Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Cross-referenceopen allclose all
Reason / purpose:
data waiving: supporting information
Reference
The vapour pressure of the test substance was determined using isothermal thermogravimetric effusion method according to the OECD Guidleine 104 (Brekelmans, 2012). 
Vapour pressure:
0 Pa
at the temperature of:
25 °C

<8.4E-7 Pa at 20°C

Reason / purpose:
data waiving: supporting information
Reference
The appearance of the test substance was determined according to EPA OPPTS 830.6303 (Börjesson, 2012). 
Physical state at 20°C and 1013 hPa:
solid
Form:
other: paste
Colour:
white
Colour intensity:
light
Reason / purpose:
data waiving: supporting information
Reference

Overall, considering the repeated dose studies with the read across substances (e.g., Coco TMAC) as mentioned in the Biocides assessment report, the main critical effects associated with these substances were due to their corrosive properties. The systemic effects such as the reduction of body weight and food consumption were considered to be secondary compared to the corrosive properties of the substances. Therefore, in the absence of ‘true’ systemic effects and in line with the biocides assessment reports, the derivation of a systemic DNEL has been considered to be non-relevant and only a qualitative local risk assessment has been conducted for the test substance.

Toxic effect type:
concentration-driven
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
40.3 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Guideline compliant read across study
Endpoint conclusion:
no study available
Endpoint conclusion:
no study available
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
Due to some deficiencies in the study, the 90-day oral study has been considered further for hazard and risk assessment.
Endpoint conclusion:
adverse effect observed
Study duration:
subacute
Species:
rabbit
Quality of whole database:
The test substance has been classified as corrosive (no threshold derived)

Oral:

Study 1: A study was conducted to determine the oral repeated dose toxicity of the read across substance, C16 TMAC (24 -26% active in water), according to a method similar to OECD Guideline 407, in compliance with GLP. Groups of 10 male and female rats were administered 0, 30, 100 and 300 mg/kg bw/day of read across substance by oral gavage for 28 days. The read across substance used was a 24-26% aqueous solution but it is not clear if the doses mentioned were corrected. There were no treatment-related changes at the 30 and 100 mg/kg bw/day. In the high-dose group there was an increase in water consumption, changes in the absolute and relative weights of the adrenals and spleens (in males) without corresponding effects on haematology, clinical chemistry and histology. The forestomach of the high-dose group showed few microscopic changes, however animals in the high-dose recovery group showed a complete and regular regeneration of the forestomach mucosa. Hence, the forestomach effects were considered to be due to the irritating properties of the read across substance rather than symptoms of systemic toxicity. Under the study conditions, the rat 28 d NOEL for systemic effects was considered to be at 100 mg/kg bw/day, which is corrected to 25 mg a.i./kg bw/day (assuming it is not been done in the study report) (Potokar, 1991). Based on the results of the read across study, similar effects and NOAEL can be expected for the test substance.

Study 2: A 90-day study was conducted to determine the oral repeated dose toxicity of the read across substance, Coco TMAC (active: 35.5%), according to OECD Guideline 408 and EU Method B.26, in compliance with GLP. Sprague-Dawley rats were administered the test substance at concentrations of 0, 100, 500 or 2000 ppm (i.e., corresponding to 0, 22, 113 and 273 mg/kg bw/day in males and 0, 25, 121, 297 mg/kg bw/day in females) in the diet for 90 d. The active ingredient dose equivalent were calculated to be 0, 7.9, 40.3 and 96.9 mg a.i./kg bw/day in males and 8.8, 42.9, 105.3 mg a.i./kg bw/day in females. The highest dose of 2000 ppm was reduced to 1000 ppm from Day 29 onwards due to deterioration in health of the test animals at 2000 ppm. At the highest dose, the treatment-related findings were clinical signs of toxicity, reduced body weight gain and food efficiency, organ weight changes and microscopic changes in the spleen and kidneys. At the mid dose, reduced body weight gain (males) and reduced food consumption, reduced absolute heart weight and higher incidence of haemosiderin accumulation in the kidneys of males was observed. No treatment-related effects were observed at the lowest dose. Based on the results of the study, dietary administration of the test substance to rats for a period of 90 d at levels up to 273 mg/kg bw/day resulted in toxicologically significant effects at the high dose and marginal effects at the next lower dose of 113 mg/kg bw/day (500 ppm). No such effects were demonstrated at the lowest dose of 22 mg/kg bw/day (100 ppm).The changes observed at the mid dose (500 ppm) were considered to be minor, isolated effects associated with the reduced palatability of the test substance and were considered not to represent an adverse health effect. Therefore, based on effects on body weight, food efficiency and clinical signs the study authors established the NOAEL at the mid-dose level of 500 ppm (i.e., equivalent to 113 mg/kg bw/day or 40.3 mg ai./kg bw/day) (Jones, 2002).The accumulation of haemosiderin in the spleen and kidneys at high and mid doses can be considered questionable for their toxicological relevance as they were not associated with any signs of bleeding (black faeces, increased spleen weight, accelerated erythropoiesis) and occurred in the absence of any effects on haematological parameters. Also, their levels in the males remained below the levels in female, whereas typically there is no known difference between the sex of animals for this effect. Further, the reduction in body weight and body weight gain, was attributed to local gastrointestinal irritation/corrosion and consequent reduced food intake without observing any primary systemic effect.

As per the Biocides assessment report on Coco TMAC, which was published by the Italian authorities in April 2016, the NOAEL in the above study was reported to be at the lowest dose 100 ppm (i.e., corresponding to 22 mg/kg bw/day or 7.9 mg a.i./kg bw/day). This was based on reduced food consumption with consequent lower body weight gains over the study period (10%) and the occurrence of haemosiderine in kidneys a dose-dependence effect that was considered to be treatment-related at LOAEL (500 ppm). Only at levels when serious differences in body weight were more than 20% compared to the control, other clinical effects occurred. Similar results were obtained from subchronic feeding studies with other read across substances didecyldimethylammonium chloride (DDAC; CAS: 7173-51-5) (NO(A)EL=42 mg/kg bw/day) and C12-16 ADBAC (NOAEL of 68 mg a.s./kg bw/day) in rats, where the critical effect upon oral exposures were decreased body weight gain. Results from 90-day dog studies with read across substances DDAC and C12-16 ADBAC, with corresponding NOAELs at 15 and 45 mg a.i./kg bw/day (i.e., 486 and 1250 ppm), do not indicate species differences towards mechanism of toxicity by quaternary ammonium compounds. Further, the two highest doses (10 and 20 mg/kg bw/day) in a 1-year oral gavage study in dogs for DDACresulted in g.i.-related complications including emesis and abnormal faeces, resulting in death of 2 out of 4 animals at 20 mg/kg bw/day. The irritation/corrosive properties linked 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. Only small amounts of the test substance were considered to be systemically available without giving rise to any significant systemic effect except for 10-15% decrease in body weight, which were considered to be secondary to effects in the gut. The NOAEL for local effects on gut mucosa was fixed equal to 3 mg/kg bw/day, whereas the systemic NOAEL was at 10 mg/kg/day for DDAC. Based on the outcome of the effect assessment, it was concluded that the AEL cannot be regarded as a “true” systemic threshold and therefore AEL approach based risk assessment should not to be performed. Consequently only a semi-quantitative local risk assessment was considered for the active substance (ECHA biocides assessment report, 2016).

Study 3:

A 1-year study was conducted to determine repeated dose toxicity of the read across substance, C16 TMAB (99% active) in rats. Read across substance was given to the male and female Sprague-Dawley rats in the drinking water at concentrations of 0.007, 0.014 and 0.032 % i.e., equivalent to 10, 20 and 45 mg/kg bw/day. Male and female rats of the high dose groups showed a significantly reduced body weight development, decreased efficiency of food consumption, decreased skeletal growth. In both males and females, an increased relative caecum weight was found in the high (males and females) and mid (males only) dose groups. No compound related changes were observed in haematological and clinical-chemical analyses of blood and urine. No gross necropsy changes were seen, and no microscopic alterations were found in the wall of stomach and small intestine of treated rats. No other tissues were histopathologically examined. The effects on growth and body weight development observed in the study are considered to be an indirect effect of the administration of read across substance in the drinking water. Since the read across substance caused diarrhoea which resulted in a faster passage of food through the gastrointestinal tract and reduced absorption of nutrients. The increased relative caecum weight may be due to proliferation of the endothelial cell layer caused by an increased replacement rate due to a faster flux of the intestinal contents. This explanation is supported by the lack of histopathologic alterations of the small intestine. Under the study conditions, the NOAEL for the read across substance was considered to be 45 mg/kg bw/day and NOEL for the read across substance was considered to be 10 mg/kg bw/day (Isomma, 1976).Based on the results of the read across study, similar effects and NOAEL can be expected for the test substance.

Overall, considering the repeated dose studies with Coco TMAC or other read across substances as mentioned in the Biocides assessment report, the main critical effects associated with these substances were due to their corrosive properties. The systemic effects such as the reduction of body weight and food consumption were considered to be secondary compared to the corrosive properties of the substances. Therefore, in the absence of ‘true’ systemic effects and in line with the biocides assessment reports, the derivation of a systemic DNEL has been considered to be non-relevant and only a qualitative local risk assessment has been conducted for the test substance.

Dermal

A 28-day study was conducted to determine the repeated dose dermal toxicity of the read across substance, C16 TMAC (54.5% active in aqueous isopropanol), in New Zealand albino rabbits (both sexes) according to a method similar to OECD Guideline 410. The purity was not specified and the study included a lower than recommended number of animals (i.e., 10/group rather than 20/group as per guideline) and histopathology was performed only on limited organs. The read across substance (0 and 10 mg/kg bw/day) was applied to the shaved, intact skin of groups of 5 New Zealand albino rabbits/sex/group for 6.5 to 7 h, 5 days/week for 4 weeks. Dermal irritation readings were recorded daily. The animals were weighed weekly during the exposure period. Blood was collected for haematology measurements before initiation of dosing and prior to termination. Liver and kidneys weights were recorded at necropsy and limited histopathology was conducted. There were no systemic treatment-related effects on body weights, haematology, organ weights, gross necropsy findings or histopathology. Treated areas of the skin showed mild to marked acanthosis with active mitosis, hyperkeratosis, and partial to extensive necrosis of the epidermis and hair follicles, partly with encrustation and exudate. Under the study conditions, the 28d NOAEL for male and female rabbits were determined to be 10 mg/kg bw/day (TRS-HPV, 2001). Based on the results of the read across study, similar absence of systemic effects can be expected for the test substance.

Inhalation

The substance has a low vapour pressure (VP = 2.9E-6 Pa at 25°C), which is below the cut-off of 0.01 Pa set for defining low volatility substances, as per the ECHA Guidance R.7a. Therefore, due to it paste like or creamy physical state and low VP, the test substance is unlikely that it will form inhalable dust, mist or fumes when handled and used in solid form. In case inhalable forms of the substance (either pure or in aqueous solutions) are created under particular conditions (e.g., spraying, elevated temperature/pressure), appropriate risk management measures (due to corrosive nature of the test substance) such as closed systems, exhaust ventilation or wearing of respirators are implemented to control exposure. Under such conditions, the risk to humans following inhalation exposure can be considered minimal and further testing involving vertebrate animals may be omitted, in accordance with Annex XI (1.2) of the REACH regulation. Nevertheless, a qualitative risk assessment has been carried out for this route, due to the corrosive nature of the test substance and the fact that the available repeated dose oral studies with the read across substance did not show any primary systemic effects; all observed effects were attributed to local gastrointestinal irritation/corrosion and consequent reduced food intake.

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

Reason / purpose:
data waiving: supporting information
Reference
Hazard assessment conclusion:
no hazard identified
Hazard assessment conclusion:
no hazard identified
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Hazard assessment conclusion:
no hazard identified
Hazard assessment conclusion:
no hazard identified
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Hazard assessment conclusion:
medium hazard (no threshold derived)
Hazard assessment conclusion:
no hazard identified
Hazard assessment conclusion:
no hazard identified
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Hazard assessment conclusion:
no hazard identified
Hazard assessment conclusion:
no hazard identified
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Hazard assessment conclusion:
no hazard identified
Justification:
starting point is a NOAEL
Hazard assessment conclusion:
no hazard identified
Hazard assessment conclusion:
medium hazard (no threshold derived)

Data source

Materials and methods

Results and discussion

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion