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Administrative data

Description of key information

The potential toxicity of quaternary ammonium compound, di-C16 -18 -alkyldimethyl, chloride following repeated administration  was assessed using:
- A subacute (28-day) oral toxicity study performed in rats according to OECD guideline 407 in compliance with Good laboratory practices (Hoechst, 1990)
- A subchronic (90-day) feeding study performed in Beagle-dogs according to a method similar to OECD guideline 408 (Lindberg, 1971).

Based on some limitations of the 90-day feeding study in dogs, the valid 28-day subacute toxicity study in rats is taken for risk characterisation which is in accordance with the existing EU risk assessment on Dioctadecyldimethylammonium chloride. Based on the results of this study, the NOAEL with regard to systemic oral toxicity was established at 100 mg/kg body weight per day.

In an earlier study predating official test guidelines and Good Laboratories Practices, rabbits received technical grade Dioctadecyldimethylammonium chloride (75% active in isopropanol/water) via the dermal route of exposure. Twenty applications (5 per week for 4 consecutive weeks) of 2 mL of 0, 0.2 and 2% aqueous test substance solutions (corresponding to about 0, 4 and 40 mg/kg body weight per day) induced mild local dermal effects but no clinical or morphological signs of substance related systemic toxicity. The NOAEL for dermal systemic effects was greater 40 mg/kg body weight per day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
40 mg/kg bw/day
Study duration:
subacute
Species:
rabbit

Additional information

The repeated dose toxicity of quaternary ammonium compound, di-C16 -18 -alkyldimethyl, chloride was investigated by oral and dermal routes in several subacute and subchronic studies performed in rats and dogs using either technical grade or pure dioctadecyldimethylammonium chloride (DODMAC) or dihydrogenated tallowalkyldimethylammonium chloride (DHTDMAC).

Four studies were recorded for this endpoint: the study of Hoechst (1990) performed by oral route was identified as a key study and supported by the studies of Lindberg and smith (1971). These last two studies were conducted by Industrial Bio-Test Laboratories Inc.(IBT) and no information was available as to whether these studies had been audited. Based on section 3.1.8 of the Manual for investigation of HPV chemicals regarding the acceptance and use of IBT studies (OECD, last update on december 2005), when a study has not been audited by either EPA or FDA (this is the assumption here), and if the findings of the IBT study were consistent with a study conducted at a later date in another laboratory, then the data could be used but should be considered only as a supportive evidence. in this case, the IBT studies are used in support with another independent reference (hoechst, 1990) and consolidate the toxicological profile of the substance.

The last available study (Hoechst, 1974) predated official test guidelines and GLP but give some information on the potential systemic toxicity of the substance via the dermal route of exposure.

Repeated dose toxicity: oral

In a subacute (28-day) oral toxicity study (Hoechst, 1990), dioctadecyldimethylammonium chloride (90% active in 5% isopropanol 5% water) was administered by gavage in sesame oil at doses of 0, 20, 100, and 500 mg/kg to Wistar rats. The study was performed according to OECD guideline 407 in compliance with the principles of Good Laboratory Practices.Dosages were calculated on nominal concentration values.

Beginning at the 8th day (females) and 14th day (males) of treatment some high dose animals showed squatting position, abnormal gait, disregular and noisy breathing. Reduced spontaneous activity, retracted flanks and distended abdomen were also seen in some high dose females.

Body weight gain was slightly (non-significantly) lower in high dose males and females compared to the control values.

Hematology revealed significantly reduced reticulocyte counts in high dose males which were within the normal range for this species, sex and age, whereas no other red cell parameter was changed. Mean values for segmented neutrophile ratio were increased in high dose males and females due to abnormal rates in two males and three females. Lower concentrations of albumin and the albumin-globulin ratio and higher gamma-globulin values were observed in males of the high dose group (all changes were significant).

Absolute and relative organ weights of the adrenals were determined to be significantly increased in high dose males. Adrenal weights of high dose females were also higher than controls, however adrenals from three females only were weighted. Macroscopically, enlargement of the adrenals was seen in one female and discoloration of the adrenal surface was evident in three females of the high dose group. Corresponding to these observations in the adrenals, two females had cortical necrosis with peripheral granulocytic infiltration, one of this was hemorrhagic. Furthermore in a single high dose female ulceration of the forestomach was found. The NOAEL from this study was considered to be 100 mg/kg bw/d.

In a subchronic (90 -day) feeding study (Lindberg,1971), 4 male and 4 female Beagle dogs per group received dihydrogenatedtallow dimethyl ammonium chloride (purity unknown) at dose levels of 0,14,140 and 2800 ppm via the diet. The study included investigations on clinical signs, food

consumption, body and organ weights, selected parameters on haematology, clinical chemistry and urinalysis on days 45 and 90, and histopathology of numerous organs / tissues. No test substance-related effects were seen following 90 days of administration. The NOAEL of DHTDMAC in Beagle dogs from this study was established at 2800 ppm in the diet, corresponding to about 756 mg/kg body weight per day in males and 935 mg/kg body weight per day in females.

In another subchronic (90 -day) feeding study combined to a reproductive assay (Smith, 1971), dihydrogenatedtallowdimethylammonium chloride (purity unknown) was administered to rats at dose levels of 0, 7, 140 and 2800 ppm. No treatment-related mortalities were observed.

There was a slight depression in weight gain of the treated rats compared to controls, however there was no dose-response relationship. Food consumption was lower for all treated groups compared to controls but it appears that the rats were not the same age at the start of the study and there were large differences in the starting weights and subsequent weights because of this. This may explain the differences in weight gain, and the differences in food consumption as food consumption data were not corrected for body weight.

There were no differences in haematology, clinical chemistry or urinalysis between 2800 ppm rats and controls.Lesions noted at histopathological examination were those of spontaneous disease and not unusual for rats. The most frequent findings were lesions in the trachea and lungs, indicating chronic murine pneumonia. Lesions occurred in both treated and control rats.The NOAEL of DHTDMAC in rats from this study was established at 2800 ppm in the diet.

Repeated dose toxicity: dermal

in a dermal repeated dose study (Hoechst, 1974), technical grade dioctadecyldimethylammonium chloride containing 75% active in isopropanol /water was applied onto rabbit skin. The study predated official test guidelines and GLP but give some information on the potential systemic toxicity of quaternary ammonium compound, di-C16 -18 -alkyldimethyl, chloride via the dermal route of exposure.

Groups of 3 male and 3 female rabbits (strain "Gelbsilber") received 20 dermal applications (5 days per week for 4 consecutive weeks) of aqueous solutions containing 0, 0.2 and 2% DHTDMAC (corresponding to about 0, 4 and 40 mg/kg body weight per day). General behaviour, general health condition, food consumption were not influenced by the treatment. Haematology, clinical chemistry and urinalysis revealed no significant findings. Gross pathology of the animals at study termination as well as histopathological investigations revealed no substance related changes. Local skin effects in form of slight redness and foldings were observed in some of the high dose animals.

Based on the results of this study the NOAEL for systemic dermal effects was greater 40 mg/kg body weight per day (2% (v/v) aqueous test substance solution).

Based on the limitations of the 90 -day feeding studies, the subacute oral 28 -day study in rats is considered the most appropriate for evaluation purposes. This view is in line with the conclusions of the existing EU risk assessment on Dioctadecyldimethylammonium chloride.


Repeated dose toxicity: via oral route - systemic effects (target organ) glandular: adrenal gland

Justification for classification or non-classification

Based on all available data, quaternary ammonium compounds, di-C16 -18 -alkyldimethyl, chloride does not require classification with regard to repeated dose toxicity according to Regulation EC no. 1272/2008 (CLP) or Directive 67/548/EEC (DSD).