Registration Dossier

Administrative data

Description of key information

No data are available for the primary alkylamine octadecylamines with regard to repeated dose toxicity. However, the 28-day oral toxicity test with (Z)-octadec-9-enylamines (Genamin OL 100 D) can be used based on read-across principles. This approach is in line with the existing EU risk assessment on primary alkylamines. Groups of five male and female rats recieved the test item by oral gavage at dose levels of 0, 3.25, 12.5 or 50 mg/kg body weight per day for a period of 28 days. At a dose of 50 mg/kg body weight per day clinical signs such as gait abnormalities, reduction in body weight gain and clinical pthology findings indicating mild toxic effects on the liver and kidneys were found. Effects observed at the mid-dose level (12.5 mg/kg) were slight reduction in growth. At the low dose group of 3.25 mg/kg body weight per day no effects were observed. Hence, the NOAEL of this study was placed at 3.25 mg/kg body weight per day. In accordance with the existing EU risk assessment on primary alkylamines, this value is considered to be valid also for octadecylamines and will be used for all relevant exposures by route-to-route extrapolation for this category of chemicals.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

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

Additional information

The term `primary alkylamines` stands for a group of substances which share essential chemical key aspects. From a toxicological point of view, this category of chemicals exhibite a closely related effect spectrum not only related to qualitative but also quantitative aspects. On that basis, read across of data from one primary alkylamine to another is broadly accepted and has been used in the existing EU risk assessment on primary alkylamines. Hence, the same principles are applied here.

There are no human data available on repeated dose toxicity of octadecylamines as for the whole class of primary alkylamines. Likewise no data from repeated dose studies are available for the inhalatory route of exposure. For the dermal route of exposure limited data exist from non-guideline studies which, however, do not allow to establish a dermal systemic NOAEL but which can be used to support the practicability of read-across principles. Additionally, the available data from these studies do allow the derivation of an overall minimal concentration (LOAEC local) for primary alkylamines of 0.3 % that induces skin irritation.

For the oral route of exposure information from guidline-compliant subacute 28 -day studies are available for (Z)-octadec-9 -enylamine (CAS-No. 112 -90 -3) and tallow alkylamines (CAS-No. 61790 -33 -8) which demonstrated a closely related toxicity profile. Additional data in form of a chronic feeding studies in rats and dogs exist for octadecylamine (CAS-No. 124 -30 -1). However, due to limitations in quality, these are not used as key studies but do support the derived conclusions. Based on validity considerations therefore the available data for (Z)-octadec-9 -enylamine and for tallow alkylamines are used for the assessment and read-across is applied for all primary alkylamines considered in this category approach. Leading health effects after oral exposure

were mortalities at higher dose-levels associated with precedent bad general health status and gait abnormalities, erosions of the mucosa of the gastrointestinal tract, accumulation of histiocytes in the submucosa of the distal parts of the small intestine and in the mesenteric lymph nodes, and mild toxic effects in liver and kidneys. With respect to local effects, the available data clearly demonstarte that primary alkylamines cause damage along the exposure route, i.e. the mucosa of the gastrointestinal tract. The data also indicate a cytotoxic potential at any site of contact along the exposure route and can be explained by the strong dermal irritative / corrosive nature of the primary alkylamines.

Taking the approach of applying read-across implies that the most sensitive NOAEL for the endpoint `repeated dose toxicity` is used for the assessment which was derived from the valid oral 28 -day study on (Z)-octadec-9 -enylamine (CAS-No. 112 -90 -3). The NOAEL from this study was 3.25 mg/kg body weight per day which will be also used as starting point for the route-to-route evaluations with regard to the inhalative and dermal exposure patterns. This approach is supported by findings from a 2 -year chronic toxicity study in rats and a 1 -year chronic feeding study in dogs which yielded in oral NOAELs of about 10 and 3 mg/kg body weight per day respectively. Based hereupon, additional testing was not considered necessary in the existing EU risk assessment on primary alkylamines. For the dermal route, however, a local LOAEC for effects on the dermis of 0.3 % can be applied.


Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: duodenum; digestive: ileum; digestive: jejunum; digestive: liver; urogenital: kidneys

Justification for classification or non-classification

The category approach for primary alkylamines is also applied for classification considerations, and a `Xn (harmful) with R48/22 - danger of serious damage to health by prolonged exposure if swallowed` is proposed for octadecylamines which is in line with the proposed classification from the EU risk assessment on primary alkylamines. However, it should be noted that the available data consistently points to a primarily local mode of action due to the strong irritative / corrosive properties of primary alkylamines which, however, leads to secondary effects with relevance of systemic toxicity.