Vapour pressure:

0.006 Pa

at the temperature of:

25 °C

- The vapour pressure was found to be <1.5 × 10-3 Pa (i.e. <1.1 × 10-5 mm Hg) at 20°C and <5.8 × 10-3 Pa (i.e. <4.3 × 10-5 mm Hg) at 25°C.

- Data presented in 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 an additional vapour pressure study with VP values of 5.9E-06, 1.1E-05 and 2.3E-04 at 20, 25 and 50ºC respectively (US ISC).

As a conservative approach, the relatively higher vapour pressure value <5.8 × 10-3 Pa at 25°C of the purified form of the registered substance has been considered further for hazard/risk assessment.

Cross-reference 2

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.

Cross-reference 3

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. 

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