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Description of key information

No repeated dose toxicity data are available for the substance MK92K and no testing is proposed. Due to the corrosive nature of the substance and its likely low systemic absorption, it is considered that the effects of the substance are very likely to be limited to the site of contact. Testing for repeated dose toxicity cannot therefore be supported on scientific grounds an additionally for reasons of animal welfare. 

Key value for chemical safety assessment

Additional information

No repeated dose toxicity data are available for the substance MK92K and no testing is proposed. Due to the corrosive nature of the substance and its likely low systemic absorption, it is considered that the effects of the substance are very likely to be limited to the site of contact. Testing for repeated dose toxicity cannot therefore be supported on scientific grounds an additionally for reasons of animal welfare. The dose levels used in any studies of repeated dose toxicity would be limited by the corrosivity of the substance in order to avoid significant local effects on the gastrointestinal tract, skin or respiratory tract. The results of any studies would not therefore add any value to the database or be of any relevance to the risk assessment.

 

Published reviews of the available repeated dose toxicity data for related quaternary ammonium compounds are available in documents published by the US and Canadian authorities. The data do not indicate any notable or clearly treatment-related systemic toxicity and demonstrate that the effect of exposure to this group of compounds is primarily local. The results confirm the findings of older, published studies.

 

Read-across between different quaternary ammonium compounds is considered to be appropriate as the available metabolism data do not identify any molecular cleavage, which would liberate different chemical species and potentially result in significantly different toxic effects.

  

Repeated dose oral toxicity

 

The substance MK92K is corrosive and (based on its physicochemical properties and read-across from similar quaternary ammonium compounds) is considered likely to be poorly systemically absorbed following oral administration. It is therefore very likely that the effects of the repeated oral administration of MK92K in an animal study will be largely local (due to irritation/corrosion at the site of contact), with little or no systemic effects other than those secondary to the effects of the substance on the gastrointestinal tract.

 

 Repeated dose oral toxicity data for DDAC

 

The available repeated dose toxicity data for the related quaternary ammonium compounddidecyldimethylammonium chloride (DDAC) have been reviewed by the US EPA (2006) and also in a Canadian review (Henderson, 1992). The data are summarised below.

 

90-day rat study

 

A study was performed in rats at dietary dose levels of up to 3000 ppm (calculated to be equivalent to approximately 300 mg/kg bw/d using default conversion factors). High (80%) mortality was seen at the highest dose level of 3000 ppm; surviving rats in this group showed markedly reduced bodyweights associated with pathological changes of the gastrointestinal tract. The EPA document notes gross pathological observations and non-neoplastic microscopic findings at the top dose level including a higher incidence of glycogen depletion in the liver and contracted spleens; the Canadian review considers these effects to be secondary to the bodyweight effects seen in this group. Deaths were attributed to severe effects on the gastrointestinal tract and shock. No treatment-related effects were seen at a dose level of 1000 ppm (100 mg/kg bw/d).

 

90-day mouse study

 

High mortality was observed in a 90-day dietary mouse study performed at dose levels of up to 3000 ppm DDAC (calculated to be equivalent to approximately 600 mg/kg bw/d using default conversion factors). Treatment with 3000 ppm resulted in virtually 100% mortality within a few days due to wasting and dehydration secondary to local effects on the gastrointestinal tract. Reduced weight gains were also apparent at 1000 ppm (200 mg/kg bw/d); no effects were seen at lower dose levels.

 

90-day dog study

 

In a feeding study, groups of dogs were administered DDAC at dietary dose levels of 0, 5, 15 and 50 mg/kg bw/d. Marked decreases in weight gain, food consumption and food efficiency were seen at the top dose level. Clinical chemistry, haematology, urinalysis, and pathology did not reveal any treatment-related systemic effects at any dose level.

 

One-year dog study

 

Groups of dogs were gavaged with DDAC at dose levels of up to 30 mg/kg bw/d. Treatment at the top dose level resulted in severe effects on bodyweights and food consumption which necessitated the cessation of treatment and a consequent reduction of the dose level to 20 mg/kg bw/d. Findings at 10 and 20 mg/kg bw/d of emesis, salivation and diarrhoea are attributable to the local effects of the test material on the gastrointestinal tract. The Canadian review notes some limited evidence of systemic toxicity (decreases in erythrocyte and clinical chemistry parameters) at 20 mg/kg bw/d; the EPA document considers haematological findings in this study to be normal but notes decreased cholesterol levels in females. However this finding may equally be secondary to the local effects of the test material.

 

2-year rat study

 

Reduced weight gain and food consumption were seen at the highest dose level of 1500 ppm (equivalent to 75 mg/kg bw/d). The EPA document notes increased incidence of sinusoidal blood, haemosiderosis and histiocytosis in the mesenteric lymph nodes of high dose animals; however the Canadian review does not consider these findings to be clearly treatment-related. No carcinogenicity was observed in this study.

 

2-year mouse study

 

Reduced weight gain and food consumption but no treatment-related systemic effects were seen at the highest dose level of 1000 ppm (equivalent to 150 mg/kg bw/d). No carcinogenicity was observed in this study.

 

 

Repeated dose oral toxicity data for ADBAC

 

The available repeated dose toxicity data for the related quaternary ammonium compoundalkyldimethyl benzyl ammonium chloride (ADBAC) have been reviewed by the US EPA (2006). A number of older published studies are also available. The data are summarised below.

 

90-day rat studies

 

Administration of ADBAC at dietary dose levels of up to 8000 ppm resulted in mortality associated with reduced weight gain and food consumption and gastrointestinal pathology at 4000 and 8000 ppm; reduced weight gains were also seen at 1000 ppm. Systemic effects were limited to histopathological observation of haemorrhage of the brain and lungs at 4000 ppm.

 

Alfredsonet al (1951) administered ADBAC in the diet at dose levels of up to 1% (10000 ppm, equivalent to approximately 1000 mg/kg bw/d for 12 weeks. Mortality was seen at levels of 0.5% and 1%.

 

15-week dog study

 

Alfredsonet al(1951) performed a dietary study in which dogs were fed ADBAC at dietary dose levels of up to 1% for 15 weeks. Deaths occurred at dose levels of 0.5% and higher, with effects on food consumption and bodyweight seen at dose levels of 0.125% and higher. Gross necropsy revealed changes in the stomach and small intestine including necrosis, haemorrhage and the presence of blood. The authors conclude that the findings of this study are consistent with a ‘pure gastrointestinal irritant’.

 

1-year dog study

 

Groups of dogs were administered ADBAC in the diet at dose levels of up to 1200 ppm. Reduced food consumption and weight gain was seen in both sexes at 1200 ppm; reduced weight gain was seen in females at 400 ppm.

 

2-year rat studies

 

Groups of rats were administered ADBAC in the diet at dose levels of up to 2000 ppm (equivalent to a mean achieved intake of 116 mg/kg bw/d). Findings in this study were limited to reduced weight gain and lower bodyweights in both sexes at 2000 ppm. There was no evidence of systemic toxicity from clinical chemistry, haematology or urinalysis; pathological investigations did not reveal any effects of treatment. There was no evidence of carcinogenicity in this study (EPA, 2006).

 

In an older study (Fitzhugh & Nelson, 1948), administration of ADBAC in the diet to weanling albino rats at a level of 0.5% (5000 ppm; 500 mg/kg bw/d) resulted in 100% mortality within ten weeks. Effects on bodyweight were seen in this group and also at lower dose levels of 0.25% (2500 ppm) and 0.125% (1250 ppm). Clinical signs (anorexia and diarrhoea) were noted at the high dose level; necropsy revealed caecal distension.

 

The results of this study contrast with those of Harshbarger (1942; reported in Alfredson et al, 1951) in which no bodyweight effects were noted at a dietary dose level of 0.3% (3000 ppm) after ‘a few weeks’.

 

In a further two-year study (Shelanski 1949, reported in Alfredsonat al, 1951), lower bodyweights were reported in rats gavaged were ADBAC at a dose level of 25 mg/kg bw/d, with no effects apparent at 5 or 12.5 mg/kg bw/d.

 

Alfredson et al (1951) administered ADBAC in the diet at dose levels of up to 0.5% (5000 ppm, equivalent to approximately 250 mg/kg bw/d. Mortality was seen at 0.5% largely during the first three weeks of the study; anorexia, diarrhoea, reduced weight gain and food consumption were also seen in this group. Haematology did not reveal any effects of treatment in any group. Gross necropsy revealed the distension of the caecum with fluid, gastritis and the presence of red/brown material in the stomach; histopathology revealed necrosis of the gastric mucosa, with no effects in other organs. The authors conclude that the findings are consistent with a ‘pure gastrointestinal irritant’.

 

2-year mouse study

 

Groups of mice were administered ADBAC in the diet at dose levels of up to 1500 ppm (equivalent to a mean achieved intake of 230-290 mg/kg bw/d). Findings in this study were limited to reduced weight gain and lower bodyweights in both sexes at 1500 ppm. Pathological investigations did not reveal any effects of treatment. There was no evidence of carcinogenicity in this study.

Justification for classification or non-classification

No data are available, however it is predicted that the systemic toxicity of the substance will not be significant. No classification for repeated dose toxicity is therefore proposed according to the CLP Regulation (1272/2008).