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Description of key information

Reliable data on repeated dose toxicity of AAPBs are available for the oral route from 28-day and 90-day gavage studies as well as from a 90-day feeding study in rats. In these studies performed according to the corresponding OECD Guidelines on C8-18 AAPB and Coco AAPB, up to and including the highest tested doses, no indication of any systemic toxicity of AAPBs relevant in view of a potential serious health risk for humans was found. NOELs derived from the 90-day gavage and the 90-day feeding study relevant in view of a potential serious health risk for humans were the highest tested doses of 300 mg a. i./kg bw/day (corresponding to 1000 mg product (a. i. ca. 30 %)/kg bw/day) and 1 % in feed (corresponding to 731 mg product/kg bw/day and 247 mg a. i./kg bw/day based on measured food consumption), respectively.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
300 mg/kg bw/day

Additional information

Reliable data on repeated dose toxicity of AAPBs are available from 28-day and 90-day gavage studies as well as from a 90-day feeding study in rats.

In a subchronic toxicity study according OECD guideline 408 (1991), C8-18 AAPB (30.3 % a. i.) was administered to 10 male and 10 female Sprague-Dawley rats per dose by gavage at dose levels of 0, 250, 500, 1000 mg/kg bw/day (corresponding to ca. 75, 150, and 300 mg active ingredient/kg bw) for 90 days. The aqueous test item was further diluted with aqua destillata to achieve the scheduled doses. Concentrations in test formulations were analytically verified.

The substance was tolerated without any systemic effects. Up to and including the highest dose tested of 1000 mg/kg bw, there were no compound related effects in mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, organ weights including weights of ovaries and testes, systemic organ pathology and histopathology including inspection of epididymides, testes, prostate, seminal vesicle, ovaries, mammary gland and uterus.

The only treatment related effect seen in this study was a local inflammatory response at the site of application (forestomach gastritis) most probably caused by an irritant effect of the test item. These appeared in gross pathology findings in form of some stomach ulcer at fundus and cardia region in one male and one female rat at 1000 mg/kg bw/day, and in microscopic findings in form of squamous hyperplasia, submucosal edema, inflammatory cell filtration at a dose level of >= 500 mg/kg bw/day (2/10 male and 2/10 female rats at a dose level of 500 mg/kg bw, and at 1000 mg/kg bw in 6/10 males and 3/10 females). The severity of the forestomach gastritis was judged by the pathologist as minimal to moderate. Forestomach gastritis is a common finding in rat gavage studies on irritative test items. This treatment related finding is generally forced by the gavage exposure regime with constantly repeated bolus ingestion, normally reversible after cessation of treatment and almost missing when the test items are applicated via food or the drinking water. The reversibility of AAPB induced rat forestomach gastritis and its missing when the test item is applicated via food have been proven in a subacute gavage study with recovery group (Cognis, 1991) and in a subchronic feeding study (Unilever, 1994), respectively. A forestomach or a functional correlate to the rat forestomach is missing in humans. The irritative rat forestomach gastritis is judged as not relevant in view of a potential serious health risk for humans due to significant different anatomic situation and exposure probability in humans.

Therefore,the NOEL derived from this study relevant to human DNEL calculation is the NOEL for systemic effects which is the highest tested dose of 300 mg a. i./kg bw/day (= 1000 mg product (a. i. ca. 30 %)/kg bw/day.

The LOEL local effects (500 mg/kg bw/day, corresponding to ca. 150 mg active ingredient/kg bw), based on local irritative effects at the site of application (forestomach gastritis), is judged as not relevant to humans due to significant different anatomic situation and exposure probability in humans.

Comparable effects at the same dose level were also seen in the 28 -day gavage study, in which in addition, reversibility of forestomach gastritis was proved.

In a further subchronic toxicity study according OECD guideline 408, Coco AAPB (a. i. 33.8 %) was administered to 12 male and 12 female Colworth Wistar rats per dose via food at dose levels of 0.00 %, 0.04 %, 0.10 %, 0.40 % and 1.00 % (corresponding to 0, 28, 71, 288 and 731 mg product/kg bw (9.5, 24, 97 and 247 mg a. i./kg bw/day)) for 90 days. Additional animals in satellite groups (control and high dose, 5 males and 5 females, each) were kept for further 32 days without treatment to detect recovery from, or persistence of toxic effects. Concentrations in diet formulations were analytically verified and substance intake was calculated from recorded food consumption.

The substance was tolerated without any systemic effects relevant in view of an potential serious health risk for humans. Up to and including the highest dose tested of 1 % in feed (corresponding to 731 mg product/kg bw/day and 247 mg a. i./kg bw/day), there were no dose related effects on mortality, clinical signs, body weight, food consumption, water consumption, haematology, urinalysis and histopathology including inspection of seminal vesicles, prostate, epididymides, testes, mammary glands, ovaries and fallopian tubes, uterus, cervix and vagina.

The only treatment related effects ascertainable at termination of treatment but not after the recovery period were reduced food conversion efficiencies and organ weight changes in the caecum and liver. The enlarged caecum observed at necropsy in some male and female rats fed 0.40 % and 1.00 % test item was reflected in the statistically significant increases recorded in the absolute and relative, full and empty caecal weights for both male and female rats fed 1.00 % test item. These animals fed 1.00 % test item also showed reduced absolute and relative liver weights, reduced abdominal fat depots corresponding to the reduced food efficiency and several possibly associated plasma and serum biochemical changes. There was no histopathological correlate for the organ weight changes in caecum and liver. All alterations were completely reversible in the recovery group after 32 days without treatment.

Enlargement of the rat caecum with or without subsequent effects on caecum weight, food conversion and nutritional status is a common and frequently response to feeding poorly-absorbable or osmotically-active substances, such as xylitol, sorbitol, sucralose or natural sugars like d-ribose, general changes in nutritional diet composition or application of compounds with effects on the caecal microflora. In the absence of histopathological alterations, the rat caecum changes are taken as physiological adaptive responses and considered to be of no toxicological significance. An increase in liver weight without any histopathological correlate is commonly not considered to reflect an adverse effect but should be considered as an adaptive metabolic response which in known to be reversible. As also in this study, the increase in liver weight was without any histopathological correlate and has been proved to be reversible, the liver weight alteration is not considered to be an adverse effect relevant in view of an potential serious health risk for humans.

Therefore,the NOEL derived from this study relevant in view of a potential serious health risk for humans is the highest tested dose of 1 % in feed (corresponding to 731 mg product/kg bw/day and 247 mg a. i./kg bw/day).

The LOEL is 0.4 % in feed (corresponding to 288 mg product/ kg bw/day and 97 mg a. i. /kg bw/day), based on transient effects on food conversion efficiencies and organ weights of caecum and liver, judged as not relevant to humans in view of a potentially serious health risk due to missing histopathological correlate and proved reversibility.

Justification for classification or non-classification

There is no evidence for intrinsic toxic properties of AAPBs relevant to humans obtained from the results of reliable, relevant and adequate subacute and subchronic oral studies on rats.

Therefore no classification is required for repeated dose toxicity according to CLP, EU GHS (Regulation (EC) No 1272/2008) and directive 67/548/EEC with respect to systemic toxicity.