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EC number: 925-259-5
CAS number: 140921-24-0
Based on physico-chemical characteristics, particularly water solubility and octanol-water partition coefficient absorption via oral and inhalation route is expected to be low. However, slow dermal absorption could not be excluded. Incozol EH is immediately hydrolysed into “fully hydrolysed Incozol EH” and 2-ethylhexanal. If absorbed, passive diffusion and active transport through aqueous pores is likely to be an entry route to the systemic circulation. No metabolic activation of Incozol EH and its hydrolysis products is expected. Excretion via faeces is assumed to be the main excretion pathway of “fully hydrolysed Incozol EH” due to its molecular weight. Oxidation and conjugation products of 2-ethylhexanal were shown to be excreted via urine. Based on hydrolytical conversion of Incozol EH bioaccumulation is not likely to occur based on physico-chemical properties of the hydrolysis products.
Toxicological profile of Incozol EH
An acute oral toxicity study conducted with Incozol EH using rats revealed a LD50 value of greater the 2000 mg/kg bw (Bayer, 1991). Signs of intoxication were rough coat, increased salivation and apathy, observed within 24 hours post-treatment. In a second study diuresis was observed when Incozol EH was administered once orally to rats at 5000 mg/kg bw. No animal died. No mortality and no systemic signs of toxicity occurred in an acute dermal toxicity study with the test item (Bayer 1992). The LD50 value was therefore determined to be greater than 2000 mg/kg bw. No dermal irritation symptoms were observed in all animals. No acute inhalation toxicity study was performed with Incozol EH as inhalation exposure is considered negligible due to its low vapour pressure.
In two in vivo skin irritation studies conducted with Incozol EH on rabbits no skin irritation was observed (Bayer 1978, Bayer 1991). Incozol EH did not cause severe eye irritation in two in vivo eye irritation studies on rabbits (Bayer 1978, Bayer 1991). A guinea pig maximisation test (GPMT) revealed that Incozol EH has skin sensitising properties (Bayer, 1992).
Incozol EH did not induced reverse mutations in two bacterial reverse mutation tests (Ames test) with four Salmonella typhimurium strains both in the absence and presence of a metabolic activation system (Bayer, 1988, 1991). An in vivo micronucleus test on mice revealed no increase of micronucleated normochromatic erythrocytes. The test substance was therefore judged to be not clastogenic in vivo (Bayer, 1992). Additionally, the test item did not induce statistically significant increases in DNA strand breaks at any of the tested dose levels in liver or stomach cells in an in vivo Comet assay.
A 28 day repeated dose toxicity study with Incozol EH was performed in male and female Wistar rats. The chemical was administered orally (by gavage) once a day for a total of 28 days at 0 (vehicle control), 40, 200 and 1000 mg/kg bw/day. No mortality was observed through this study. An increased water consumption compared to control group was observed in male and female animals of the high dose group. Food consumption was only increased in female animals of the 1000 mg/kg bw/day dose group. In hematological and histopathological analysis, no test item related effects could be observed on blood parameters and hematopoietic organs up to 200 mg test item/kg bw/day in male animals and up to 1000 mg/kg bw/day in female animals. There was a significant decrease in hemoglobin concentration and hematocrit value and a lower reticulocyte count compared to control group in male animals of the high dose group. Administration of 1000 mg/kg bw/day revealed an increased AST activity in female animals and a reduced ALT activity in male animals compared to control group. Albumin and total protein level were significantly increased in both sexes of the 1000 mg/kg bw/day dose group. There was a significant increase of liver weights in male and female animals of the 1000 mg/kg bw/day dose group. In the same dose group, an increased adrenal gland and kidney weight was observed in male and female animals, respectively. As there was no macroscopic or microscopic pathological correlation a test item related kidney damage is not considered. In the absence of any blood biochemical effect or macroscopic or microscopic organ and tissue alterations the respective NOAEL was set to 200 mg/kg bw/day for male and female animals.
Toxicokinetic analysis of Incozol EH
Incozol EH is a pale yellowish liquid at room temperature with a molecular weight of 598.8578 g/mol. The calculated water solubility of the substance is 1.68 mg/L at 20 °C. The log Pow of Incozol EH was estimated to be 6.85. Based on this log Pow, a BCF of 652.3 L/kg wet-wt was calculated. The vapour pressure of Incozol EH is approximately 0.001 Pa at 25 °C. In an aqueous solution, Incozol EH is immediately degraded hydrolytically to 2-ethylhexanal and 1,6 hexanediyl-bis-carbamic acid bis(N-hydroxyethyl-2-aminoethyl) ester (“fully hydrolysed Incozol EH”). Both hydrolysis substances have a lower log Pow value than Incozol EH itself (approximately ‑1.03 for “fully hydrolysed Incozol EH” and 3.07 for 2-ethylhexanal). Also the BCF values are lower as compared to Incozol EH (approximately 3.162 L/kg wet-wt for “fully hydrolysed Incozol EH” and 49.27 L/kg wet-wt for 2-ethylhexanal). Water solubility of both hydrolysis products is higher than of Incozol EH itself (16 g/L for “fully hydrolysed Incozol EH” and 450 mg/L for 2-ethylhexanal). The vapour pressure of 2-ethylhexanal is above the value of Incozol EH (2.8 hPa).
Incozol EH was shown to immediately hydrolyse when getting in contact with water. Therefore, bioavailability after oral exposure was assessed only for the hydrolysis products 2-ethylhexanal and “fully hydrolysed Incozol EH”. Based on physico-chemical properties especially water solubility and log Pow value of “fully hydrolysed Incozol EH”, dissolution in the gastro-intestinal fluids and contact with the mucosal surface might occur and may allow direct uptake into the systemic circulation through aqueous pores or via carriage of the molecules across the membrane with the bulk passage of water. Passive diffusion might be a preferred entry route of 2-ethylhexanal into systemic circulation as it has lipophilic properties and a low water solubility. Clinical signs after a single administration of 2000 mg Incozol EH/kg bw in 1,2-propanediol in an acute oral toxicity study performed on rats were considered to be treatment-related and not associated to bioavailability of the test item. However, long-term administration of high doses of Incozol EH in a 28-day repeated dose toxicity study on rats indicated that the compound or rather its hydrolysis products became bioavailable.
Based on the vapour pressure of approximately 0.001 Pa at 20 °C Incozol EH is not expected to become airborne in its vapour form. However, if Incozol EH is degraded hydrolytically, inhalation exposure of 2-ethylhexanal, one of the hydrolysis products, could not be excluded due to its higher vapour pressure in comparison to Incozol EH itself. If the substance would reach the lungs, absorption directly across the respiratory tract epithelium by passive diffusion is likely to occur due to its log Pow value (3.07) and water solubility (450 mg/L).
Based on the molecular weight and physico–chemical properties of Incozol EH dermal penetration ofthe substance might be slow. It is general accepted that if a compound’s molecular weight is above 500 g/mol and water solubility falls between 1-100 mg/L, absorption can be anticipated to be low to moderate. These assumptions based on the physico-chemical properties are further supported by the results achieved from a GPMT which revealed that Incozol EH has skin sensitising properties and is thus absorbed dermally to a certain extent.
Taken together, physico-chemical properties and experimental data indicate a low bioavailability of Incozol EH via oral and dermal route. Bioavailability after inhalation exposure is considered to be unlikely due to the low vapour pressure of the non-hydrolysed compound.
Assuming that 2-ethylhexanal as one of the hydrolysis products is absorbed into the body following oral intake, it may be distributed into the interior part of the cells by passive diffusion due to its lipophilic properties and in turn the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues. Direct transport through aqueous pores is likely to be an entry route to the systemic circulation of “fully hydrolysed Incozol EH” due to its higher water solubility compared to 2-ethylhexanal.
Based on its log Pow and BCF value Incozol EH might have a weak bioaccumulation potential. However, as it immediately hydrolyses when getting in contact with water bioaccumulation in the human body can be excluded. This assumption is supported by the lower BCF values of the hydrolysis products compared to Incozol EH.
Based on the structure of the molecule, Incozol EH immediately degraded hydrolytically after being in contact with an aqueous solution. The first degradation product “fully hydrolysed Incozol EH” may be further degraded hydrolytically to a certain extend to diethanolamine, 1,6-hexanediamine and carbon dioxide under basic conditions. 2-ethylhexanal is estimated to be oxidised to 2-ethylhexanoic acid which was shown to be conjugated with glucuronic acid or further oxidised to2-ethyl-1,6-hexanedioic acid,2-ethyl-6-hydroxyhexanoic acid and 2-ethylketohexanoic acid (English et al, 1998).No metabolic activation of Incozol EH and its hydrolysis products is expected as indicated by the negative in vitro genotoxicity assays in the presence of S9 mix.
As discussed above, Incozol EH will be hydrolysed after being in contact with an aqueous solution and will probably not be excreted in its non-hydrolysed form. The degradation product “fully hydrolysed Incozol EH” might be biliary excreted due to its molecular weight (>300 g/mol in rat). Renal excretion might be a preferred excretion pathway of degradation products of “fully hydrolysed Incozol EH” described above. Oxidation and conjugation products of 2-ethylhexanal were shown to be excreted via urine (English et al, 1998).
Based on physico-chemical characteristics, particularly water solubility and octanol-water partition coefficient absorption via oral and inhalation route is expected to be low. However, slow dermal absorption could not be excluded. Incozol EH is immediately hydrolysed into“fully hydrolysed Incozol EH” and 2-ethylhexanal. If absorbed, passive diffusion and active transport through aqueous pores is likely to be an entry routes to the systemic circulation. No metabolic activation of Incozol EH and its hydrolysis products is expected. Excretion via faeces is assumed to be the main excretion pathway of “fully hydrolysed Incozol EH” due to its molecular weight. Oxidation and conjugation products of 2-ethylhexanal were shown to be excreted via urine. Based on hydrolytical conversion of Incozol EH bioaccumulation is not likely to occur based on physico-chemical properties of the hydrolysis products.
ECHA (2008), Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.
Marquardt H., Schäfer S. (2004). Toxicology. Academic Press, San Diego, USA, 2nd Edition 688-689.
English JC, Deisinger PJ, Guest D. (1998) Metabolism of 2-ethylhexanoic acid administered orally or dermally to the female Fischer 344 rat. Xenobiotica; 28(7):699-714.
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