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Assessment of the Toxicokinetic Behaviour

 

There were no studies available in which the toxicokinetic properties of glycerol, ethoxylated, esters with acrylic acid were investigated.

 

Glycerol, ethoxylated, esters with acrylic acid having a molecular weight range of 520 - 690 g/mol is soluble in water (measured water solubility: 8.4 - 26.7 g/L at 20°C). It has a vapour pressure of < 0.000001 hPa at 20°C (measured) and the measured log Po/w was 0.8 - 2.5 at 23 °C and pH 6.2.

 

Absorption

In an acute toxicity test, performed according to OECD guideline 423, three females received 2000 mg/kg bw and six females received 300 mg/kg bw Glycerol, ethoxylated, esters with acrylic acid by gavage (BASF AG, 2005). The LD50 was > 300 and < 2000 mg/kg bw. At gross necropsy, moderate or severe, (red) hyperemia in the glandular stomach and slight, red discoloration of contents of the small intestine was seen in the animals that died during the study (2000 mg/kg bw), as well as black discoloration of contents of the small intestine. No macroscopic pathologic abnormalities were noted at termination of the study in the surviving animals (300 mg/kg bw). Thus, no clear signs of systemic availability of the substance after oral uptake were observed.

 

In addition, Glycerin 3 EOTA was tested in a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test according to OECD TG 422 (BASF SE, 2010). The substance was administered orally via gavage to Wistar rats at doses of 50, 150, and 500 mg/kg bw/day for a total of 49 days (females) and 30 days (males), respectively. No clear signs of systemic toxicity were observed as mortality and adverse clinical observations were confirmed by pathology to be subsequent to local irritant effects of the test substance in the fore- and glandular stomach leading to erosions or ulcers associated with inflammation and subsequently as proliferative response secondary to ulceration leading to squamous cell hyperplasia in the forestomach. In the glandular stomach ulceration was associated with focal hyperemia. However changes in clinical chemistry and haematology can be interpreted as signs of systemic uptake (for details see Chapter “Repeated Dose Toxicity”).

 

Based on the results of the described acute and repeated dose toxicity studies, some indication of oral uptake of glycerol, ethoxylated, esters with acrylic acid is given. But, the majority of the clinical findings, if not all, were considered secondary to local irritation in the fore- and glandular stomach. Only the effects on haematology and clinical chemistry may be indicative of systemic availability of the substance. Higher cholesterol blood levels observed in both sexes in the repeated dose study were considered to be indicative of an altered liver metabolism induced by the substance.

 

This assessment is supported by an acute inhalation study conducted with a liquid aerosol of the substance in Wistar rats according to OECD TG 403 (BASF SE, 2010) at measured concentrations of 0.051, 0.213 and 0.996 mg/L. Cascade impactor measurements confirmed MMADs of the aerosol particles well within the respirable range. The LC50 for both sexes was determined to be 0.541 mg/L. Clinical signs of toxicity comprised signs of respiratory tract irritation and poor general state amongst others. Abnormalities observed at gross pathological examination of deceased and surviving animals were restricted to the lungs. Histopathological examination of the animals exposed to 0.051 mg/L revealed in the nasal cavity severe focal ulceration and/or inflammation of squamous epithelium localized at the base of the nasal cavity indicative of severe irritation of the upper respiratory tract. No clear signs of systemic uptake of the substance were reported.

 

On the other hand, glycerol ethoxylated, esters with acrylic acid was tested for its potential to cause skin sensitization in two Local Lymph Node Assays (BASF AG, 2004). Based on the results of these studies, the substance has to be regarded as a potential skin sensitizer, giving strong evidence for systemic availability after dermal application in mice.

 

Therefore, systemic bioavailability of the substance after oral and dermal exposure has to be taken into consideration for the assessment of the substance. After inhalation of an aerosol, systemic availability is uncertain since all substance-related effects were restricted to the port of entry, i.e. respiratory tract and lungs. However, based on the physico-chemical parameters of the substance (molecular weight, log Po/w, water solubility) absorption after inhalation is possible (REACh Guidance Chapter R.7c, ECHA 2008).

 

Metabolism

Available studies on genetic toxicity in-vivo (mouse micronucleus assay) were negative, i.e. there is no indication of a reactivity of the substance or its metabolites with endogenous macromolecules like DNA under the test conditions. In addition, there are indications from an in vitro HPRT Locus Assay in CHO cells that possible transformation products from liver metabolism might be less cytotoxic than the parent compound. After incubation without S-9 mix the substance was cytotoxic at concentrations of 2.5 µg/mL and above; after metabolic activation with S-9 mix the substance or its metabolites were cyctotoxic only at 50 µg/mL or higher concentrations.

 

Potential liver metabolites were calculated by OECD toolbox 1.00. Here, the liver metabolism simulator provided 29 different metabolites, mostly hydroxylated products of the parent compound or hydrolysis products after cleavage of one or several of the acrylate ester linkages. Therefore, acrylic acid (CAS 79-10-7) is one of the possible and most probable transformation products of glycerol, ethoxylated, esters with acrylic acid. The subsequent metabolism described for acrylic acid involves metabolism to carbon dioxide via the propionate degradation pathway.

 

Bioaccumulation

Taking into account the low to moderate log Po/w, the high water solubility and the considerations on metabolism, accumulation of glycerol, ethoxylated, esters with acrylic acid is considered unlikely.