Ethanamine, N-ethyl-, reaction products with polyethylene-polypropylene glycol ether with trimethylolpropane (3:1) acrylate (>1 <6.5 mol EO and >1 < 6.5 mol PO)

Endpoint summary

Additional information

There are no studies available assessing the absorption or metabolism of Propylidynetrimethanol, ethoxylated and propoxylated, reaction products with diethylamine (Laromer LR 8889). Laromer LR 8889 is a light beige, clear, viscous liquid at 20 °C. Its constituents have a molecular weight of 232-1172 g/mol [1]. Laromer LR 8889 has a very low vapor pressure of <0.000001 hPa (at 20°C), a log pow of 0.9-5.2 (at 23°C), and a water solubility of 1.2-2.3 g/l.

Oral absorption

Absorption is a property of a substance to diffuse across biological membranes. Generally, oral absorption is favored for log Pow values between -1 and 4 and for molecular weights below 500 g/mol. Molecular weights above 1000 do not favour absorption. Therefore, many of the lower weight constituents of Laromer LR 8889 most likely diffuse across intestinal membranes. In an oral repeated dose toxicity study according to OECD 422, increased liver weights and increased lipid accumulation in the liver were observed at 1000mg/kg. These adaptive changes show that test substance was absorbed and metabolized in the liver.

Dermal absorption

Liquids, like Laromer LR 8889, are taken up more readily than dry particulates via dermal absorption. In general, low molecular weight and log Pow values between 1 and 4 favor dermal absorption, particularly if the water solubility is high. Molecular weights above 500 hinder compounds from being taken up. Based on the water-solubility of 1.2-2.3 g/l and the log pow of 0.9-5.2, Laromer LR 8889 is considered lipophilic, but not to a degree that would prevent passage from the stratum corneum into the epidermis. Thus, a high dermal uptake is expected. Nevertheless, its molecular weight of 232-1172 g/mol might hinder a considerable portion of Laromer LR 8889 from passing the dermal barrier. In an LLNA study [4], Laromer LR 8889 had a clear sensitizing potential. So at least a part of the test substance must have been taken up. In conclusion, at least some components of Laromer LR 8889 are absorbed after dermal exposure.

Inhalative absorption

Absorption via the respiratory route also depends on physico-chemical properties like vapor pressure, log Pow and water solubility. Laromer LR 8889 has a very low vapor pressure of <0.000001 hPa at 20°C. Therefore, inhalation of vapor of the respective substance is very unlikely to occur. Theoretically, if inhalation of the substance occurred during handling, Laromer LR 8889 is favourable for absorption directly across the respiratory tract epithelium by passive diffusion based on the moderate log P value of 0.9-5.2.

 

Based on the results of the described toxicity studies and the physico-chemical properties, Laromer LR 8889 is well absorbed after oral, dermal, or inhalation exposure.

 

Metabolism

Laromer LR 8889 is a complex mixture of acrylic esters, tertiary amines and ethers, all containing Propylidyntrimethanol as basic compound [1]. Theoretically, acrylic ester metabolism may consist of epoxidation of the acrylic double bond and subsequent hydrolysis and GSH conjugation, or of an oxidation at the C terminus to the acid followed by ß-oxidation involving degradation of the alkyl chain, or of an ester hydrolysis leading to the release of acrylic acid. For example, n-Butyl acrylate was shown to be hydrolyzed by a representative mammalian esterase (Porcine hepatic esterase) [5]. Furthermore, after oral administration, the major portion of n-butyl acrylate was hydrolyzed by carboxyesterase to acrylic acid and butanol and eliminated as CO₂in male rats [6]. Acrylic acid is rapidly metabolized by oxidative pathways to carbon dioxide which is formed via acrylyl-CoA by the non-vitamin-B12-dependent pathway of mammalian propionate catabolism [7]. About 80% of an ingested dose of acrylic acid was exhaled as carbon dioxide within 24 hours. The kidneys and liver may be major sites of acrylic acid metabolism [8], which is supported in the case of Laromer LR8889 by the increased liver weight after repeated oral exposure. In blood, e.g., after dermal uptake, ester hydrolysis plays only a very minor role. Instead, the acrylic group is rapidly conjugated to glutathion [9, 10].

The metabolism of tertiary amines is mediated primarily by cytochrome P-450 and MFAO, leading to alpha-C oxidation and N-oxidation, respectively [11]. Theoretically, tertiary amines can also be glucuronidated.

Accumulation

Taking into account the log Po/w (0.9-5.2), the water solubility (1.2-2.3 g/l) and the considerations on the metabolism, accumulation of Laromer LR 8889 is considered to be unlikely.

Excretion

Seeing Laromer LR 8889 is very easily metabolized yielding small and water-soluble metabolites: Due to their respective molecular weights below 300 and their respective water solubility, unmetabolized leftover- Laromer LR 8889 and its metabolites are most likely excreted via urine and exhaled as CO₂.

 

References

[1] BASF study on characterization of Laromer 8889 no. 16L00510, 2016

[2] BASF study on acute oral toxicity in rats no. 10A0355/921091, 1994

[3] BASF study on repeated dose toxicity in rats no. 85R0422/16C101, 2018

[4] BASF study on skin sensitization in mice no. 58V0422/16A216, 2018

[5] BASF AG, 2001. Relative Rates of Hydrolysis of Butyl Acrylate Isomers by Mammalian Esterases, Report No. 01R-026 (Rohm and Haas Company), April 12, 2001

[6] Sanders J.M. et al., 1988. Metabolism and disposition of n-butyl acrylate in male Fischer rats, Drug Metabolism and Disposition, 16(3), 429-434.

[7] European Union Risk Assessment Report (EU RAR), 2002, Acrylic Acid, CAS 79-10-7, rapporteur: Germany, ISBN 92-894-1272-0

[8] Black et al. (1993), Metabolism of acrylic acid to carbon dioxide in mouse tissues. Fundam. Appl. Toxicol. 21(4): 97-104

[9] Miller, Ayres, Rampy, McKenna (1981). Metabolism of acrylate ester in rat tissue homogenates. Fundamental and applied toxicology 1:410 -414

[10] McCarthy, Hayes, Schwartz, Witz (1994). The reactivity of selected acrylate ester toward glutathione and deoxyribonucleosides in vitro: Structure-activity relationships. Fundamental and applied toxicology 22, 543 -548

[11] Rose et al, 1989. The metabolism of tertiary amines. Med Res Rev. 3(1):73-88.