Registration Dossier

Administrative data

Description of key information

Oral
The 90-day dietary administration of C12-C18 TMAC to rats up to the level of 273 mg a.i./kg bw/day resulted in toxicologically significant effects at the highest dose of 273 mg a.i./kg bw/day and marginal effects at the mid dose of 113 mg a.i./kg bw/day. No such effects were demonstrated at the lowest dose of 22 mg/kg bw/day. Therefore, the 'No Observed Effect Level' (NOEL) was considered to be 22 mg a.i./kg bw/day. The effects observed at the mid dose 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 the "No Observed Adverse Effect Level" (NOAEL) should be regarded as 113 mg a.i./kg bw/day.
Dermal
Except for mild to marked acanthosis, hyperkeratosis, and partial to extensive necrosis of the epidermis and hair follicles at the site of application, no systemic treatment-related effects were observed in a 28-day study conducted with structurally similar C16 TMAC in rats. Under the conditions of the test, the 28 day dermal NOAEL of the test substance for male and female rabbits was established at 10 mg/kg bw/day. However, due to some deficiencies in the study (number of test animals per group was 10/group rather than 20/group as per guideline and histoptahology of limited organs), the NOAEL of the 90-day oral study was used as the starting point to derive the corresponding DNEL.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
113 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The information requirements for this tonnage band is sufficiently met with the available data.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
The information requirements for this tonnage band is sufficiently met with the available data.

Mode of Action Analysis / Human Relevance Framework

Additional information

Oral

In an OECD guideline 408 study the effects of repeated oral administration for 90-days in rats was conducted to determine the effects C12-C18 TMAC. The test substance was administered through the diet to Sprague-Dawley rats at levels of 0, 100, 500 and 2000 ppm (corresponding to 22, 113 and 273 mg/kg bw/day). The highest dose of 2000 ppm was reduced to 1000 ppm from Day 29 onwards due to deterioration in health of treated animals at 2000 ppm. At the highest dose, the treatment- related findings were clinical signs of toxicity, reduced body weight gain, reduced 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 effect was observed at the lowest dose. Hence, the 'No Observed Effect Level' (NOEL) was considered to be 100 ppm (i. e., equivalent to 22 mg/kg bw/day). The changes observed at 500 ppm were considered to be minor, isolated effects associated with the reduced palatability of C12-C18 TMAC and were considered not to represent an adverse health effect. Hence, in this risk assessment the "No Observed Adverse Effect Level" (NOAEL) should be regarded as 500 ppm (i. e., equivalent to 113 mg a.i./kg bw/days) (Joneset al.,2002).

Inhalation

No information could be found on the respiratory sensitisation potential of C12-C18 TMAC. However, quaternary ammonium compounds in general are not known to be respiratory sensitisers. The substance is a waxy solid with a low vapour pressure which forms clumps at room temperature. Due to it’s physical state and physical chemical properties it is unlikely that this substance will form inhalable dust, mist or fumes during normal processing and use conditions. In case inhalable forms of the substance are created under particular conditions (e. g. spraying, elevated temperature/pressure), appropriate risk management measures 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.

Dermal

A study was conducted to determine the acute dermal toxicity of the structurally similar test substance C16 TMAC in male or female New Zealand albino rabbits. The test substance (purity not specified) was applied (5 days/week for 4 weeks) to groups of five New Zealand albino rabbits/sex/group at dose levels of 0 and 10 mg/kg bw/day to shaved, intact skin for 6.5 to 7 hours. There were no systemic treatment-related effects on body weight, haematology, organ weight, gross necropsy findings or histopathology, except for treated areas of the skin that 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 conditions of the test, the 28 day acute dermal NOAEL of the test substance for male and female rabbits was found to be 10 mg/kg bw/day.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Key study conducted according to the OECD guideline in compliance with GLP and is assigned Klimisch score 1.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
The test substance has a very low vapour pressure, so the normal processing and use conditions will not generate inhalation exposure. In case aerosols or vapours are created under particular conditions (e. g. spraying, elevated temperature/pressure), appropriate risk management measures such as closed systems, exhaust ventilation or wearing of respirators are implemented to control exposure. Furthermore, the potential for inhalation is not significant to justify this study. The substance is classified as corrosive and testing would unnecessarily harm animals and therefore further testing involving vertebrate animals may be omitted, in accordance with Annex XI (1.2) of the REACH regulation.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
The substance is a waxy solid with a low vapour pressure which forms clumps at room temperature. Due to it’s physical state and physical chemical properties it is unlikely that this substance will form inhalable dust, mist or fumes during normal processing and use conditions. In case inhalable forms of the substance are created under particular conditions (e. g. spraying, elevated temperature/pressure), appropriate risk management measures 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.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Key study

Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: spleen; urogenital: kidneys

Justification for classification or non-classification

Based on the available data derived from the subchronic study (113 and 273 mg a.i./kg bw/day, respectively) in which clinical signs of toxicity, reduced body weight gain, reduced food efficiency, organ weight changes and microscopic changes in the spleen and kidneys were observed only at the highest test dose and the subacute dermal NOAEL of the structurally similar substance of 10 mg/kg bw/day, C12-C18 TMAC does not require classification according to EC DSD (67/548/EEC) and EC CLP criteria (EC 1272/2008).