Fatty acids, sunflower-oil, conjugated, maleated,reation products with diethanolamine, maleated tall-oil fatty acids and triethanolamine

Endpoint summary

Additional information

The toxicokinetic properties are assessed via evaluation of the PC parameters of the registered substance itself (CAS 1415316 -96 -9), as well as the available data on its toxicologically most relevant components, diethanolamine (DEA, CAS 111 -42 -2), and Triethanolamine (TEA, CAS 102 -71 -6).

The registered substance is a vicious liquid with a high water solubility (log PoW of app. -4, completely miscible in water). The molecular weight of > 1000g/mol would usually not favour oral absorption. But since the substance is a salt, which will quickly dissolve in the aqueous solution in the intestine, the resulting ions should be small enough to pass the intestinal barrier (estimated MW of 100-600g/mol). The assumption of oral bioavailability is supported by the high water solubility and systemic toxicity observed after repeated exposure, even though the latter only proves that one of the constituents, DEA, was able to enter the body, due to the low toxicity of the remaining components.

Absorption after inhalation is thought to occur based on the same physico-chemical parameters as mentioned above. The vapour pressure measurement was flawed by the presence of a substantial amount of water in the sample, but based on the properties of its components, vapour pressure is expected to be very low. Consequently, exposure via inhalation is only relevant, if aerosols are generated.

Dermal uptake will likely be limited by the very high water solubility, which will prevent it to cross the lipid rich environment of the stratum corneum, and the molecular weight of at least some of the ions. Additionally, there were no clinical signs or local irritation after acute dermal exposure. But since dermal absorption occurred for the most toxic component DEA (see below), no factor for low dermal uptake is introduced during the risk assessment.

No bioaccumulation is expected based on the low PoW of app. -4. The substance can dissolve in the blood, but will not easily enter cell membranes. Instead, metabolism might take place in the liver followed by urinary excretion. This theory matches the target organs (liver, kidney) observed after repeated oral exposure. As described below, half-lives of the components DEA and TEA differ significantly, presumably since DEA is conserved via a mechanism the usually retains ethanolamine. This difference might at least partly explain the differences in toxicological properties observed between the two amines.

DEA

DEA is well absorbed following oral administration in rats (57%) and to a lower degree after dermal administration (3-16% in rats; 25 – 60% in mice). When applied dermally, DEA appears to facilitate its own absorption, as higher doses were more completely absorbed than lower doses. DEA (20 mg/cm²) applied to skin preparations in vitro showed penetration rates of 6.7% (mouse) > 2.8% (rabbit) >0.56% (rat) > 0.23% (human). Availability via all routes of exposure is also supported by the fact that the obtained NOAEL / LOAEL values and associated effects are comparable in the available 90-day studies after dermal, oral, or inhalation exposure.

Distribution to the tissues was similar via all routes examined. DEA is cleared from the tissues with a half-life of approximately 6 days. The highest concentrations are observed in liver and kidney, which matches the target organs after repeated exposure. Accumulation of DEA at high levels in liver and kidney is assumed by a mechanism that normally conserves ethanolamine, a normal constituent of phospholipids. DEA is incorporated as the head group to form aberrant phospholipids, presumably via the same enzymatic pathways that normally utilize ethanolamine

Metabolism after oral administration revealed non-metabolised DEA and smaller proportions of N-methyl-DEA (N-MDEA), N,N-dimethyl-DEA (N’N-DMDEA) and DEA-phosphates co-eluting with phosphatidyl ethanolamine and phosphatidyl choline. After digestion 30% of the phospholipids were identified as ceramides and the remaining 70% as phosphoglycerides. DEA is excreted primarily in urine as the parent molecule (25-36%), with lesser amounts of O-phosphorylated and N-methylated metabolites.

TEA

Studies in experimental animals indicated that TEA is absorbed through the skin. Differences in the rate of absorption between rats and mice have been described regarding dermal exposure. In mice, most of the topically applied 14C-TEA is absorbed, and only 2% to 11% is detected at the site of application after 48 hours.The dermal absorption of TEA in rats was less extensive and much slower than in mice. An absorption, distribution, metabolism, and excretion study by NTP (2004) found that after 72 hours of exposure, only 20% to 30% of the applied dermal dose of TEA (68 or 276 mg/kg) was absorbed in rats and 60% to 80% was absorbed in mice (79 or 1120 mg/kg). These differences in absorption have been attributed either to the different doses used in comparative studies or to species-specific factors.

In addition to animal studies, human skin penetration of TEA was tested in vitro using diffusion cell techniques. Oil-in-water emulsions containing 1% or 5%14C-TEA were added to the stratum corneum side of 200-300 µm thick human skin sections and penetration of radioactivity into and through the skin (into a receptor fluid, sampled up to 24 hours after application) was determined. At pH 8.0, 1.1 and 1.2% of the dose was absorbed into the receptor fluid with a total penetration of 22.0 and 16.5% for 1 and 5% TEA, respectively. At pH 7.0, 0.43 and 0.28% was absorbed into the receptor fluid with a total penetration of 9.8 and 5.8% after 24 hours for 1 and 5% TEA, respectively. After 48 hours at pH 7.0, 0.68 and 0.60% was absorbed into the receptor fluid with a total penetration of 9.6 and 6.9%, for 1 and 5% TEA respectively. This pH-related difference reflects the higher percentage of unionised test material pH 8.0

No data on oral and inhalation exposure is available. Based on the low molecular weight, high water solubility, and effects described in the OECD 421, absorption via both routes is expected to be high.

The elimination of 14C-TEA-derived radioactivity from the blood of mice after a 1 mg/kg intravenous injection displays two-phase elimination kinetics with an initial rapid distribution phase (0.3-0.6 hour half-life) followed by a slower elimination phase (10-hour half-life). Radioactivity in blood after dermal application of 2000 mg/kg neat TEA declined in a bi-exponential manner through 3-hour post-dosing with a rapid initial phase (half-life of 1.9 hr) followed by a slower terminal phase (half-life of 31 hr).Both rats and mice rapidly excreted the absorbed dose, primarily in urine (followed by faeces) after i.v. and dermal exposure. Regarding dermal exposure, in rats, less than 1% of the dose was present in the tissue samples (except the dose site) 72 hours after treatment. The heart, kidney, liver, lung, and spleen contained elevated concentrations of radiolabel relative to blood.