Reaction mass of 7-azatridecane-1,13-diamine and hexamethylenediamine

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
There were no studies on toxicokinetics for the submission substance identified. Nevertheless there were studies available on hexamethylene diamine (HMD), one of the two main constituents of the submission substance, and general information on aliphatic amines. 
Primary amines were detected in various organs after intravenous application and metabolism found included e.g. oxidization via monoamine oxidase to aldehydes, followed by metabolic conversion to carboxylic acids via dehydration. Furthermore beta-oxidation was observed resulting in excretion of CO2. Thereby various steps are found to be dependent on the aliphatic chain length (e.g. monoamine oxidase selective binding). Some amines are excreted mostly unmetabolised in the urine (e.g. ethylamine or diethylamin). 
Investigations using 1,6-hexamethylene diamine (HMD) revealed rapid excretion (within 10 h) in urine as parent compound and N-acetyl-1,6-hexamethylene diamine metabolites after oral administration to human volunteers. Enzymatic polymorphisms might influence velocity of excretion (acetylation status).
Following oral administration of HMD-1,6-[14C]dihydrochloride (HMD salt) to male rats, about 20% of the administered dose was recovered as CO2 after 72 h while urinary and faecal excretion accounted for 47% and 27% of the administered radioactivity, respectively.
Short description of key information on absorption rate: 
No key study was identified for the submission substance and only very general information on aliphatic amines could be gathered.  In general dermal absorption of short chained amines is relatively well. Nevertheless dermal absorption decreases with increasing chain length (i.e. >= C6).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There were no studies on toxicokinetics, metabolism and distribution for the submission substance. Nevertheless as the submission substance presents a reaction mass consisting of Bis(hexamethylene)triamine (BHMT) and Hexamethylene diamine (HMD), data on the two main constituents are thought to be suitable information. Moreover general information on aliphatic amines was taken as supportive data.

One publication collected data on various primary and secondary amines. The study authors summarised that taken from these data short chained amines are absorbed relatively well through the skin. Dermal absorption decreases with increasing chain length (i.e. >= C6). In the same study data on distribution, metabolism and excretion were presented. The study authors summarised that after intravenous application of primary aliphatic amines, they were detected in the lung, liver, kidney, heart, spleen and brain. Metabolism found included oxidization via monoamine oxidase to aldehydes, followed by metabolic conversion to carboxylic acids via dehydration. Furthermore beta-oxidation was observed resulting in excretion of CO2. Monoamine oxidase selective binding was reduced with increasing chain length of the amines. Moreover the excretion via CO2 was found to be dependent on the chain length, too. Primary amines with C6 were shown to have the highest elimination rate via CO2. The rate diminishes with alterations in chain length (increasing as well as decreasing; <<C6>>). Some amines are excreted mostly unmetabolised in the urine (e.g. ethylamine or diethylamin; Greim et al., 1998).

Furthermore there were specific investigations using 1,6-hexamethylene diamine (HMD), one of the main constituents of the submission substance. In human volunteers, HMD orally administered is rapidly excreted (within 10 h) in urine as parent compound and 6 -aminohexanoic acid metabolites. Fast acetylators excreted more HMD than the slow acetylators. The available human data show considerable inter-individual variation in the elimination of the 6-aminohexanoic acid metabolite and that the elimination of HMD was based on whether the individuals were fast or slow acetylators (Brorson et al., 1990).

Following oral administration of HMD-1,6-[14C] dihydrochloride (HMD salt, HDDC) to male rats, about 20% of the administered dose was recovered as CO2 after 72 h while urinary and faecal excretion accounted for 47% and 27% of the administered radioactivity, respectively. Two peaks were found in urine with one of them, corresponding to 30 % of total radioactivity in urine and comigrating with 1,6-diaminohexane. Of several tissues examined, the highest concentrations of residual radioactivity were found in the prostate at 24 and 72 h post-administration. However, this result was not considered as relevant for HMD-related effects considering the information lacking in the materials and methods together with the low absolute values recorded in the prostate. In a read across strategy, the bioavailability of HDDC was likely to be similar as HMD considering that after ingestion, HMD is hydrolysed in the stomach by the gastric chlorhydric acid in the conducting to HDDC (David and Heck, 1983).

Discussion on bioaccumulation potential result:

There were no studies on toxicokinetics, metabolism and distribution for the submission substance. Nevertheless as the submission substance presents a reaction mass consisting of Bis(hexamethylene)triamine (BHMT) and Hexamethylene diamine (HMD), data on the two main constituents are thought to be suitable information. Moreover general information on aliphatic amines was taken as supportive data.

One publication collected data on various primary and secondary amines. The study authors summarised that after intravenous application of primary aliphatic amines, they were detected in the lung, liver, kidney, heart, spleen and brain. Metabolism found included oxidization via monoamine oxidase to aldehydes, followed by metabolic conversion to carboxylic acids via dehydration. Furthermore beta-oxidation was observed resulting in excretion of CO2. Monoamine oxidase selective binding was reduced with increasing chain length of the amines. Moreover the excretion via CO2 was found to be dependent on the chain length, too. Primary amines with C6 were shown to have the highest elimination rate via CO2. The rate diminishes with alterations in chain length (increasing as well as decreasing; <<C6>>). Some amines are excreted mostly unmetabolised in the urine (e.g. ethylamine or diethylamin; Greim et al., 1998).

Furthermore there were specific investigations using 1,6-hexamethylene diamine (HMD), one of the main constituents of the submission substance. In human volunteers, HMD orally administered is rapidly excreted (within 10 h) in urine as parent compound and 6 -aminohexanoic acid. Fast acetylators excreted more HMD than the slow acetylators. The available human data show considerable inter-individual variation in the elimination of the 6-aminohexanoic acid metabolite and that the elimination of HMD was based on whether the individuals were fast or slow acetylators (Brorson et al., 1990).

Following oral administration of HMD-1,6-[14C]dihydrochloride (HMD salt) to male rats, about 20% of the administered dose was recovered as CO2 after 72 h while urinary and faecal excretion accounted for 47% and 27% of the administered radioactivity, respectively. Two peaks were found in urine with one of them, corresponding to 30 % of total radioactivity in urine and comigrating with 1,6-diaminohexane. Of several tissues examined, the highest concentrations of residual radioactivity were found in the prostate at 24 and 72 h post-administration. However, this result was not considered as relevant for HMD-related effects considering the information lacking in the materials and methods together with the low absolute values recorded in the prostate.

In a read across strategy, the bioavailability of the dihydrochloride was assumed to be similar to HMD, considering that after ingestion HMD is protonated in the stomach by the gastric hydrochloric acid, leading to the dihydrochloride (David and Heck, 1983).

Discussion on absorption rate:

No key study was identified for the submission substance. However as the two main constituents are aliphatic amines and therefore general information on dermal apsorption of this group of chemicals was presented in this section. One publication collected data on various primary and secondary amines. The study authors summarised that taken from these data short chained amines are absorbed relatively well through the skin. Nevertheless dermal absorption decreases with increasing chain length (i.e. >= C6).