4-hydroxybutyl acrylate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Please see for more information the read-across justification in Section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

See source records for information.

Reference 2

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

key study

Justification for type of information:

Please see for more information the read-across justification in Section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Dose:

12.5 mg/kg bw

Parameter:

percentage

Absorption:

ca. 66 %

Remarks on result:

other: 48 hr

Reference 3

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Conclusions:

These in vitro metabolism results indicate that all nine acrylate esters (methyl acrylate (MA), ethyl acrylate (EA), butyl acrylate (BA), iso-butyl acrylate (iso-BA), tert-butyl acrylate (tert-BA), 2-hydroxyethyl acrylate (HEA), 2-hydroxypropyl acrylate (HPA), 2-ethylhexyl acrylate (2-EHA), and 2-propylheptyl acrylate (2-PHA)) can be quickly metabolized primarily through hydrolysis to AA and/or glutathione conjugation in vivo.

Executive summary:

This study was conducted to investigate in vitro hydrolysis and glutathione conjugation rates

of selected acrylates. Nine acrylates, including methyl acrylate (MA), ethyl acrylate (EA),

butyl acrylate (BA), iso-butyl acrylate (iso-BA), tert-butyl acrylate (tert-BA),

2-hydroxyethyl acrylate (HEA), 2-hydroxypropyl acrylate (HPA), 2-ethylhexyl acrylate

(2-EHA), and 2-propylheptyl acrylate (2-PHA), were chosen for initial experimental

determination of metabolism rates in rat liver microsomes and whole rat blood at a single

substrate concentration (500 μM). Additionally, Km and Vmax determinations were made by

performing incubations utilizing various concentrations (32.25, 62.5, 125, 250, and 500 μM)

and a single rat liver microsomal protein concentration of 0.1 mg/mL or 0.5 mg/mL. After

rates were determined, a third set of incubations were performed to evaluate the ability of

each acrylate to conjugate with glutathione in the presence of glutathione transferases

(GST).

In rat liver microsomes, eight acrylate esters (excluding tert-BA) were hydrolyzed to form

the metabolite acrylic acid (AA). For some acrylates (i.e., EA, BA, iso-BA), the half-life

values calculated from the concentration of the remaining parent acrylate were comparable

to the half-life values calculated from the parent acrylate concentration calculated from AA

formation, indicating that these parent compounds were metabolized to AA. The small

acrylates (MA, EA, BA, iso-BA) and the large acrylate (2-EHA) have a half-life of less than

8.5 minutes (0.77-8.2 min); HEA, HPA, and 2-PHA have half-life values of longer than

15 minutes. Under these rat liver microsomal conditions, tert-BA is relatively stable.

In whole rat blood, all nine acrylate esters are rapidly metabolized. However, unlike the rat

liver microsomal incubations, the concentrations of the acrylates calculated from the formed

AA were significantly lower than the concentrations of the remaining corresponding

acrylates. Thus, despite significant loss in parent acrylates, there is not a corresponding

formation of AA in blood. In fact, AA was not quantifiable from blood incubations of MA,

tert-BA, or HPA. As opposed to liver microsomal incubations, tert-BA was quickly

metabolized in rat blood. Based on the measured concentrations of the remaning parent

acrylates and the concentrations of the parent acrylates calculated from the formed AA, the

half-life values for all acrylates are less than 12 minutes in rat blood (0.99-11.2 min).

In the serial substrate concentrations (32.25, 62.5, 125, 250, and 500 μM) of acrylate esters,

further experiments were conducted to determine Km and Vmax values for acrylate ester

hydrolysis to AA in rat liver microsomes. Km and Vmax values were determined for seven of

nine acrylate esters excluding HEA and tert-BA. The measured Km and Vmax values range

from 503 to 2002 (μM) and 169 to 1188 (nmol/min/mg), respectively.

All nine acrylates formed a single GSH conjugate in the presence of GST. The rate of

formation of these GSH conjugates ranged from 1.2 to 3.94 nmol/mg protein/min.

Overall, these in vitro metabolism results indicate that all nine acrylate esters can be quickly

metabolized primarily through hydrolysis to AA and/or glutathione conjugation in vivo.

Description of key information

The pharmacokinetics of 14C-HEA (14C-2-hydroxyethyl acrylate) in male rats following oral, intraperitoneal, dermal or inhalation exposure were determined to investigate possible route- or dose-dependent differences in disposition and bioavailability. The data show that rapid and complete absorption of HEA occurred following intraperitoneal or oral administration to rats. However, dermal absorption of HEA was markedly slower than after oral or IP administration and was not complete within 48 hr.

A fast metabolic elimination was shown in in vitro toxicokinetic study in which nine acrylates including 2 -hydroxyethyl acrylate and 2-hydroxypropyl acrylate were tested. The in vitro metabolism results indicate that all nine acrylate esters (methyl acrylate (MA), ethyl acrylate (EA), butyl acrylate (BA), iso-butyl acrylate (iso-BA), tert-butyl acrylate (tert-BA), 2-hydroxyethyl acrylate (HEA), 2-hydroxypropyl acrylate (HPA), 2-ethylhexyl acrylate (2-EHA), and 2-propylheptyl acrylate (2-PHA)) can be quickly metabolized primarily through hydrolysis to AA and/or glutathione conjugation in vivo.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - dermal (%):

66

Additional information

No reliable studies concerning toxicokinetics, metabolism and distribution were identified for 4-hydroxybutyl acrylate (HBA). However, the structural analogue 2-hydroxyethyl acrylate (CAS No. 818-61-1) was investigated in rats using several routes of exposure. The metabolism, distribution and excretion of uniformly labelled 14C-2-hydroxyethyl acrylate was examined in male Fischer 344 rats using oral, intraperitoneal, dermal and inhalation routes of exposure. The results of the study indicate that once the chemical becomes systemically available, it is rapidly metabolized and eliminated from the body as either CO2 in the expired air or urinary metabolites. More than 70 % of the administered dose of HEA-derived 14C was excreted within 12 hr post-dosing or post-exposure as urinary metabolites and as 14CO2 in the expired air for the oral, intraperitoneal, and inhalation routes. No qualitative differences in urinary metabolites between routes were observed, indicating no marked route-dependent differences in the metabolic fate of 2 -hydroxyethyl acrylate (HEA). According to the metabolic scheme proposed by BAMM (1992) metabolism occurs by two primary routes, hydrolysis of the ester linkage by carboxylesterase to acrylic acid and ethylene glycol, and conjugation with glutathione (GSH). Both pathways serve to detoxify 2-hydroxyethyl acrylate. In rats, the metabolism of ethylene glycol proceeds via the alcohol and aldehyd dehydrogenase pathway finally resulting in the formation of CO2 and acrylic acid which is rapidly incorporated into the normal cellular metabolism via the propionate degradative pathway. Conjugation of 2-HEA with GSH can occur spontaneously by a Michael addition or can be mediated by GSH transferase. The conjugated form is rapidly excreted by the kidney. Based on the structural similarity of HEA and HBA, similar kinetics of 4-hydroxybutyl acrylate are anticipated.

Discussion on bioaccumulation potential result

No reliable studies concerning toxicokinetics, metabolism and distribution were identified for 4-hydroxybutyl acrylate (HBA). However, the structural analogue 2-hydroxyethyl acrylate was investigated in rats using several routes of exposure. Based on the structural similarity of 2 -hydroxylethyl acrylate and 4 -hydroxybuthyl acrylate, similar adsorption kinetics of 4 -hydroxybutyl acrylate are anticipated. Based on this in principle, GI-, respiratory- and dermal absorption of 4-hydroxybutyl acrylate to a major extent is not expected due to physico chemical properties (log Pow: 0.77; water solubility: 1000 g/L, molecular weight: 144.16 g/mol).

In vitro Studies

To determine the in vitro rate of degradation or metabolism of 2-HEA in rat blood, male Fischer 344 rats were anesthetized, exsanguinated via cardiac puncture and their blood obtained. Triplicate samples (along with corresponding blank) were prepared at three concentration levels (100, 10 and 1 µg 2-HEA/mL) for each time point selected. In addition to the 2-HEA spiking solutions, an internal standard (2-hydroxyethyl methacrylate, 2-HEMA at a concentration of 0.5 µg/mL) was added at 15 seconds, 30 seconds, 1 min, 2 min and 5 min after spiking. Quantification of 2-HEA in the blood extracts by gas chromatography-mass spectrometry was based on comparison of the extract response to the external standard response taking into account the ratio of the 2-HEA response to that of the internal standard (2-HEMA). The in vitro half-life of 2-hydroxyethyl acrylate in rat blood was approx. 100 sec (BAMM 1992).

In vivo Studies

The metabolism, distribution and excretion of uniformly labelled14C-2-hydroxyethyl acrylate was examined in male Fischer 344 rats using oral, intraperitoneal, dermal and inhalation routes of exposure (BAMM 1992). For the oral and intraperitoneal routes of exposure rats (4 animals/dose level/route of exposure) received a single dose of 2.5 or 50 mg/kg body weight (approximately 20 μCi), respectively. For the inhalation exposure six rats were exposed to a target vapour concentration of 8 ppm (corresponding to approx. 0.0385 mg/L and to approx. 0.2 µCi/L)14C-HEA for 6 hours nose only under dynamic flow-through conditions. For the dermal exposure 4 rats were treated under occlusive conditions with14C-HEA at a dose of 12.5 mg/kg body weight (approximately 15-20 μCi). The results of the study indicate that once the chemical becomes systemically available it is rapidly metabolized and eliminated from the body as either CO2 in the expired air or urinary metabolites. More than 70 % of the administered dose of HEA-derived 14C was excreted by 12 hr post-dosing or post-exposure as urinary metabolites and as 14CO2 in the expired air for the oral, ip, and inhalation routes. For the oral and intraperitoneal routes (2.5 mg/kg bw) 35-36 % of the administered dose was expired as14CO2 and 43 - 47 % of the dose excreted via urine by 48 hours post-dosing. At 50 mg/kg bw following oral and ip administration, there was some evidence of saturation kinetics, with 40 – 45 % of the dose expired as 14CO2 and 33 – 36 % of the dose excreted in the urine. The rate of absorption of HEA appeared to be route-dependent and was complete within 4 hr or less when HEA was given by the oral or ip routes of administration. Following dermal administration 66 % of the dose was slowly absorbed within 48 hours of the application with the remaining 33 % being associated with the application site. Of the absorbed dose 27 % was excreted in the urine as metabolites of HEA and 27 % was excreted in the expired air as 14CO2. For inhalation 39 % of the14C-activity recovered at 48 hr was eliminated in the urine and 41 % was expired as 14CO2. For all routes, 9 – 16 % of the dose or recovered activity was found in the tissues and carcass and less than 3 % in the faeces. The half-lives of elimination of radioactivity in the urine and for expired 14CO2 were 14 h and 17 h, respectively. The half-life of elimination of radioactivity in the plasma was determined to be 26 hr and did not represent the parent chemical. No qualitative differences in urinary metabolites between routes were observed, indicating no marked route-dependent differences in the metabolic fate of HEA. HPLC analyses were performed on pooled urine specimens from all treatment groups and exposure routes. Radiochromatograms of the urinary metabolites contained four major peaks or peak groups of radioactivity. One metabolite could be identified as N-acetyl-S-(carboxylethyl)cysteine by GC/EI/MS. No attempts were made to identify the other three major 14C peaks, however, none of the three peaks were found to correspond to the retention times of HEA or acrylic acid. The available metabolic data on HEA is consistent with information on other acrylates where hydrolysis of the ester functionality is the primary metabolic pathway. By analogy with e.g. ethyl acrylate or acrylic acid it is expected that a minor metabolic pathway for HEA will be via conjugation with glutathione with the resulting mercapturic acid derivatives being excreted in the urine. This is supported by the identity of one of the major urinary metabolites of HEA.

Conclusion

Animal studies indicated rapid metabolism via hydrolysis of the ester functionality with the subsequent rapid metabolism of the hydrolysis products to produce exhaled CO2 or urinary metabolites (mercapturic acid derivatives). There were no marked route-dependent differences in the metabolic fate of HEA when administered by the oral, intraperitoneal, dermal or inhalation routes of exposure. Based on the similarity of the results for HEA with other acrylic acid esters, similar kinetics of 4-hydroxybutyl acrylate are anticipated.

Discussion on absorption rate

No reliable studies concerning dermal absorption were identified for 4-hydroxybutyl acrylate. However, the structural analogue 2-hydroxyethyl acrylate was investigated in rats by the dermal route of exposure. The metabolism, distribution and excretion of uniformly labelled 14C-2-hydroxyethyl acrylate was examined in male Fischer 344 rats using dermal application (BAMM 1992). 4 rats were treated under occlusive conditions with 14C-HEA at a dose of 12.5 mg/kg body weight (approximately 15-20 μCi). Following dermal administration 66 % of the dose was slowly absorbed within 48 hours of the application with the remaining 33 % being associated with the application site. Of the absorbed dose 27 % was excreted in the urine as metabolites of HEA and 27 % was excreted in the expired air as 14CO2. HPLC analyses were performed on pooled urine specimens. Radiochromatograms of the urinary metabolites contained four major peaks or peak groups of radioactivity. One metabolite could be identified as N-acetyl-S-(carboxylethyl)cysteine by GC/EI/MS. The dermal absorption of HEA was relatively slow with a half-life in the order of 24 hr or greater, which was confirmed by plasma and red blood cell radioactivity concentration-time curves, amount remaining on the skin at sacrifice, and the lag time in peak urinary and CO2 excretion. Based on the structural similarity of HEA and HBA, similar adsorption kinetics of 4-hydroxybutyl acrylate are anticipated.