[2-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxoallyl]oxy]ethyl][3-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxoallyl]oxy]propyl]dimethylammonium chloride

Endpoint summary

Description of key information

Based on its physico-chemical characteristics, the substance is considered to be bioavailable after oral absorption and after inhalation. Dermal absorption of the substance in toxicologically relevant amounts is unlikely. Dermal uptake for the substance is expected to be very low. This is supported by the estimated Kp value of 0.000307 cm/hr using the (Q)SAR Database DERMWIN v 2.01 (EPI Suite) indicative for a very low dermal penetration potential according to DK-EPA heuristics (User Manual for the Internet Version of the Danish (Q)SAR Database, Database Version 1, May 2005).
Following uptake the compound can be distributed through the body. Thereby a pronounced metabolism is not expected. It is expected that after potential absorption the substance will be rapidly excreted via the urine and the feces.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

50

Additional information

In line with chapter R.7 c (ECHA, 2012) the main toxicokinetic properties of the substance are assessed on the basis of its physico-chemical properties and with special regard to the results of the standard toxicity studies performed with this substance. Specific toxicokinetics or dermal absorption studies are not available for the substance. However, a (Q)SAR for dermal penetration has been performed and is discussed below.

1. Relevant physico-chemical properties of the substance

Molecular weight: 636.22 g/mol

Physical state: solid

logPow: 1 at 23°C (estimated value)

Water solubility: < 100 g/L

Vapour pressure: <0.000001 hPa at 20 °C

Surface tension: 43 mN/m, (1g/L)

Hydrolysis: The substance is considered to hydrolyse slowly in contact with water

pH 4: 2015 h (20°C), 1119 h (25°C)

pH 7: 684 h (20°C), 349 h (25°C)

pH 9: 29 h (20°C), 14 h (25°C)

 

2. Absorption:

Oral absorption

In general, large molecules with a molecular weight above 1000 g/mol do not favour oral absorption. Based on its molecular weight of 636.22 g/mol the substance is expected to be absorbed in the GI tract. The fact that signs of systemic toxicity (histopathological findings in the liver) were noted in the key subacute oral toxicity study (BASF, 2013, 85R0382/11S134) pointed out that the test item was able to pass the intestinal wall. Since the hydrolysis half life of the substance is higher than the transit time in the stomach and the small intestine it is most likely that the parent compound and not its hydrolysis products are present in the GI tract. The estimated log Pow value of 1 leads to the conclusion that absorption of the substance occurs by passive diffusion which generally requires a moderate log Pow value (between -1 and 4). Due to the good water solubility (100 g/L) the absorption by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid.

Absorption of surfactants may be slightly enhanced because of damage to the cell membranes. The surface tension of an aqueous substance solution was determined (BASF, 2013, 12L00211). Within this study a surface tension of 43 mN/m (20°C) was determined for a concentration of 1 g/L indicating slight surface activity. Therefore, an enhanced absorption by damage of cell membranes cannot be excluded for the test substance at high dose levels.

 

Absorption after inhalation

The substance is considered to be absorbed if it is inhaled. This assumption is based on the good water solubility and the moderate log Pow (between -1 and 4) in combination with the surface activity which is favourable for absorption in the lung. Due to the negligible vapour pressure of the substance and the resulting low volatility, an inhalation exposure to the compound's vapour phase is very unlikely. As for the oral absorption, it is assumed that the parent compound and not its metabolite will be absorbed through the respiratory epithelia.

 

Dermal absorption

For dermal absorption a substance must be sufficiently lipophilic to cross the major barrier i.e. the stratum corneum. Furthermore, the substance must be adequately soluble in water to partition from the stratum corneum into the dermis. Since the registered substance showed a log Pow between -1 and 4 and a high water solubility dermal absorption is likely. However, a molecular weight above 500 indicates that the molecule is too large and thus dermal uptake is not favoured. Based on the molecular weight of 636.22 g/mol dermal absorption of the registered substance is anticipated to be low. This is supported by the results of an acute dermal toxicity study (BASF/Bioassay GmbH, 2011, 11A0382/11X054) performed in rats. During this study no mortality and no systemic toxic effects were observed for the highest dose and the respective LD50 was determined to be greater than 2000 mg/kg bw. Since the surface tension of the substance in aqueous solution is above 10 mN/m, the substance is no surfactant and will via this property not elicit a substantial change in skin barrier function. Furthermore, the substance showed no skin irritating properties (BASF AG, 1988,18H0153/882077) which might affect skin barrier function. In conclusion, dermal uptake of the substance is considered to be very low. This is further supported by the estimated Kp value of 0.000307 cm/hr using a (Q)SAR Database (EPI Suite, DERMWIN v 2.01) indicative for a very low dermal penetration potential according to DK-EPA heuristics (User Manual for the Internet Version of the Danish (Q)SAR Database, Database Version 1, May 2005).

3. Distribution/Metabolism:

 

In an acute toxicity study (BASF AG, 1980, 79/631) a test item preparation was administered orally to rats. As general clinical signs dyspnea, apathy, urine yellow, shortness of breath and poor general state were noted for all animals. In view of these clinical signs a distribution of the test item in the body cannot be ruled out. However, since the substance has a relatively large molecule size and a hydrophilic character a wide distribution and diffusion across the membranes is not to be expected.

In general, metabolism will render a xenobiotic molecule more polar and harmless, leading to fast and quantitative excretion which is considered to be the case for the registered substance. No conversion into a metabolite that was more cytotoxic or more genotoxic than the parent substance was noted for the registered substance when comparing in vitro test results with metabolic activation to in vitro test results without metabolic activation system (genetic toxicity tests). Thus, the formation of reactive metabolites is unlikely.

4. Excretion:

Substances with log Pow of 3 or less would be unlikely to accumulate in organisms. Based on its estimated log Pow of 1 the substance has a low potential to bioaccumulate in the human body. Furthermore, it was demonstrated in an experimental study that the substance does not significantly accumulate in organisms (BASF Japan, 1983, 35093). In a subacute oral toxicity study (BASF SE, 2013, 85R0382/11S134) yellow discolouration, originating from the test item, was found in the urine and the feces. The results lead to the conclusion that a direct excretion via the urine and feces occurred after oral exposure at high doses.

 

5. Generic absorption rates:

Based on the above information and due to the fact that there are no specific toxicokinetic data available, the generic values of 50 % for oral absorption and inhalation absorption of respirable aerosols are applicable. Since the molecular weight of the substance is above 500 g/mol and the log Pow is moderate, i.e. in the range of > -1 to < 4, its dermal absorption rate will by default not exceed 10% (EFSA, 2012). This is further supported by the result of the DERMWIN v 2.01 calculation idicating a very low dermal penetration potential of the substance.

 

References

ECHA (2012). Guidance on information requirements and chemical safety assessment, chapter R.7c: Endpoint specific guidance.

ECHA-12-6-23-EN.R.7.12 Guidance on Toxicokinetics.

EFSA (2012). Guidance on dermal absorption. EFSA Journal; 10 (4): 2665.