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EC number: 700-570-7 | CAS number: 1217271-49-2
The test item is an almost colourless and odourless liquid at ambient conditions.Its molecular weight is 422.65 g/mol. The substance hydrolyses rapidly (within less than a minute at 25 °C) upon contact with water. Therefore, physico chemical parameters of the two hydrolysis products are also considered relevant in regards to toxicokinetic assessment. Water solubility was estimated by QSAR calculation for the parent substance to be 6.64 mg/L. Hydrolysis product 1 (i. e. Aldehyde M) could not be determined since this substance hydrolyses itself very rapidly (half-life = ca. 1 h at 25 °C). Hydrolysis product 2, Hexamethylenediamine, (HMD) is well soluble in water with a water solubility of 637 g/L.
Regarding logPow values, there was no such value determined for the parent, logPow of Aldehyde M was determined to be 1.69 and for HMD 0.5 at 25 °C, respectively.The vapour pressure of the parent substance, The test item is very low, i. e. 0.0047 Pa at 20 °C) and a similarly low volatility can be anticipated based on low vapour pressures of 52 and 27 Pa for Aldehyde M and HMD, respectively.
Bioavailability via oral route is strongly linked to physico-chemical properties of the substance (ECHA Guidance, 2017). Generally, absorption in the gastrointestinal tract (GIT) is favored for substances with a molecular weight below 500 g/mol and a logPow in the range of -1 to 4. The test substance itself having a molecular weight of 422.65 g/mol would therefore be on the edge of being favored for absorption. However, the test item is hydrolytically unstable and will degrade rapidly to its hydrolysis products within an aqueous environment such as body fluids. Therefore, molecular weights of hydrolysis products, i. e. 171.2 and 116.2 g/mol, are also taken into account. Both indicate well absorption. In addition, logPow values of 1.69 (Aldehyde M) and 0.4 (HMD) are also meeting the general criteria for becoming readily bioavailable.
The above considerations are supported by experimental toxicity data. Even though no adverse signs of toxicity were observed in an acute as well as an repeated oral toxicity study in rats with the test item, clinical signs indicating diuresis and increased urine excretion are likely associated to the test item or its hydrolysis products.
In the acute oral toxicity study with female rats, the test item did not induce any mortality, leading to an LD50 of > 2000 mg/kg bw. No clinical signs were noted. No pathological changes could be observed after the observation period of 14 days.
Repeated administration of the test item to rats revealed clinical signs of such as darker than normal and wet bedding material, nuzzling up the bedding material (male and female) and salivation (male) at 1000 mg/kg bw/day. Darker than normal and wet bedding material – indicative of diuresis – was detected in each cage of animals administered with 1000 mg/kg bw/day from Day 5 up to the end of the treatment period. In the lack of related findings in clinical chemistry parameters or in organ pathology, these findings were considered to be not adverse. Salivation and nuzzling up the bedding material were seen transiently and were with short duration. Body weight development as well as food consumption was unchanged when comparing the treated groups the control animals. Further, no other signs of toxicity could be found in regards to reproductive performance or offspring development.
Overall, the increased excretion activity of the kidneys indicates that the parent and or its hydrolysis products become systemically available after oral administration and subsequently are to be eliminated thereafter. In this study, dark coloration of the bedding material was described to not only result from moisture but may also be indicative for a dark coloured metabolite. These findings indicate that the compound or its hydrolysis products becomes bioavailable and are of low toxicity.
No data on repeated dose toxicity are available for Aldehyde M. Based on an acute oral toxicity study Aldehyde M induced central nervous system and emotion symptoms such as decreased activity in all three animals of the first step on the treatment day 30 min after the treatment. In the second step, CNS - and emotion symptom as decreased activity was observed in one animal (out of three) on the treatment day between 30 min and 1 hour after the treatment. In the other two animals, no clinical symptoms were observed on the day of the treatment and during the 14-day observation period. The body weight development was normal in all animals. Therefore, well and rapid absorption of Aldehyde M upon oral ingestion can be anticipated.
HMD is classified for acute oral and dermal toxicity, giving indication that it is readily absorbed via both routes.
No data on repeated dose toxicity via the oral route are available, only via the inhalation and the dermal route. Based on data with a structural analogue substance, HMD is considered to also become readily and rapidly bioavailable by the oral route.
Due to its low vapour pressure (<0.01 Pa at 20 °C) and high boiling point (> 150 °C) it is unlikely that the test item itself will be available as gas or vapour in the air. However, if it was the case absorption via inhalation route is considered possible due to the rapid hydrolysis upon contact with mucosal membranes of the respiratory tract. This would enable uptake of hydrolysis products which are smaller in molecular size and of better water solubility facilitating absorption across the respiratory tract epithelium by passive diffusion. This assumption is supported by repeated dose toxicity data available with HMD. Based on effects observed in this study, readily bioavailability of HMD upon inhalation can be assumed.
Similarly, based on physicochemical properties of the test item penetration through the skin is assumed to be low. It is generally accepted that if a compound’s water solubility falls between 1-100 mg/L, absorption can be anticipated to be low to moderate. This assumption based on the physicochemical properties of the test item is further supported by the results achieved from the LLNA showing skin sensitising properties. Thus, a small amount of the compound or its hydrolysis products might penetrate the skin. Noteworthy, the test item is classified as irritating to the skin and eye, thus penetration by dermal damage may also take place. However, since HMD, one of the hydrolysis products, is classified for acute dermal toxicity, the absence of pronounced clinical signs in the acute dermal toxicity study indicate low amount of hydrolysis when administered on the bare skin. HMD itself is classified as skin corrosive and Aldehyde M as both skin and eye corrosive. Therefore, it is anticipated that hydrolysis of the test item on the skin does not take place in a significant amount, since effects as expected from its hydrolysis products were not observed. This further supports the assumption that the test item itself will not be readily absorbed via the skin. Nevertheless, the test item was found to be a skin sensitizer indicating that at least to some small extent the test item itself or its hydrolysis product was absorbed.
Taken together, physicochemical properties and experimental data indicate bioavailability of the test item and/or its hydrolysis products via oral, dermal and inhalation route.
Assuming that the test item or its hydrolysis products become bioavailable to the organism following oral, dermal or inhalation intake, they may be distributed into the body fluids due to moderate to high hydrophilicity and low logPow values of both hydrolysis products. In turn the extracellular concentration may be higher than intercellular concentration. As outlined before, it is expected that the test item itself does not reach the blood system before being hydrolysed to a significant extend. The physicochemical properties of the hydrolysis products favour systemic distribution. The results from the repeated dose toxicity study with the test item indicate that the kidneys are the primary target organs based on the increased excretion activity. Due to the rapid hydrolysis reaction in the body, it is unlikely that the test item can bioaccumulate. Moreover, both hydrolysis products are highly water soluble and have a low log Pow value and are thus also of no concern for bioaccumulation.
Based on the chemical structure of the test item and its hydrolysis products they may be metabolized by Phase I enzymes while undergoing functionalization reactions aiming to increase the compound’s hydrophilicity. Furthermore, Phase II conjugation reactions may covalently link an endogenous substrate to the parent compound or the Phase I metabolite in order to ultimately facilitate excretion.
Metabolism to more toxic metabolites is not expected, neither for the parent nor for the degradation products, based on the results obtained in the in vitro bacterial reverse mutation test (Ames test) as well as the HPRT and in the chromosome aberration test in the presence of a metabolic activation system.
As discussed above, the test item will hydrolyse rapidly in an aqueous environment and will probably not be excreted as such. Due to their small molecular weight and moderate to well water solubility both hydrolysis products are rather excreted via urine than faeces. This assumption is supported by observations made in the repeated dose oral toxicity study, where significantly increased urine excretion up to diuresis was observed in the high dose treated animals. Generally, in the rat renal excretion is facilitated for water-soluble molecules with a molecular weight below 300 g/mol.
Based on its physicochemical characteristics, particularly water solubility and logPow absorption via oral, inhalation and dermal route is expected to be low to moderate for the test item itself. However, due to the rapid hydrolysis reaction in aqueous environment its hydrolysis products are considered to become bioavailable via the oral and inhalation route and albeit to a less extend via the dermal route. Based on their physicochemical properties the test item itself as well as its hydrolysis products are unlikely to bioaccumulate. Hydrolytic and metabolic conversion is expected and conjugation of Phase I-metabolites may further increase hydrophilicity. Excretion via urine is assumed to be the main excretion pathway of degradation products and metabolites formed based on observations in repeated dose toxicity study.
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