1,3-Cyclohexanedimethanamine, N1,N3-bis(2-methylpropylidene)-

Endpoint summary

Description of key information

Based on its physical-chemical properties particularly water solubility and logPow Incorez 397 will most likely be absorbed via the GI-tract. Dermal absorption and absorption via inhalation routes were considered less significant. If bioavailable, Incorez 397 will most likely distribute in intracellular compartments. Based on the chemical structure the substance is likely to be metabolised by phase I and II enzymes. Excretion is likely via urine and faeces. Bioaccumulation in the human body is not expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicological profile of Incorez 397

 

Acute oral toxicity of Incorez 397 was tested in a study performed in female rats according to OECD guideline 423. Based on the results a LD50 value greater than 2000 mg/kg bw was determined. Female animals were treated in two steps with 2000 mg/kg bw by oral gavage. In the first step one animal was treated with 2000 mg/kg bw and as no mortality occurred three further animals were treated with the same dose. In the first treated animal, distur-bances of the autonomic functions including diarrhoea and diuresis were observed on day 1. No clinical signs were noted in the three additionally treated animals. Gross pathology revealed no changes in any of the animals. Further, Incorez 397 was tested for acute dermal toxicity in a limit test performed in rats according to OECD guideline 402. Based on the results a dermal LD50 value greater than 2000 mg/kg bw was determined. Five male and five female rats were topically treated for 24 h with 2000 mg/kg bw (semi-occlusive). No clinical signs or signs of systemic toxicity were noted. The test item caused dermal irritation symp-toms including slight to sever erythema very slight oedema and other signs (dry skin surface, wounds, crusting) during the 14-day observation period. In conclusion, no acute systemic toxicity was observed during acute toxicity testing through oral and dermal routes.

Incorez 397 was tested for skin irritation/corrosion in a study performed in rabbits according to OECD guideline 404. Based on the results of the study Incorez 397 was determined to be corrosive to the skin. Due to welfare reasons, in vivo eye irritation testing was not performed.

Based on the results of a local lymph node assay performed in mice according to OECD guideline 429 Incorez 397 was considered to be skin sensitising.

Incorez 397 was tested for genotoxicity in an Ames test according to OECD Guideline 471. The substance was not considered mutagenic with and without metabolic activation. Further, Incorez was tested for genotoxicity in an in vitro mammalian HPRT test according to OECD guideline 476 and for clastogenicity in an in vitro mammalian chromosome aberration test according to OECD guideline 473. Overall, Incorez 397 was considered to be non mutagenic and non clastogenic with and without metabolic activation.

Incorez 397 was tested for long-term toxicity in a 14-day dose rang finding (DRF) test and a 28-day subacute toxicity test performed in rats according to OECD guideline 407. In the DRF-test a NOAEL of 1000 mg/kg bw/day was determined. The 28-day study revealed a NOAEL of 609 mg/kg bw/day. In the DRF-test animals were treated by oral gavage with doses of 50, 250 and 1000 mg/kg bw/day. Observations were limited to the high dose group. Clinical signs were noted including decreased activity, salivation, nuzzling up of bedding material, swollen abdomen, prone position, closed eyes and piloerection. Further, male animals showed reduced body weight at the end of the study. Haematology examinations revealed slightly higher white blood cell and platelet counts and percent of reticulocytes (RET) in male and female animals. The effects were considered to be related to the test item, but toxico-logical relevance could not be concluded. Gross necropsy showed no changes.

In the 28-day study animals were treated by oral gavage with doses of 50, 250 and 1000 mg/kg bw/day. Observations were again limited to the high dose group. One male and one female animal were found dead on day 9, therefore, the high dose was lowered to 750 mg/kg bw/day. Based on the outcome of the DRF-test and the state of the remaining animals of the high dose group, mortality was considered to have occurred due to individual sensitivity towards the test item rather than severe toxicity. The dose setting was in line with the guideline specifications for repeated dose testing. Further effects observed during testing included clinical signs as moderate salivation in the mid dose group and marked salivation, nuzzling up of bedding, decreased activity decrease and Straub tail. After the dose reduction clinical signs were limited to salivation and nuzzling up of bedding. Moreover, the body weight of male animals was reduced at the end of the study. Slight changes in clinical pa-thology were noted but the values were without statistical significance. No other observations were noted. The analytical determination of the treatment formulations revealed degradation of the test substance during the second analysis, with contents ranging from 71 to 83 %. Therefore, the actual doses were corrected accordingly and the real concentration of the high dose group thus calculated to be 937/609 mg/kg bw/day (1000/750 mg/kg bw/day).

Incorez 397 was tested in a reproduction/developmental screening test performed in rats according to OECD guideline 421. Based on the results a NOAEL of 750 mg/kg bw/day was determined for developmental/fertility effects. Animals were treated with doses of 100, 250 and 750 mg/kg bw/day by oral gavage. No effects on reproduction or development were ob-served during testing. Notably, male animals of the high dose group showed reduced food intake during the first two weeks of the study. Subsequently the body weight gain was signifi-cantly reduced during the first two weeks. The body weight gain went normal during the last weeks of testing but the body weight was still reduced at the end of the study. No effects were noted for clinical pathology or gross necropsy but as histopathology was limited to reproductive organs a toxicological relevance could not be excluded. Thus the NOAEL for pa-rental effects was determined to be 250 mg/kg bw/day. In conclusion, Incorez 397 was con-sidered to be not reprotoxic.

 

Toxicokinetic analysis of Incorez 397

 

Incorez 397 is liquid at room temperature with a molecular weight of 250.42 g/mol. The va-pour pressure of Incorez 397 at 20 °C is 47The water solubility of Incorez 397 is 0.98 mg/L at pH 7. A log Pow of 5.13 and a BCF value of 1129 L/kg wwt were calculated (USEPA EPISUITE, 2008).

 

Absorption:

 

Based on the molecular weight (250.42 g/mol) and logPow (5.13) the substance is likely to be absorbed in the GI tract. However, uptake via passive diffusion is unlikely, as this pathway is favoured for substances with logPow ranging between -1 and 4. Further, Incorez 397 is not expected to cross the gut epithelial by passing through aqueous pores or bulk passage of water, due to the molecular weight. Moreover, micellular solubilisation by bile acids is likely. Substances absorbed as micelles are likely to enter the lymphatic system and thereby by-pass the liver. Results obtained in a DRF-test and from subacute toxicity testing showed changes in haematology parameters indicating a biological response and thus systemic dis-tribution. Therefore, oral absorption of Incorez 397 is considered likely.

Based on the vapour pressure of Incorez 397 (47 Pa) the substance is not likely to distribute into air at room temperature. However, as the substance is liquid, inhalation of aerosols is likely. The water solubility is very low (0.98 mg/L), therefore, the substance is not expected to significantly dissolve in the mucus lining the respiratory tract. Further, the logPow indicates that Incorez 397 is to lipophilic to partition from the alveolar and capillary membranes into the blood system. Overall, respiratory absorption is considered less likely.

Dermal absorption of Incorez 397 is not considered likely as the logPow is high and the water solubility is very low. The substance is sufficiently lipophilic to enter the stratum corneum but, due to the low water solubility, will not partition into the epidermis. This is supported by re-sults obtained from acute dermal toxicity testing showing no signs of systemic absorption. As the substance was found to be corrosive to skin in in vivo dermal irritation/corrosion testing damage to the skin may enhance penetration. However, dermal absorption is considered less likely.

 

Distribution:

 

Based on its physical-chemical properties, particularly logPow and water solubility, Bioavail-able Incorez 397 is likely to be distributed through the lymphatic system by micellular solubi-lisation. Based on its logPow the substance is likely to distribute into cells. Repeated expo-sure may result in a build up of intracellular concentrations particularly in fatty tissues. This is further indicated by the moderate BCF-value (1129 L/kg wwt) further indicates that intracellu-lar distribution is likely. A specific tissue affinity was not indicated during subacute toxicity testing. The potential of bioaccumulation is thus not high.

 

Metabolism:

 

Based on chemical structure, the substance may be readily metabolised by phase I enzymes with subsequent conjugation catalysed by phase II enzymes. No conversion into genotoxic or clastogenic metabolites is expected, supported by the results of an Ames-test an in vitro mammalian HPRT-test and an in vitro mammalian chromosome aberration test. In phase I reactions Incorez 397 may be metabolised by cytochrome P450 dependent oxidation of the C-7 or C-12 atom adjacent to the cyclohexane core. The breakdown products may be further metabolised by phase I enzymes or be readily conjugated by phase II dependent addition of hydrophilic residues rendering the metabolites more polar.

 

Excretion:

 

Excretion of Incorez 397 would most likely occur via faeces and urine after metabolic degra-dation of the parent compound. High molecular weight metabolites following conjugation reactions with glucoronide or glutathione are likely to be excreted via bile. Low molecular weight molecules such as sulphated conjugates tend to be excreted via urine.

 

Summary:

 

Based on its physical-chemical properties particularly water solubility and logPow Incorez 397 will most likely be absorbed via the GI-tract. Dermal absorption and absorption via inhalation routes were considered less significant. If bioavailable, Incorez 397 will most likely distribute in intracellular compartments. Based on the chemical structure the substance is likely to be metabolised by phase I and II enzymes. Excretion is likely via urine and faeces. Bioaccumulation in the human body is not expected.