Cyclohex-1,2-ylenediamine

Endpoint summary

Description of key information

No substance specific data is available for the submission substance. However, there is data available on alipathic amines in general and structurally related substances, i.e. Cyclohexylamine (CAS 108-91-8) or a cis-1,4-diaminocyclohexane-PtII chelate complex. From these data it can be anticipated that the submission substance is bioavailable after dermal, inhalation or oral exposure. Metabolism includes deamination and hydroxylation. The metabolites or the unchanged compound are mostly excreted via the urine. The half-life of amine compounds is short (few hours).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

No substance specific data for toxicokinetic (ADME) considerations are available for 1,2-diaminocyclohexane (DCH).

 

Nevertheless, general information on aliphatic amines was taken as supportive data. Furthermore, information on cyclic primary amines was obtained from a platinum complex with 1,4-DCH (i.e., PtCl2(cis-1,4-DCH)) and a structurally similar molecule of DCH (i.e., cyclohexylamine).

 

The review from Greim et al. (1998) provides data on various primary and secondary amines, which were mostly aliphatic. After dermal application, short chained amines (primary and secondary) appear to be absorbed relatively well through the skin in general. According to the authors, dermal absorption decreases with increasing chain length (i.e. >= C6). The study authors further summarised that after intravenous application of primary aliphatic amines, these were detected in the lung, liver, kidney, heart, spleen and brain. Metabolism found included oxidization via monoamine oxidase (MAO) to aldehydes, followed by quick metabolic oxidation to carboxylic acids via dehydrogenation through aldehyde dehydrogenase (ALDH). Furthermore, beta-oxidation was observed resulting in excretion of CO₂. MAO 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). Some amines are excreted mostly non-metabolised in the urine (e.g., ethylamine or diethylamine; Greim et al., 1998).

An in vitro study from Kasparkova (2010) showed that PtCl2(cis-1,4-diaminocyclohexane) was taken up into human ovarian carcinoma cells (A2780). After 4 and 24 hours 4.7 and 38 pmol Pt/10⁶ cells was found respectively, i.e., 1.3- to 2-fold the amount of cisplatin which was taken up by these cells within the same timeframe. The result showed that cis-1,4-diaminocyclohexane facilitated the uptake of Pt into the cell (Kasparkova, 2010).

 

In another publication from Greim (2003), it was found that cyclohexylamine was 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-lives were 1 to 2 or 1 to 3 hours, respectively. Highest tissue concentrations in rats 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. Additionally, cyclohexylamine was found to freely diffuse through the placental barrier. 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. Approximately 90% (or even more) of cyclohexylamine was 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 (from 2.5 to 10 mg/kg body weight), the renal clearance of cyclohexylamine decreased, which showed that secretion processes were easily saturated in humans. In summary cyclohexylamine was 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 observed 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 was excreted non-metabolised (Greim, 2003).

 

Moreover, taking into account the physical-chemical properties and the toxic effects after exposure to the submission substance (summarised below) it is concluded that DCH becomes 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 substance after oral, dermal or inhalation exposure.


• As well as toxic effects were observed for the submission substance after subacute or subchronic oral application (most conservative oral NOAEL = 50 mg/kg bw/day (OECD 408 Study, LabCorp study no. 8439543, 2022)).


• Moreover, the physical-chemical characteristics of DCH (i.e. molecular weight approx. 116.2; water solubility: completely miscible (at 23.5 °C); partition coefficient (0 > log Kow) are generally 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).


• However, the substance is ionisable: predicted pKa1 and pKa2 (SPARC) are very close (10.35 and 7.1) and based on dissociation degree calculated via Henderson-Hasselbach equation, within the relevant pH range (pH 4 to pH 9) the compound is practically completely present as the diammonium cation in the environment and within living organisms, thus the substance does not readily diffuse across biological membranes.

 

References used, which are included in IUCLID as 'other information':

Greim H, Bury D, Klimisch H J, Oeben-Negele M, Ziegler-Skylakakis K (1998). Toxicity of aliphatic amines: structure-activity relationship. Chemosphere, Volume 36, Issue 2, Pages 271–295.

 

Greim, H. (2003). Cyclohexylamin. Gesundheitsschädliche Arbeitsstoffe, Toxikologisch-arbeitsmedizinische Begründungen von MAK-Werten, Loseblattsammlung, 36. Lfg DFG Deutsche Forschungsgemeinschaft, WILEY-VCH Verlag Weinheim.

 

Kasparkova, J.; Suchankova, T.; Halamikova, A.; Zerzankova, L.; Vrana, O.; Margiotta, N.; Natile, G.; Brabec, V (2010). Cytotoxicity, cellular uptake, glutathione and DNA interactions of an antitumor large-ring PtII chelate complex incorporating the cis-1,4-diaminocyclohexane carrier ligand. Biochemical Pharmacology, 79, 552-564.