Registration Dossier

Administrative data

Description of key information

Oral
The 90-day dietary administration of the read-across substance 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 a.i./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 the read-across substance 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 test substance/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:
Both repeated dose studies were conducted with the structurally similar test substances (i.e., cetrimonium chloride and coco alkyl trimethyl ammonium chloride according to the OECD guideline as well as in compliance with GLP and have Klimisch score 1. 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

Mode of Action Analysis / Human Relevance Framework

Additional information

Oral

A 28 day repeated dose toxicity study was conducted according to OECD guideline 407. Groups of 10 male and female rats were administered the read-across substance C16 TMAC by oral gavage at dose levels of 0, 30, 100 and 300 mg/kg bw/day for 28 days. The test substance used was a 24-26% aqueous solution but it is not clear if the doses mentioned were corrected for undiluted test substance. There were no substance-related changes at the dose of 30 and 100 mg/kg bw/day. There was an increase in water consumption, changes in the absolute and relative weights of the adrenals and spleens (in males) at the high dose group but corresponding findings in the haematology, clinical chemistry and histology were not observed. The forestomach of the high dose group showed few microscopic changes. The animals of 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 test substance rather than symptoms of systemic toxicity. Under the test conditions, the NOAEL for systemic effects was determined to be 300 mg/kg bw/day (Potokar M, 1991).

Sprague-Dawley rats were administered the read-across substance C12-C18 TMAC for 90 days in the diet according to OECD guidelines at dose levels of 0, 100, 500 and 2,000 ppm (corresponding to 22, 113 and 273 mg a.i./kg bw/day). The highest dose of 2,000 ppm was reduced to 1,000 ppm from Day 29 onwards due to deterioration in health of the test animals at 2,000 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 NOEL was considered to be 100 ppm (i.e., equivalent to 22 mg a.i./kg bw/day). The changes observed at 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. The NOAEL was therefore 500 ppm (i.e., equivalent to 113 mg a.i./kg bw/days) (Jones et al.,2002).

Dermal

A 28 day repeated dermal toxicity study was conducted in New Zealand albino rabbit (both sexes) exposed to the read-across substance C16 TMAC. The purity was not specified and the study included a lower number of animals (i.e., 10/group rather than 20/group as per guideline) and only histopathology of limited organs was performed. The test substance was applied (5 days/week for 4 weeks) to groups of 5 New Zealand albino rabbits/sex/group at the dose levels of 0 and 10 mg test substance/kg bw/day to the shaved, intact skin for 6.5 to 7 hours. 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. A complete list of tissues was collected for histopathological evaluation. There were no systemic treatment-related effects on the 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 conditions of the test, the NOAEL for male and female rabbits was found to be 10 mg test substance/kg bw/day (Spicer EJF, 1979).


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
90-day study is more robust and longer duration study compared to 28-day study; the NOAEL of 90-day study is also more conservative.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
The substance is a paste with a low vapour pressure. Due to it physical state and physical chemical properties, it 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 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 inhalation - local effects endpoint:
The substance is a paste with a low vapour pressure. Due to it physical state and physical chemical properties, it 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 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:
Only one study available.

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 NOAELs, it can be concluded that C16-C18 TMAC does not require classification according to EC (67/548/EEC) and CLP (EC 1272/2008) criteria.