2-Propenoic acid, γ-ω-perfluoro-C8-14-alkyl esters

Endpoint summary

Description of key information

2-Propenoic acid, gamma-omega-perfluoro-C8-14-alkyl ester [CASN 85631-54-5] is a perfluoroalkylethyl acrylate (FTAC, i.e. target) built from the perfluoro-alkylethanol (n:2 FTOH mixture, i.e. source, CASN 68391-08-2) and acrylic acid derivate and thus represents a multi constituent substance according to REACH definition. In order to fill data gaps for the perfluoroalkylethyl acrylate (FTAC, i.e. target) required under REACH Regulation (EC) 1907/2006 (testing requirements for individual substances derived from the application of Annexes VI to X have to be fulfilled for registration purposes), a read across approach from data of the structure related n:2 FTOH (perfluoro-alkylethanol) is chosen. This approach is justified based on structural similarities as well as metabolic considerations in that n:2 FTOH mixture (source) is considered not only the metabolic breakdown product of FTAC (target, for details see section 13 of the IUCLID) but is considered also the basic toxicological principle.

In order to compare the absorption and distribution of the registration substance FTAC (target substance) two screening studies following identical test designs were performed to substantiate potential read-across to the mixed n:2 FTOH (source substance).

Further, data on the absorption, distribution, metabolism and elimination (ADME) of the pure chain cut fluorotelomere alcohol 8:2 FTOH (CAS no. 678-39-7, i.e. one of the main constituents in the mixed n:2 FTOH source substance) are used to demonstrate distribution and elimination of the 8:2 FTOH (Fasano et al., 2006).

Additionally in vitro data with the structural analogue Tridecafluorohexylethyl Methacrylate  (6:2 FTMAC, CASN 2144-53-8) are available. In vitro experiments were performed using freshly isolated male SD rat and male CD1 mouse hepatocytes.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

In order to compare the absorption and distribution of the registration substance FTAC (target substance) two screening studies following identical test designs were performed to substantiate potential read-across to the mixed n:2 FTOH (source substance). Both substances were administered by gavage to 6 groups of 5 male rats each at 1000 mg/kg bw/day. The test substance was administered to 1 group of 5 Sprague Dawley rats for 5 consecutive days and to 5 groups for 10 days. To investigate toxicokinetic behavior, a recovery period of 84 days was included to establish fluorine-time-profiles.  On selected days (5, 10, 13, 24, 52, 94) 5 rats per group were euthanized and the blood, livers, and fat were collected. Body weights and clinical signs were recorded on each day of dosing and then weekly during the recovery period. Blood, liver and fat samples were analyzed for fluorine. The measured fluorine concentrations were normalized for the amount of fluorine present in the administered dose and expressed as ppm fluorine (= µg fluorine/g tissue or ml blood) per g fluorine administered. No test substance-related mortality occurred and no clinical signs were observed. The mean body weight gain of rats dosed with the source substance was similar to the rats dosed with the target substance. Elevated relative liver weights were observed on day 10 and 13 for both tested substances and on day 5 for the source substance. After day 13 the relative liver weights for both test substances treated rats were within the normal range.

In general, comparable fluorine-time-profiles were observed for both substances, indicative of very similar distribution and elimination patterns of fluorine to and from blood and both tissues (liver and fat). As explained in the read-across justification a common metabolic degradation pathway is considered which can easily explain the very similar profiles by assuming that the mixed acrylate (target substance) is rapidly cleaved by carboxyl esterases into the same fluorinated alcohol components. Taking this into account, the target substance could therefore result in the same fluorinated alcohol components which are present in the source substance and thus distribution and elimination kinetics of both products would be nearly identical. This is supported by the knowledge on the metabolism of common alkyl acrylates which are degraded via carboxylesterase hydrolysis to the respective alcohols and acrylates. There are two basic metabolic pathways for alkyl acrylates [ECETOC working group. Ethyl acrylate. ECETOC Joint Assessment of Commodity Chemicals Vol:28, 61 p (1994) ]. The first and most significant pathway is carboxyl-esterase hydrolysis of the ester bond, resulting in the formation of alcohol and acrylic acid. Acrylic acid, which may also be formed during mixed acrylate hydrolysis, is further metabolized to CO₂via the propionic acid pathway.

In conclusion the comparative 10-day gavage studies revealed very similar toxicokinetics indicated by comparable fluorine-time-profiles and thus, very similar distribution and elimination of fluorine to and from liver, fat and blood. Supported by the knowledge that cleavage of the ester bond is the main metabolic pathway for alkyl acrylates, these results allow to conclude that repeated dosing of the target substance to rats will result in the same toxicological profile and effect pattern and thus in similar NOAELs as described for the FTOH (source substance).

Further, the absorption, distribution, metabolism and elimination (ADME) of the pure chain cut fluorotelomere alcohol 8:2 FTOH (CAS no. 678-39-7, i.e. one of the main constituents in the mixed n:2 FTOH source substance) is well investigated (Fasano et al.,

2006). Following a single oral dose at 5 and 125 mg/kg 14C labeled 8:2 FTOH in male and female rats, the maximum concentration of 8:2 FTOH in plasma occurred by 1h post-dose and cleared rapidly with a half-life of less than 5 hours. The majority of the 14C 8:2 FTOH (>70%) was excreted in feces, and 37 -55 % was identified as parent. Less than 4 % of administered dose was excreted in urine, which contained low concentrations of perfluorooctanoate (about 1 % of total 14C). Metabolites identified in bile were principally composed of glucuronide and glutathione conjugates, and perfluorohexanoate was identified in excreta and plasma, demonstrating the metabolism of the parent FTOH by sequential removal of multiple CF2 groups.

The distribution and elimination kinetics of the parent compound FTAC (target) into breakdown product n:2 FTOH mixture is supported by in vitro data (Anand et al., 2012) of the structural analogue 6:2 FTMAC (Tridecafluorohexylethyl Methacrylate [2144-53-8]) based on metabolism studies in mouse and rat hepatocytes. In these studies the parent compound was rapidly (T_1/2= < 3min) metabolized to the respective 6-2 FTOH (Fluorotelomer alcohol [647-42-7]) and 6-2 FTOH -related metabolites.