Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Results have been read-across from a suitable structural analogue substance, Fatty acids, C18 unsaturated, reaction products with diethylenetriamine (also referred to a Tall oil diethylenetriamine imidazoline).
A combined repeated dose/reproduction screening toxicity study according to OECD 422 with Tall oil diethylenetriamine imidazoline resulted to a NOAEL of 30 mg/kg bw/day based on the increased incidence/severity of macrophage foci in the mesenteric lymph node observed at 100 mg/kg bw/day, the highest dose tested.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

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

Additional information

Discussion on read-across:

The result of a OECD 422 study has been read-across from Fatty acids, C18 unsaturated, reaction products with diethylenetriamine (also referred to as Tall oil diethylenetriamine imidazoline). This read-across substance is a starting material in the manufacture of Fatty acids, C18 unsaturated, reaction products with diethylenetriamine, acetate salts, which is a complex mixture of reaction products derived from the neutralisation of fatty acid-diethylenetriamine imidazoline (the read-across substance) with acetic acid. It is therefore considered that the results obtained from studies on Fatty acids, C18 unsaturated, reaction products with diethylenetriamine are suitable to read-across to and for use in the evaluation of Fatty acids, C18 unsaturated, reaction products with diethylenetriamine, acetate salts.

The below results for Tall oil diethylenetriamine imidazoline can be considered as a worst-case assessment for Fatty acids, C18 unsaturated, reaction products with diethylenetriamine, acetate salts. This is due to the expectation that the neutralisation of the Tall oil diethylenetriamine imidazoline to the acetate salts form would be anticipated to decrease the toxicity of the substance (if the neutralisation was to have any toxicological effect).

Tall oil diethylenetriamine imidazoline is corrosive to the skin (and presumed corrosive to the eyes). Fatty acids, C18 unsaturated, reaction products with diethylenetriamine, acetate salts is not corrosive to the skin, but is severely irritating and classified as a skin irritant. Therefore, the OECD 422 results obtained from Tall oil diethylenetriamine imidazoline may again represent a worst case assessment for the actetate salts form, as some of the effects seen in the study were effects due to the local irritancy/corrosivity of the tested substance and application of test substance, rather than true systemic effects. These effects could be anticipated to be decreased for the actetate salts.

Based on this information it was considered that in the interests of animal welfare, a OECD 422 study conducted using

Fatty acids, C18 unsaturated, reaction products with diethylenetriamine, acetate salts was not justified, and that the substances repeated dose toxicity could be adequately assessed using the results obtained from a OECD 422 study conducted using Tall oil diethylenetriamine imidazoline, which are discussed below.

OECD 422 study with Tall oil diethylenetriamine imidazoline:

A combined repeated dose/reproduction screening toxicity study according to OECD 422 has been performed with Tall oil diethylenetriamine imidazoline. A rangefinder and maximum tolerated dose concluded that the maximum tolerated dose for Tall oil diethylenetriamine imidazoline when administrated orally for 10 days to rats is 250 mg/kg/day.

 

In the full study Tall oil diethylenetriamine imidazoline was administered by daily oral gavage to male and female Wistar Han rats at dose levels of 0, 10, 30 and 100 mg/kg/day. The males were exposed for 2 weeks prior to mating, during mating, and up to termination (for 28 days). The females were exposed for 2 weeks prior to mating, during mating, during post-coitum, and at least 4 days of lactation (for 42-55 days).

The changes in clinical biochemistry parameters in animals at 100 mg/kg/day at the end of the treatment period were generally slight in nature (i.e. mostly within the normal range) and were fully reversible after a 14-day recovery period in males. Moreover, no morphological changes were observed that would support these changes which included higher alanine and aspartate aminotransferase activity and creatinine level in males, and lower total protein and urea level in males and females respectively. Therefore, these changes were not considered to be of toxicological relevance.

The lower prostate and seminal vesicle weight, and lower prostate to body weight ratio at the end of the treatment period in males at 100 mg/kg/day were absent at the end of the recovery period in males, and were not supported by any histopathological lesions or reproductive toxicity. No toxicological relevance was ascribed to these findings.

Histopathology revealed foamy macrophage foci in the ileum of all selected males and females at 100 mg/kg/day, a slightly increased incidence and degree of macrophage foci in the mesenteric lymph node of both sexes at 100 mg/kg/day, and increased incidence of lymphoid atrophy in the thymus of females at 100 mg/kg/day. At the end of the 14-day recovery period for males, foamy macrophage foci in the ileum had completely resolved, whilst macrophage foci in the mesenteric lymph node persisted at higher severity than observed at the end of treatment. Given the persistence of this finding it was considered to be of an adverse nature.

No toxicologically significant changes were noted in any of the remaining parental parameters investigated in this study (i.e. clinical appearance, functional observations, body weight, food consumption, haematology and macroscopic examination).

Based on the increased incidence/severity of macrophage foci in the mesenteric lymph node at both the end of treatment and recovery period in males, a parental No Observed Adverse Effect Level (NOAEL) of 30 mg/kg/day was derived.

 

Considering that macrophages in the mesenteric lymph nodes are a local, porte d’entrée related effect due to the route of application, and not a systemic effect per se, the level of 100 mg/kgbw/day could also be argued to represent a NOAEL for systemic effects.

 

To determine the NOAEL for repeated dose more accurately, a full 90-day study (OECD 408) is proposed for Tall oil diethylenetriamine imidazoline.

The available data on amidoamines/imidazolines (AAI) indicated that for AAI based on lower polyethyleneamines (EA) higher toxicity is observed compared to AAI based on higher EA. Therefore, AAI derived from diethylenetriamine (DETA) are anticipated to show more toxicity than those derived from triethylenetetramine (TETA) and tetraethylenepentamine (TEPA).

Justification for classification or non-classification

Classification for STOT-RE Cat. 2 is required in case of significant toxic effects at levels ≤ 100 mg/kgbw/d in case of standard 90-day study. In case of 28-day studies this can be multiplied by 3.

A combined repeated dose/reproduction screening toxicity study according to OECD 422 with Tall oil diethylenetriamine

resulted in a NOAEL of 30 mg/kg bw/day based on the increased incidence/severity of macrophage foci in the mesenteric lymph node observed at 100 mg/kg bw/day, the highest dose tested.

These macrophages in the mesenteric lymph nodes could be regarded as a local, porte d’entrée related effect due to the route of application, and not a systemic effect per se. Therefore, the level of 100 mg/kgbw/day could also be argued to represent a NOAEL for systemic effects.

It is not likely that serious toxicity could be expected at levels requiring to consider classification for STOTS-RE.

Given that the toxicity of Fatty acids, C18 unsaturated, reaction products with diethylenetriamine, acetate salts, is not anticipated to be higher than that of Tall oil diethylenetriamine, it is considered that classification for STOTS-RE is not required for the acetate salts.