Registration Dossier

Administrative data

Description of key information

There is no evidence on relevant intrinsic acute toxic activity of AAPB constituting a hazard to human health. Acute toxicity data on AAPBs are available for the oral and for the dermal route. Acute animal studies by inhalation route are unjustified. Due to its very low  vapour pressure, an exposure  to AAPB  vapour is negligible. Generation of aerosols may be theoretically possible, however the estimated exposure is very low. Furthermore, systemic toxicity relevant to humans did not appear neither in acute nor in repeated dose toxicity studies by other exposure routes. Considering the exposure probability and the available information on the intrinsic toxic activity of the substance, an inhalative risk to humans is unlikely and therefore, the conduct of an inhalative  toxicity study is unjustified. 

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Dose descriptor:
LD50
2 335 mg/kg bw

Additional information

There is no evidence on relevant intrinsic acute toxic activity of AAPB constituting a hazard to human health. Acute toxicity data on AAPBs are available for the oral and for the dermal route. Acute animal studies by inhalation route are unjustified. Due to its very low vapour pressure, an exposure to AAPB vapour is negligible. Generation of aerosols may be theoretically possible, however the estimated exposure is very low. Furthermore, systemic toxicity relevant to humans did not appear neither in acute nor in repeated dose toxicity studies by other exposure routes. Considering the exposure probability and the available information on the intrinsic toxic activity of the substance, an inhalative risk to humans is unlikely and therefore, conduct of an inhalative toxicity study is unjustified. The acute toxicity of the whole group of AAPBs is expected to be in the same range as variability in the fatty acid moiety is not expected to be relevant to the intrinsic systemic toxicity of the compounds.

The acute toxicity of AAPB in rats is low, with a dermal LD50 value greater than 2000 mg product/kg bw (i.e., greater than 620 mg active substance/kg bw), and an oral LD50 value of 2335 mg active substance/kg bw in a full acute toxicity study. In addition, several supporting oral acute toxicity limit tests with dose levels of 10000 or 5000 mg product/kg bw are available. Only in one of these studies, which resulted in a LD50 of >10000 mg product (35 % active substance)/kg bw (corresponding to > 3500 mg active substance/kg bw), the effective dose based on active substance covers the guideline limit dose of 2000 mg/kg bw. In the further studies a limit dose level of 5000 mg product was tested, corresponding to 1500 to 1960 mg active substance/kg bw considering the respective active substance content of the products (30 -39.2 %). In these studies LD50 was generally greater than 5000 mg/kg bw based on product. Only one study resulted in a LD50 in the range of 5000 mg product/kg bw. As details on the specific composition of this product are not available, a reason for the slightly higher toxicity of this specific product can not be given. Other than irritation, there were no clinical signs reported after acute dermal exposure. After oral exposure to high doses the most relevant findings were decreased motor activity, diarrhea, and ataxia. Prominent gross pathology findings in oral studies are hyperemia of stomach and intestine mucosa, and thickened forestomach mucosa.

Relevant data in detail

In the key study on acute oral toxicity, performed according to US Guideline Appraisal of the Safety of Chemicals in Food, Drugs and Cosmetics, FDA, 1959, which is comparable to the OECD guideline 401 (1981), 5 male and 5 female Wistar rats were given a single oral dose of Coco AAPB (30 % a.i.) as delivered by the sponsor at doses of 5.0, 6.3, 7.94, and 10.0 ml/kg bw. Animals were then observed for 14 days. This study was selected as key study considering reliability, adequacy and relevance including dose scheme and dose level based on active ingredient.

At 5.0, 6.3, 7.94, and 10.0 ml/kg bw 2/10, 2/10, 6/10, and 8/10 animals died, respectively. Most animals died within 24 hours p.a.. Weight gains were normal in all animals. Clinical signs at >= 5 ml/kg bw were decreased motor activity, coordination disturbances, abnormal body posture, piloerection, diarrhoea, skin/mucosa cyanosis and decreased body temperature with dose response relationship. At >= 7.94 ml/kg bw animals showed prone position. Clinical signs were observed at 20 minutes, 1 h and 3 h after application. Except of slight diarrhoea in one animal in dose groups 6.3, 7.94 and 10 ml/kg bw, each, all symptoms were reversible after 24 hours. 7 days after application, all surviving animals were free of clinical symptoms. Gross pathology examination of animals found dead revealed reddened gastric and intestinal mucosa. Animals sacrificed at study termination 14 days p.a. had light reddened intestinal mucosa.

Oral LD50 Combined =  7.45 ml/kg bw after 14 d

Oral LD50 Combined =  8.1 ml/kg bw after 24 h

LD50 determined refers to the test substance as delivered by the sponsor. Amount of active ingredient in test item is 30 %. The density is roughly 1 g/ml. Therefore the calculated oral LD50 combined referring to 100 % active substance = 2335 mg/kg bw after 14 d. Coco AAPB is of low toxicity based on the LD50 in males and females.

The low oral toxicity seen in this study is confirmed by a further study in which the tested dose based on a.i. also exceeds the limit dose of 2000 mg/kg bw of the recent EU and OECD guidelines. In this study, performed according to OECD Guideline 401, 1981, 5 male and 5 female Bor: WISW (SPF TNO) rats were given a single dose of Coco AAPB (a.i. 35 %) as delivered by the sponsor at a dose of 10000 mg/kg bw (limit test). Animals were then observed for 14 days. 1/5 males and 2/5 females died within 24 hours after dosing. Clinical sings observed 30-60 min after dosing were rough fur, hunched position, slowed motions, aggressiveness, slight sedation and ataxia and strong diarrhoea. 1h - 7 days after dosing: animals showed prone position, diuresis, slight trembling, shrunken flanks and tumbling. 7 days after application, all surviving animals were free of clinical signs. All animals gained weight during the observation period. Gross pathology of the deceased revealed in 1 animal hyperemia of stomach and intestine mucosa, renal pelvis and adrenals and thickened forestomach mucosa an in the 2 further decedents thin and shiny forestomach mucosa. 3/7 animals sacrificed at study termination 14 days p.a. showed focal thickened (in parts chondroic) forestomach mucosa.

Oral LD50 Combined: > 10000 mg/kg bw

LD50 determined refers to the test substance as delivered by the sponsor. Amount of active ingredient in test substance is 35 %. Therefore the calculated oral LD50 combined referring to 100 % active substance is > 3500 mg/kg bw.

Coco AAPB is of low toxicity based on the LD50 in males and females.

There are several further supporting acute oral toxicity studies, performed on products containing 30 – 39.2 % a.i. Coco AAPB in aqueous solutions, confirming the low acute toxicity. In these studies LD50 was generally greater than 5000 mg/kg bw based on product (i.e., greater than 1500 mg active substance/kg bw). Only one study resulted in a LD50in the range of 5000 mg product/kg bw. As details on the specific composition of this product are not available, a reason for the slightly higher toxicity of this specific product can not be given.

In the key study on acute dermal toxicity, performed according to EU Method B.3 and OECD Guideline 402, 5 male and 5 female CD rats (Crl:COBS CD(SD)BR) were dermally exposed to Coco AAPB (a.i. 31 %) as delivered by the sponsor for 24 hours to 10% of total body surface at a dose of 2000 mg/kg bw (limit test). Test sites were covered with an occlusive dressing. After 24 hours, the test sites were rinsed with warm water. Animals then were observed for 14 days after dosing. There were no clinical signs of systemic reaction to treatment. Sites of application of the test substance showed slight or well-defined erythema in all animals on Day 2 and/or 3. On Day 4 and Day 5, slight erythema were seen in three male and four female rats, sloughing in two male rats and one female rat and hyperkeratinisation in three female rats. All skin reactions were completely reversible by Day 6 in all animals. Slightly low bodyweight gains were recorded for three females on Day 8. All other rats achieved anticipated bodyweight gains throughout the study. Terminal autopsy findings were normal.

Dermal LD0Combined: 2000 mg/kg bw

Dermal LD50Combined: > 2000 mg/kg bw

LD0 and LD50 determined refer to the test substance as delivered by the sponsor. Amount of active ingredient in test substance is 31 %. Therefore the calculated oral LD0 and LD50 combined referring to 100 % active substance is 620 and > 620 mg/kg bw, respectively.

Although, referring to active ingredient, this study does not cover the limit guideline limit dose for acute dermal studies (2000 mg/kg bw), carrying out an additional acute dermal study which covers the guideline limit dose referring to a.i. is not justified. As seen in a reliable in vivo rat study on dermal and oral absorption, the dermal absorption does not exceed the oral absorption. The dermal absorption in a reliable in vitro study on human skin was even zero. Taking into account the information on dermal absorption and the high LD50 values determined in oral studies, it can be anticipated that an acute dermal systemic toxicity leading to classification is highly unlikely.

Justification for classification or non-classification

There is no evidence on relevant intrinsic acute toxic activity of AAPB constituting a hazard to human health. In rats, oral LD50 values are greater than 2000 mg/kg bw based on active substance insofar as tested and generally greater than 5000 mg/kg bw based on product (i.e., greater than 1500 mg active substance/kg bw referring to products with 30-39.2 % a.i. in aqueous solution). The dermal LD50 value is greater than 2000 mg/kg bw based on product (i.e., greater than 620 mg active substance/kg bw). Although, referring to active ingredient, this study does not cover the limit guideline limit dose for acute dermal studies (2000 mg/kg bw), conduct of an additional acute dermal study for classification and labelling purposes which covers the guideline limit dose referring to a.i. is not justified. As seen in a reliable in vivo rat study on dermal and oral absorption, the dermal absorption does not exceed the oral absorption. The dermal absorption in a reliable in vitro study on human skin was even zero. Taking into account the information on dermal absorption and the high LD50 values determined in oral studies, it can be anticipated that an acute dermal systemic toxicity leading to classification is highly unlikely.

The conduct of acute inhalative animal studies is also unjustified, as due to its very low vapour pressure, an exposure to AAPB vapour is negligible. Generation of aerosols may be theoretically possible, however the estimated exposure is very low. Furthermore, systemic toxicity relevant to humans did not appear neither in acute nor in repeated dose toxicity studies by other exposure routes. Considering the exposure probability and the available information on the intrinsic toxic activity of the substance, an inhalative risk to humans is unlikely and therefore, the conduct of an inhalative toxicity study is unjustified.

Thus, AAPB does not comply with the classification requirements regarding acute toxicity outlined in regulation (EC) 1272/2008 or the former European directive on classification and labelling 67/548/EEC.