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Description of key information

No substance specific data is available for the submission substance. However as the submission substance is part of a category data from HMD (also a category member) as well as data from supporting substances (structural analogues) are thought to be adequate. Amines such as the submission substance are thought to be bioavailable after dermal, inhalation or oral exposure. Aborption via the dermal and oral route are well and metabolism includes deamination and hydroxylation. The metabolites or the unchanged compounds are mostly excreted via the urine. The half-life of amine compounds is short (few hours to 3 days).

Key value for chemical safety assessment

Additional information

There were no studies on toxicokinetics, metabolism and distribution for two members if this category – i.e. 1,2-diaminocyclohexane (DCH) and 2-methylpentane-1,5-diamine (MPMD). Nevertheless as these substances are part of the amine heads category data on hexamethylene diamine (HMD, another member of the same category) are thought to be suitable information. Moreover general information on aliphatic amines was taken as supportive data. Furthermore read-across from structural analogues of DCH (i.e. cyclohexylamine and a platinum complex with 1,4-DCH (i.e. PtCl2(cis-1,4-DCH)) was performed to collect information on cyclic primary amines and to show comparability..

The review from Greim et al. (1998) provides data on various primary and secondary amines, which were mostly aliphatic. 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 through aldehyde dehydrogenase. 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 diethylamine; Greim et al., 1998).

Furthermore there were specific investigations using 1,6-hexamethylene diamine (HMD), one of the amine heads category members. 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) 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 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 hydrochloric acid in the conducting to HDDC (David and Heck, 1983).

Only toxicokinetic data after oral and dermal application are available.

Cyclohexylamine is absorbed fast and completely in humans and animals (i.e. dog, rat, guinea pig, rabbit) after oral substance application. Maximum plasma concentrations were measured one to two hours after oral application to the test persons (2.5, 5 or 10 mg/kg bodyweight) and half-life was in between 3 and 5 hours. Maximum plasma concentrations were reached within one hour in rats and dogs, and half-lifes were 1 to 2 or 1 to 3 hours, respectively.

Using rats highest tissue concentrations were observed in lungs, spleen, liver, adrenal glands, hearts, gastro-intestinal tract and kidneys. About 8% of cyclohexylamine was bound to plasma proteins, whereas in humans approximately 33% was bound to human serum albumine. The observed distribution volume of 2.1 to 2.9 l/kg in humans, correlated well with the calculated value in rats of 2.7 l/kg.

Cyclohexylamine can freely diffuse through the placental barrier.

Approximately 90% (or even more) of cyclohexylamine were excreted via urine in humans and investigated animal species. As the renal clearance exceeds the creatinine clearance in humans, the substance is excreted via glomerular as well as tubular secretion. With increasing dose the renal clearance of cyclohexylamine decreased (from 2.5 to 10 mg/kg body weight), which showed that secretion processes were easily saturated in humans.

Cyclohexylamine is absorbed and excreted faster in mice than in rats. In rats plasma clearance was only half of clearance observed in mice. In studies with repeated oral exposure (up to 200 mg of cyclohexylamine per kg bodyweight) renal clearance of rats was saturated. Species differences in toxicological effects (i.e. atrophy of testes in rats, but not in mice) can be explained due to the linear dose dependent increase of cyclohexylamine in testes of rats, which was not linear in mice.

Using radioactive labelled cyclohexylamine (i.e. oral application of 25 or 200 mg per person or 50 to 500 mg/kg bodyweight in animals) revealed that within 24 hours only 1 to 2% in humans, less than 10% in female rats and guinea pigs and approximately 30% of the applied dose was metabolised.

In humans deamination was obvious, as cyclohexanol and trans-cyclohexane-1,2-diol were found. In dogs cyclohexanone as well as cyclohexanol was found. Hydroxylation of the carbon ring was obvious in rats, leading to cis-/trans-3 - or 4 -aminocyclohexanol isomers. In guinea pigs and rabbits both deamination as well as ring hydroxylation was obvious. Moreover in rabbits N-hydroxycyclohexylamine was identified in urine. This metabolite could not be found in urine of humans, rats or guinea pigs. Deamination was shown to be CYP450 mediated.

In summary Cyclohexylamine is absorbed well and fast with maximum blood and plasma concentrations being measured 1 to 2 hours post oral application in humans and half-life was observed to be in between 3 and 5 hours. Metabolism identified in humans included deamination. Deamination as well as hydroxylation of the carbon ring structure and N-Hydroxylation was obvious in different animal species. More than 90% of the substance was excreted via the urine (glomerular and tubular secretion). As only 1 to 2% of 25 or 200 mg of applied cyclohexylamine was metabolised in humans, most of the substance is excreted unmetabolised (Greim, 2003).

PtCl2(cis-1,4-diaminocyclohexane) was taken up into human ovarian carcinoma cells (A2780). After 4 and 24 hours 4.7 and 38 pmol compund/10EXP6 cells was found respectively, i.e. 1.3 to 2fold the amount of cisplatin which was taken up by these cells within the same timeframe (Kasparkova, 2010).

Taking into account the physical-chemical properties and the toxic effects of the members of this category as summarized belowit is concluded, that the substances of this category become systemically bioavailable after ingestion, inhalation or skin contact, but no quantitative conclusions on absorption and bioavailability can be drawn from the available data.

  • Acute toxicity was observed for the substances of this category after oral, dermal or inhalation exposure.
  • As well as toxic effects were observed for the substances of this category after subacute or subchronic oral application (most conservative NOAEL 150 mg/kg bw (OECD 422 Study on DCH, NOTOX No. 479003, 2007)).
  • Moreover the physical-chemical characteristics of the substances of the amine heads category (i.e. Molecular weight approx. 115; Water solubility > 900 g/L; Partition coefficient 0 > log Kow > 1) are in favour of absorption from the gastro-intestinal tract subsequent to oral ingestion as well as dermal absorption after skin contact (remark: amines are very alkaline, pH approx. 12).