Acetic acid, 2-cyano-2-[3-[(3-methoxypropyl)amino]-2-cyclohexen-1-ylidene]-, 2-ethoxyethyl ester, (2Z)-

Endpoint summary

Description of key information

The dermal absorption of 2-ethoxyethyl (2Z)-2-cyano-2-[3-(3-methoxypropylamino)cyclohex-2-en-1-ylidene]acetate was determined to be 1.63% following topical application in a cream formulation (3% w/w) to split-thickness human skin.

Key value for chemical safety assessment

Absorption rate - dermal (%):

1.63

Additional information

Relevant physico-chemical properties of 2-ethoxyethyl (2Z)-2-cyano-2-[3-(3 methoxypropylamino)cyclohex-2-en-1-ylidene]acetate (C-1701 B_C_3)

Molecular weight: 322.41 g/mol

Physical state: solid

logPow: 1.7

Water solubility: 450 mg/L

Boiling point: 306 - 315°C

Melting point: 92.2 - 93.1°C.

Vapour pressure: < 1.3 x 10^-6 Pa at 20°C

 

In the key study chosen to assess dermal penetration according to OECD TG 428 and GLP, the rate and extent of absorption of 2-ethoxyethyl (2Z)-2-cyano-2-[3-(3-methoxypropylamino)cyclohex-2-en-1-ylidene]acetate following topical application in cream formulation (3 % w/w) to split‑thickness human skin was assessed (Charles River 2013; 792670). Split-thickness human skin (12 samples from 4 individual donors) was mounted into static diffusion cells containing receptor fluid (Phosphate buffered saline (PBS) supplemented with bovine serum albumin (BSA); 5 % w/v) in the receptor chamber. The formulation was applied to the mounted human skin samples at an application rate of approximately 2 mg/cm². Percutaneous absorption was assessed by collecting receptor fluid from the receptor chamber at 0, 0.5, 1, 2, 4, 8 and 24 hours post dose. Exposure was terminated at 24 hours post dose by washing the skin surface. The solubility of the test item in the receptor fluid was found to be not rate limiting for absorption.

The majority of the test item was removed at 24 hours post dose by washing the skin surface (93.73 % of the applied dose). The stratum corneum retained 0.79 % of the applied dose (0.52 μg/cm²). The epidermis without stratum corneum contained 0.57 % (0.37 μg/cm²) and the dermis contained 0.35 % (0.23 μg/cm²). The total absorbed dose (i.e. the amount, that had penetrated through the skin into the receptor fluid) was 0.72 % (0.48 μg/cm²) of the applied dose. The dermal delivery (total absorbed dose + dermis + epidermis without stratum corneum), which was used as estimate for bioavailability for the dermal route was determined to be 1.63 % of the applied dose (1.08 μg/cm²). The mass balance for the remaining cells was complete, with 96.34 % of the applied dose recovered. Under the conditions of this in vitro study, C-1701 B_C_3 penetrated through split-thickness human skin to a low extent.

No other experimental data on toxicokinetics are available for C-1701 B_C_3. However, based on its low molecular weight of 322.41 g/mol C-1701 B_C_3 is likely to be absorbed well in the GI tract since small molecules with a molecular weight below 500 g/mol do favour absorption. Furthermore, the log P_owvalue of 1.7 leads to the conclusion that efficient absorption of this substance by passive diffusion occurs, which requires a moderate log P_owvalue (between -1 and 4). This is also in line with the moderate water solubility of 450 mg/L. The assumption of an efficient oral absorption is supported by the results of the repeated dose and reproduction/developmental toxicity studies showing test item-related systemic toxicity after oral exposure. Decreases in body weights and clinical signs have been observed consistently after two oral administrations of 2000 mg/kg bw/d in the in vivo MNT and in reproductive/developmental and subchronic repeated dose toxicity studies at lower doses. Further systemic effects on hematological parameters/clinical chemistry and the liver were observed. Based on these findings and its physicochemical properties, C-1701 B_C_3 is considered to be absorbed well in the GI tract. Taken together in a weight of evidence, bioavailability via the oral route needs to be assumed for C-1701 B_C_3.

Substances with a boiling point above 150°C have a low volatility. Since the boiling point of C-1701 B_C_3 is between 306 – 315 °C the availability for inhalation as a vapour is low. In line, the high melting point (92.2-93.1°C) does support this assumption. However, due to its physical state as solid, inhalation of particles is generally possible when handled as pure material.

Concerning metabolism, no conversion into a metabolite that was more cytotoxic or more genotoxic than the parent substance C-1701 B_C_3 was noted when comparing in vitro test results with metabolic activation to in vitro test results without metabolic activation system (genotoxicity tests). Thus, the formation of reactive metabolites is not indicated. Based on its structure C-1701 B_C_3 is expected to hydrolyze at the ester bonds present, being catalyzed by esterases. The merocyanine core is presumed to be conjugated in phase II metabolism. The low molecular weight of 322.41 g/mol, and the water solubility indicated urinary excretion as a putative route of excretion for C-1701 B_C_3. Based on the characteristics given above, a potential C-1701 B_C_3 for bioaccumulation in the human body is not indicated.