Acrylic acid, monoester with propane-1,2-diol

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Version / remarks:

parts of the guidelines are taken

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics)

GLP compliance:

yes (incl. QA statement)

Radiolabelling:

no

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Sulzfeld, Germany
- Age at study initiation: 6-12 weeks
- Weight at study initiation: 250 - 350 g prior to dosing
- Housing: During acclimatization animals were housed in groups in Polysulfonate cages (2000P; H Temp (PSU), 2065 qcm, Tecniplast). During plasmakinetic experiments animals were kept individually. in Polycarbonate cages (1291H; PC, 820 cm2, Tecniplast) for experiments 1 and 2 and in Polycarbonate cages III (800 cm2, Tecniplast) for experiments 3 – 6.
- Diet (e.g. ad libitum): Kliba lab diet (mouse/rat "GLP"); Provimi Kliba SA, Kaiseraugst, Switzerland (ad libitum)
- Water (e.g. ad libitum): tap water (ad libitum)
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The test substances were weighed in, filled up with tap water to an appropriate weight and were solved by stirring at room temperature on a magnetic stirrer for about 5 min. The resulted solutions with defined concentrations were used for the test-substance administrations. 10 mL/kg bw of test-substance preparation was dosed orally by gavage.

Duration and frequency of treatment / exposure:

once

Dose / conc.:

200 mg/kg bw/day (nominal)

Remarks:

Hydroxypropylacrylate

Dose / conc.:

117 mg/kg bw/day (nominal)

Remarks:

Propylene glycol

No. of animals per sex per dose / concentration:

4

Control animals:

no

Details on study design:

- Dose selection rationale:
By request of the sponsor the following dose levels were selected:
dose 1 with Hydroxypropylacrylate: 250 mg/kg body weight, (p.o.), (1.92 mmol/kg body weight)
dose 2 with Propylene glycol: 146 mg/kg body weight (p.o.), (1.92 mmol/kg body weight)
Based on the unforeseen toxicity of HPA at a dose level of 250 mg/kg bw under the test conditions used, the experiment was repeated with two dose groups at lower dose levels. Additionally, conditions were optimized to reduce potential stress during blood sampling. In agreement with the sponsor the additional dose levels were tested:
dose 3, Hydroxypropylacrylate: 200 mg/kg body weight, (p.o.), (1.54 mmol/kg body weight)
dose 4, Propylene glycol: 117 mg/kg body weight (p.o.), (1.54 mmol/kg body weight)
dose 5, Hydroxypropylacrylate: 50 mg/kg body weight, (p.o.), (0.38 mmol/kg body weight)
dose 6, Propylene glycol: 29 mg/kg body weight (p.o.), (0.38 mmol/kg body weight)

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood, plasma
- Time and frequency of sampling: blood samples 10 and 30 min, 1, 2, 4, 8, 24, 48, 72, 96 hours

Plasma kinetics were investigated in order to determine the pharmacokinetic parameters of the test substances in rats. It was of special interest to demonstrate the absence of HPA in the systemic circulation and to investigate the internal doses of PG (quantified as AUC) for equimolar oral doses of HPA and PG. The hypothesis of comparable internal doses of PG after oral equimolar dosings of HPA and PG is based on the assumption of a complete first pass effect of HPA by hydrolysis and its quantitative conversion into the corresponding glycol derivative.

The plasma concentrations of individual animals and thereof derived mean values after single oral administrations of HPA and PG to male Wistar rats at target dose levels of 200 and 117 mg/kg bw (corresponding to 1.54 mmol/kg bw for both test substances) . Kinetic results of dose groups 1 and 2 are not determined based on observed, unexpected toxicities of HPA at a target dose of 250 mg/kg bw under the applied test conditions. Plasma samples of these dose groups were not analysed. Kinetic results of dose groups 5 and 6 are not evaluated because these dose groups were foreseen as simultaneous back up groups in case of unexpected toxicities of HPA at a target dose of 200 mg/kg bw (dose group 3). Since dose groups 3 and 4 are assessed to be valid, plasma samples of dose groups 5 and 6 were not analysed and no kinetic results were generated.

Hydroxypropyl acrylate: target dose of 200 mg/kg bw: In male Wistar rats exposed to a single oral target dose of 200 mg HPA/kg bw (corresponding to 1.54 mmol/kg bw), the mean actual nominal dose of 206.2 mg/kg bw was administered. In plasma samples taken before, and from 0.17 hours post dosing up to 96 hours post dosing, no HPA could be detected in plasma. For the analyte PG, the maximum mean plasma concentration of 22.5 μg/mL occurred 1 hour post dosing, declined to 3.7 μg/mL at 8 hours, to 0.5 μg/mL at 24 hours and was negligible at later sampling time points. The individual maximum mean plasma concentrations for PG ranged from 14.0 to 28.0 μgmL. The terminal half-lifes ranged from 1.4 to 3.8 hours. The mean terminal half life was 2.7 hours. For the analyte PG, the calculated values for the area under the plasma concentration time curve AUD ranged for individual animals from 90 to 157 [μg x h/mL]. For rat 12, the AUD was calculated to be 57 [μg x h/mL]. However, since there were no quantitative values for the plasma samples at 4 and 8 hours, this AUD is assessed to be underpredictive and was not included into the statistics of this pharmacokinetic parameter. The calculated mean AUD for rats 9 to 11 was 125±33 [μg x h/mL]. The data of this dose group demonstrate a fast absorption of HPA after oral dosing in the rat and its metabolic first pass effect. PG could be identified as a major systemic metabolite of Hydroxypropylacrylate.

Propylene glycol: target dose of 117 mg/kg bw: In male Wistar rats exposed to a single oral target dose of 117 mg PG/kg bw (corresponding to 1.54 mmol/kg bw), the mean actual nominal dose of 116.9 mg/kg bw was administered. PG was not detected in plasma samples taken before dosing but was present in plasma samples taken between 0.17 hours to 8 hours post dosing. The maximum mean plasma concentration of 66.8 μg/mL occurred 0.5 hours post dosing, declined to 1.1 μg/mL at 8 hours and was negligible at later sampling time points. The individual maximum mean plasma concentrations for PG ranged from 61.0 to 72.0 μgmL. The terminal half-lifes ranged from 1.2 to 1.6 hours. The mean terminal half life was 1.3 hours. For the analyte PG, the calculated values for the area under the plasma concentration time curve AUD ranged for individual animals from 169 to 198 [μg x h/mL]. The calculated mean AUD was 182±12 [μg x h/mL]. The data of this dose group demonstrate a fast absorption of PG after oral dosing to rats. The measured plasma concentrations and the calculated AUD outline that unmetabolized PG is the major component of its systemic dose. In the current experiments, the calculated maximum plasma concentrations as well as the AUDs for equimolar oral doses of 1.54 mmol/kg bw of HPA and PG resulted in values of 22.5 and 66.8 [μg/mL] as well as 125 and 182 [μg x h/mL], respectively. These results demonstrate that the maximum plasma concentrations of PG is about 3-fold higher for and equimolar dose of PG compared to HPA. The corresponding internal dose of PG is 47% higher for an equimolar oral dose of PG compared to dosed HPA. It may be assumed that this observation is based on potential direct reaction of the monomer in the stomach, i.e. with glutathione, which is known for this chemistry.

Conclusions:

Overall, the data of the current study demonstrate that HPA and PG are fast metabolized when dosed orally to male Wistar rats. After one oral dose of HPA, the acrylate itself could not be determined in rat plasma, demonstrating a complete metabolic first pass effect. Consequently, for orally dosed HPA as well as for orally dosed PG, PG is the major entitiy in the systemic circulation. When the plasma concentrations of PG are compared quantitatively for an equimolar target dose of the test substances of 1.54 mmol/kg bw, the maximum plasma concentration was about 3-fold and the internal dose about 50% higher for administered PG compared to HPA.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Objective of study:

toxicokinetics

Principles of method if other than guideline:

The study was conducted to investigate in vitro hydrolysis and glutathione conjugation rates of selected acrylates

GLP compliance:

no

 

Incubation Types	Rat Liver Microsomal Incubations				Rat Blood Incubations				GSH incubations in the presence of GST
Compound Name	Ke from parent (min)	Half-Life from parent (min)	Ke from AA formation (min)	Half-Life from AA formation (min)	Ke from parent (min)	Half Life from parent compound (min)	Ke from AA fromation (min)	Half Life from AA formation (min)	Rate formation (nmol/mg protein.min)
Hydroxyethyl acrylate (HEA)	0.0089	61.1	0.0111	62.4	0.271	2.56	ND	ND	1.87
Hydroxypropyl acrylate (HPA)	0.0295	23.5	0.0231	30.0	0.704	0.985	ND	ND	2.35

2-hydroxyethyl acrylate (HEA, purity 97.52 wt%) and 2 -hydroxypropyl acrylate (HPA, purity 97.87 wt%) 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 HEA and HPA were hydrolyzed to form the metabolite acrylic acid (AA), half-life values of ranging from 30 minutes to 61 minutes

In whole rat blood, HEA and HPA are rapidly metabolized, shown by a significant and (nearly) complete loss of the parent acrylate.

The acrylates formed a single GSH conjugate in the presence of GST. The rate of formation of these GSH conjugates ranged from 1.87 to 2.35 nmol/mg protein/min.

Overall, these in vitro metabolism results imply that the acrylate esters can be quickly metabolized through hydrolysis to AA and/or glutathione conjugation in vivo.

Reference 3

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

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

Adequacy of study:

supporting study

Study period:

03 June 1987 - 10 Dec 1992

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented study report which meets basic scientific principles, acceptable for assessment

Objective of study:

metabolism

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

GLP compliance:

yes

Radiolabelling:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories (Kingston, NY; Raleigh, NC)
- Age at study initiation: young adult animals
- Weight at study initiation: approx. 200 g
- Fasting period before study: feed withdrawal approximately 8 hr prior to administration of the 14C-HEA and food was returned about 4 hr post-dosing for all routes of exposure.
- Individual metabolism cages: no data
- Diet (ad libitum): certified rodent chow (Purina Mills Inc., Purina #5002)
- Water (ad libitum): municipal tap water
- Acclimation period: at least one week plus acclimation to glass Roth-type metabolism cages for at least 2 days prior to the administration


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 h / 12 h

Toxicokinetic parameters:

half-life 1st: The in vitro half-life of 2-HEA in rat blood at concentration of 1,10 or 1000 µg/mL was 103 ± 18 seconds or 1.7 min with no observed concentration dependence over two orders of magnitude.

Metabolites identified:

not measured

Results:

 

The in vitro half-life of 2-HEA in rat blood at concentration of 1,10 or 1000 µg/mL was 103 ± 18 seconds or 1.7 min with no observed concentration dependence over two orders of magnitude.

Reference 4

Endpoint:

basic toxicokinetics

Type of information:

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

Adequacy of study:

supporting study

Study period:

03 June 1987 - 10 Dec 1992

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented, GLP-compliant study report which meets basic scientific principles, acceptable for assessment

Objective of study:

toxicokinetics

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Version / remarks:

and OECD TG 427

GLP compliance:

yes

Radiolabelling:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories (Kingston, NY; Raleigh, NC)
- Age at study initiation: young adult animals
- Weight at study initiation: approx. 200 g
- Fasting period before study: feed withdrawal approximately 8 hr prior to administration of the 14C-HEA and food was returned about 4 hr post-dosing for all routes of exposure.
- Individual metabolism cages: no data
- Diet (ad libitum): certified rodent chow (Purina Mills Inc., Purina #5002)
- Water (ad libitum): municipal tap water
- Acclimation period: at least one week plus acclimation to glass Roth-type metabolism cages for at least 2 days prior to the administration


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 h / 12 h

Route of administration:

dermal

Vehicle:

water

Details on exposure:

TEST SITE
- Area of exposure: interscapularly and as far anteriorly on the back as possible, 4 cm2
- Type of wrap if used: Immediately after dosing, the dosed area was covered with a piece of teflon@ film (4 an X 4 an) which was secured to the Stomahesive patch/well with surgical adhesive. The dosed area was then wrapped with veterinary bandaging tape.
- Time intervals for shavings or clipplings: before exposure

Duration and frequency of treatment / exposure:

48 hr exposure

Remarks:

Doses / Concentrations:
12.5 mg/kg bw (corresponding to 15-20 µCi of radioactivity)

No. of animals per sex per dose / concentration:

4

Control animals:

no

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, plasma, serum, cage washes, bile, 14CO2
- Time and frequency of sampling:
urine (0-12, 12-24 and 24-48 hr post-dosing), faeces (at 24 hr intervals), 14CO2 (0.25, 0.5, 1, 2, 4, 8, and 12 hr post-exposure) (trapped in a mixture of CO2 trapping solution (monoethanolamine: methoxy-2-propanol, 3:7, v/v) and combustion scintillant (Spectrafluor@:methoxy-2-propanol:toluene 12:22:66, v/v)
Blood samples (100 µL) for the 14C plasma and red blood cell time-couse determinations were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 30 and 48 hr after the administration of 14C-HEA by the dermal route.

Statistics:

The half-lives for the CO2 excretion and the plasma radioactivity were determined from the slope of the line obtained by regression analysis of the excretion time-course obtained from each treatment group. Statistical analysis of the data was limited to the calculation of means and standard deviations where appropriate. Pharmacokinetic analysis (calculation of half-lives, AUC's etc.) were carried out using standard methodologies.

Details on distribution in tissues:

For the dermal route of administration, about 33 % of the applied dose recovered was associated with the skin or materials used for restricting access to the dermal dose site. Of this 33 %, 11 % of the applied radioactivity was associated with the dosed skin and the remaining 22 % was recovered in the components of the bandage (Stomahesive patch/well, which defined the dosed site, Teflon@ cover and VetRap@). Nine percent of the dose was found in the tissues and carcass.

Details on excretion:

For the dermal route of administration, 27 % of the radioactivity was recovered in the urine and a similar amount of 27 % was recovered as 14CO2. Less than 1 % of the dose was found as volatile organics in the expired air and in the final cage wash and only 0.6 % of the dose was recovered in the faeces.
Following dermal application, nonquantifiable levels of 14CO2 were observed for up to one half hour post application. In addition, there was a lag in peak 14CO2 excretion as compared to the oral and ip routes of administration. This peak occurred at the 12-24 hr collection interval. By 12 hr post-dosing, only 13 % of the dose had been eliminated as 14CO2 in the expired air. The exhalation of 14CO2 derived from 14C-HEA appeared to follow first-order kinetics as a biphasic process, except following dermal administration.
For the dermal route of administration, 38 % of the total radioactivity excreted via the urine was excreted during the 0-12 hr interval and about the same percentage was excreted in the 12-24 hr collection interval.

Metabolites identified:

yes

Details on metabolites:

HPLC analyses were performed on pooled urine specimens from all treatment groups. Recovery from the HPLC System ranged from 90% to 114%. For all treatment groups, the 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 average 14C-HEA doses (mg/kg bw) administered to the dermal treatment group ranged from 84 % to 107 % of target.

No signs of toxicity were observed following dermal administration. In addition, at 48 hr post-dermal application there was an absence of skin irritation.

Since an average of only 66 % of the applied dermal dose was absorbed within 48 hr post-dosing, the dermal absorption of 14C-HEA was a relatively slow process.

The data show, that once systemically available, HEA is rapidly metabolized and eliminated from the body.

Half-lives:

Following the 12.5 mg/kg dermal dose, the half-life for the terminal phase of elimination via 14CO2 was determined to be approximately 17 hr. The half-life for the initial phase of elimination was 4.9.

For the dermal route of administration the half-life of elimination in the urine was approximately 14 hr.

The blood concentration-time profile following dermal administration showed a slow rise in 14C blood concentrations from 15 min post-dosing to peak at 12 hr postdosing, suggesting a slow rate of dermal absorption. However, following dermal absorption the plasma radioactivity concentration-time profile was monophasic suggesting a first order process of elimination. The terminal half-life for the disappearance of plasma 14C activity following dermal dosing was 45 hr. However, this may actually represent the half-life for absorption.

Distribution of radioactivity 48 hr after exposure:

Tissues	Dermal*
	12.5 mg/kg bw
Urine	27.38±3.06
Faeces	0.59±0.41
Tissues & carcass	9.19±0.93
14CO2	26.53±2.73
Volatile organics	0.36±0.45
Cage wash	0.70±0.28
Dose site	32.80±6.16
Total	97.54±1.06

* Percent of dose

Values represent Mean ± SD for 4 animals.

Reference 5

Endpoint:

basic toxicokinetics

Type of information:

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

Adequacy of study:

supporting study

Study period:

03 June 1987 - 10 Dec 1992

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented, GLP-compliant study report which meets basic scientific principles, acceptable for assessment

Objective of study:

toxicokinetics

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

GLP compliance:

yes

Radiolabelling:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories (Kingston, NY; Raleigh, NC)
- Age at study initiation: young adult animals
- Weight at study initiation: approx. 200 g
- Fasting period before study: feed withdrawal approximately 8 hr prior to administration of the 14C-HEA and food was returned about 4 hr post-dosing for all routes of exposure.
- Individual metabolism cages: no data
- Diet (ad libitum): certified rodent chow (Purina Mills Inc., Purina #5002)
- Water (ad libitum): municipal tap water
- Acclimation period: at least one week plus acclimation to glass Roth-type metabolism cages for at least 2 days prior to the administration and acclimation to the head-only chamber for approximately six days prior to the inhalation exposure


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 h / 12 h

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Details on exposure:

TYPE OF INHALATION EXPOSURE: nose only (dynamic flow-through conditions)

GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
The 14C-HEA vapour was generated by pumping air with an FMI pump (Fluid Metering Inc., Oyster Bay, NY) at the rate of 0.5 liters/min through a glass U-tube packed with glass beads and containing an aqueous solution of 1%-HEA. The 1%-HEA vapour exiting the U-tube was then diluted and mixed (in a J-tube packed with Teflon coated glass beads) with approximately 1.5 liters of air so that the total flow through the chamber was approximately 2.0 liters/min, and the target radioactivity of the vapour generated was approximately 0.2 µCi/liter. In order to accurately determine HEA exposure concentration, a sampling Port was positioned in the animals' breathing Zone to sample the chamber atmosphere. The HEA concentration and radioactivity were determined by sampling 103 mL/min of the chamber atmosphere onto silica gel tubes for 13.68 min. The 14C-HEA trapped on the silica gel was desorbed with a solution of 10% (10:90, v/v) acetonitrile in MILLI-Q @ water. Aliquots of these solutions were then analyzed by HPLC and liquid scintillation counting to determine the concentration of HEA and radioactivity in the chamber. Six samples of the chamber atmosphere were analyzed for HEA during the six hour exposure.

Duration and frequency of treatment / exposure:

once for a 6 hrs period

Remarks:

Doses / Concentrations:
8 ppm (corresponding to approx. 0.0385 mg/L)
Recalculation based on the equation c(mg/m3) = molar mass (g) / molar volume (L) x c(mL/m3) with molecular weight (116.12 g/mol) and molar volume (24.1 L at 20 °C and 1013 hPa) [DFG, MAK List, Wiley-VCH Verlag, 2005].

No. of animals per sex per dose / concentration:

4

Control animals:

no

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, plasma, serum, cage washes, bile, 14CO2
- Time and frequency of sampling:
urine (0-12, 12-24 and 24-48 hr post-dosing), faeces (at 24 hr intervals), 14CO2 (0.25, 0.5, 1, 2, 4, 8, and 12 hr post-exposure) (trapped in a mixture of CO2 trapping solution (monoethanolamine: methoxy-2-propanol, 3:7, v/v) and combustion scintillant (Spectrafluor@:methoxy-2-propanol:toluene 12:22:66, v/v)
During the inhalation exposure blood samples were collected at 0.25, 0.5, 1, 2, 4 and 6 hr, and 0.5, 1, 2, 4, 8, 20, 30 and 48 hr post inhalation exposure.

Statistics:

The half-lives for the CO2 excretion and the plasma radioactivity were determined from the slope of the line obtained by regression analysis of the excretion time-course obtained from each treatment group. Statistical analysis of the data was limited to the calculation of means and standard deviations where appropriate. Pharmacokinetic analysis (calculation of half-lives, AUC's etc.) were carried out using standard methodologies.

Details on distribution in tissues:

Following inhalation exposure, 39 % of activity recovered was eliminated in the urine and 41 % of the activity recovered was expired as 14CO2. The tissues and carcass accounted for 16 % of the activity recovered and 3 % of the recovered activity was in the faeces at 48 hr postdosing.

Details on excretion:

During the inhalation exposure an average of 25 % of the total radioactivity recovered from each animal was expired as 14CO2 by the end of the 6 hr exposure. As early as 1.5 hr post-exposure, approximately 3 % of the recovered radioactivity was excreted as 14CO2 in the breath. A total of 36 % of the recovered radioactivity was expired as 14CO2 during exposure and 12 hr post-exposure, indicating that the metabolism of inhaled 14C-HEA to 14CO2 occurred rapidly after absorption. The exhalation of 14CO2 derived from 14C-HEA appeared to follow first-order kinetics as a biphasic process, except following dermal administration.
During the 6 hr inhalation exposure 22 % of the recovered activity was excreted in the urine. By 12 hr post-exposure, 89 % of the total activity eliminated via this route had already been excreted.

Metabolites identified:

yes

Details on metabolites:

HPLC analyses were performed on pooled urine specimens from all treatment groups. Recovery from the HPLC System ranged from 90% to 114%. For all treatment groups, the 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 test atmosphere averaged 8.9 ppm HEA with an activity of 0.215 µCi/liter air. The test atrnosphere ranged from 70 % to 138 % and 55 % to 112 % of the target HEA concentration and radioactivity concentrations, respectively. No signs of toxicity were observed following inhalation exposure.

During the inhalation exposure samples of urine and faeces were collected from individual animals. The combined 14CO2 expired by all four rats was also collected from the chamber exhaust. Therefore, the percent of the recovered dose received by inhalation exposure could be determined by calculating the µg equivalents of HEA recovered during and post-exposure. Based on µg equivalents of HEA, the inhalation dose was determined to be 12.7 mg/kg bw. Similarly, by comparing the areas under the plasma curves (AUC) for the oral and ip routes of administration to the plasma AUC for the inhalation route, the inhalation dose was determined to be equivalent to a 12 mg 14C-HEA/kg body weight.

The data show, that once systemically available, HEA is rapidly metabolized and eliminated from the body.

Half-lives:

Following the 8 ppm inhalation exposure, the half-life for the terminal phase of elimination via 14CO2 was determined to be approximately 19 hr. The half-life for the initial phase of elimination was 0.52.

For the inhalation exposure the half-life of elimination in the urine was determined to be 20 hr.

The half-life of elimination of radioactivity in the plasma was 24 hr for the 8 ppm inhalation treatment group.

Distribution of radioactivity 48 hr after exposure:

Tissues	Inhalation**
	8ppm
Urine	38.56±7.05
Faeces	2.98±1.12
Tissues & carcass	16.34±1.76
14CO2	40.54
Volatile organics	0.84±0.06
Cage wash	0.53±0.28
Dose site	na
Total	100

**Percent of recovered radioactivity during the 6 hr exposure plus 14C-activity recovered in the 48 hr post-exposure.

Values represent Mean ± SD for 4 animals.

na: not applicable

Reference 6

Endpoint:

basic toxicokinetics

Type of information:

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

Adequacy of study:

supporting study

Study period:

03 June 1987 - 10 Dec 1992

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented, GLP-compliant study report which meets basic scientific principles, acceptable for assessment

Objective of study:

toxicokinetics

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

GLP compliance:

yes

Radiolabelling:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories (Kingston, NY; Raleigh, NC)
- Age at study initiation: young adult animals
- Weight at study initiation: approx. 200 g
- Fasting period before study: feed withdrawal approximately 8 hr prior to administration of the 14C-HEA and food was returned about 4 hr post-dosing for all routes of exposure.
- Individual metabolism cages: no data
- Diet (ad libitum): certified rodent chow (Purina Mills Inc., Purina #5002)
- Water (ad libitum): municipal tap water
- Acclimation period: at least one week plus acclimation to glass Roth-type metabolism cages for at least 2 days prior to the administration


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 h / 12 h

Route of administration:

intraperitoneal

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The radiotracer was diluted with non-radiolabeled HEA to obtain a target radioactivity and concentration of 20 µCi and 1.75 and 36.7 mg/mL of dosing solution, respectively. Weighed aliquots of dosing solutions were analyzed for radioactivity using liquid scintillation counting.


VEHICLE
- distilled and deionised water
- Amount of vehicle (if gavage): 1.33 mL/kg of body weight

Duration and frequency of treatment / exposure:

once

Remarks:

Doses / Concentrations:
2.5 and 50 mg/kg bw

No. of animals per sex per dose / concentration:

4

Control animals:

no

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, plasma, serum, cage washes, bile, 14CO2
- Time and frequency of sampling:
urine (0-12, 12-24 and 24-48 hr post-dosing), faeces (at 24 hr intervals), 14CO2 (0.25, 0.5, 1, 2, 4, 8, and 12 hr post-exposure) (trapped in a mixture of CO2 trapping solution (monoethanolamine: methoxy-2-propanol, 3:7, v/v) and combustion scintillant (Spectrafluor@:methoxy-2-propanol:toluene 12:22:66, v/v)
Blood samples (100 µL) for the 14C plasma and red blood cell time-couse determinations were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 30 and 48 hr after the administration of 14C-HEA by the ip route.

Statistics:

The half-lives for the CO2 excretion and the plasma radioactivity were determined from the slope of the line obtained by regression analysis of the excretion time-course obtained from each treatment group. Statistical analysis of the data was limited to the calculation of means and standard deviations where appropriate. Pharmacokinetic analysis (calculation of half-lives, AUC's etc.) were carried out using standard methodologies.

Details on distribution in tissues:

Following ip administration of 14C-HEA, between 91 and 95 % of the administered radioactivity was recovered in the urine, CO2, faeces, tissues and carcass, volatile organics and final cage wash.

Details on excretion:

At the low dose of 2.5 mg 14C-HEA/kg body weight, for the ip route of administration, approximately 43-47 % of the dose was eliminated in the urine, the primary elimination route, whereas 35-36 % of the dose was expired as 14CO2, and the tissues and carcass accounted for between 9-13 % of the dose. Less than 1.5 % of the administered dose of radioactivity was recovered in the faeces and less than 1 % was found in the final cage wash. Less than 0.2 % of the dose was recovered as volatile organics in the expired air.
At the higher dose of 50 mg/kg 14C-HEA/kg body weight, for the ip route of administration, 33-36 % of the dose was eliminated in the urine, whereas 40-45 % of the dose was expired as 14CO2. At this higher dose there was a shift from the urinary pathway as the primary route of elimination to the exhalation of 14CO2 as the primary route of elimination. As with the 2.5 mg/kg dose, the tissues and carcass accounted for 10-13 % of the dose and less than 0.6 % of the recovered radioactivity was in the final cage wash, less than 0.1 % was recovered as volatile organics in the expired air and less than 2.5 % of the dose was recovered in the faeces.
Following the ip route of administration, 0.3-1.5 % of the dose was expired as 14CO2 as early as 15 minutes post-dosing. The peak of CO2 excretion occurred during or before the 4-8 hr collection interval. By 12 hr post-dosing with 2.5 mg/kg for the ip route of administration, 31-32 % of the dose was expired as 14CO2. For this same collection interval following 50 mg/kg ip administration, 36 % of the dose was expired as 14CO2. The exhalation of 14CO2 derived from 14C-HEA appeared to follow first-order kinetics as a biphasic process, except following dermal administration.
Following ip administration, greater than 92 % of the total radioactivity excreted via the urine was excreted during the first 12 hr collection interval.

Metabolites identified:

yes

Details on metabolites:

HPLC analyses were performed on pooled urine specimens from all treatment groups. Recovery from the HPLC System ranged from 90% to 114%. For all treatment groups, the 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 average 14C-HEA doses (mg/kg bw) administered to the ip treatment group ranged from 84 % to 107 % of target.

No signs of toxicity were observed following ip administration exposure.

The data show, that once systemically available, HEA is rapidly metabolized and eliminated from the body.

Half-lives:

Following the 2.5 mg/kg and the 50 mg/kg ip dose, the half-lives for the terminal phase of elimination via 14CO2 were determined to be approximately 18, and 17 hr, respectively. The half-lives for the initial phase of elimination were 2.6, and 1.8, respectively.

The half life of elimination of radioactivity in the urine following ip administration were 16 and 13 hr for the 2.5 mg/kg bw ip and 50 mg/kg bw ip treatment groups, respectively.

Following the the 2.5 and 50 mg/kg ip doses, peak plasma concentrations of 14C were seen at the first blood sample collected (15 min post-dosing). The plasma data collected past 30 min post-dosing indicated that the plasma radioactivity was eliminated in an apparent monophasic first-order manner. The half-lives of elimination of radioactivity in the plasma were 25, 29 hr for the following

treatment groups: 2.5 mg/kg ip, 50 mg/kg ip, respectively.

Distribution of radioactivity 48 hr after exposure:

Tissues	IP*
	2.5 mg/kg bw	50 mg/kg bw
Urine	42.68±4.26	35.85±3.12
Faeces	0.76±0.31	0.57±0.14
Tissues & carcass	13.12±1.64	13.16±1.98
14CO2	34.87±2.13	40.39±3.88
Volatile organics	0.11±0.07	0.09±0.04
Cage wash	0.36±0.13	0.58±0.85
Dose site	na	na
Total	91.89±6.43	90.64±2.40

* Percent of dose

Values represent Mean ± SD for 4 animals.

na: not applicable

Reference 7

Endpoint:

basic toxicokinetics

Type of information:

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

Adequacy of study:

supporting study

Study period:

03 June 1987 - 10 Dec 1992

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented, GLP-compliant study report which meets basic scientific principles, acceptable for assessment

Objective of study:

toxicokinetics

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

GLP compliance:

yes

Radiolabelling:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories (Kingston, NY; Raleigh, NC)
- Age at study initiation: young adult animals
- Weight at study initiation: approx. 200 g
- Fasting period before study: feed withdrawal approximately 8 hr prior to administration of the 14C-HEA and food was returned about 4 hr post-dosing for all routes of exposure.
- Individual metabolism cages: no data
- Diet (ad libitum): certified rodent chow (Purina Mills Inc., Purina #5002)
- Water (ad libitum): municipal tap water
- Acclimation period: at least one week plus acclimation to glass Roth-type metabolism cages for at least 2 days prior to the administration


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 h / 12 h

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The radiotracer was diluted with non-radiolabeled HEA to obtain a target radioactivity and concentration of 20 µCi and 1.75 and 36.7 mg/mL of dosing solution, respectively. Weighed aliquots of dosing solutions were analyzed for radioactivity using liquid scintillation counting.


VEHICLE
- distilled and deionised water
- Amount of vehicle (if gavage): 1.33 mL/kg of body weight

Duration and frequency of treatment / exposure:

once

Remarks:

Doses / Concentrations:
2.5 and 50 mg/kg bw

No. of animals per sex per dose / concentration:

4

Control animals:

no

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, plasma, serum, cage washes, bile, 14CO2
- Time and frequency of sampling:
urine (0-12, 12-24 and 24-48 hr post-dosing), faeces (at 24 hr intervals), 14CO2 (0.25, 0.5, 1, 2, 4, 8, and 12 hr post-exposure) (trapped in a mixture of CO2 trapping solution (monoethanolamine: methoxy-2-propanol, 3:7, v/v) and combustion scintillant (Spectrafluor@:methoxy-2-propanol:toluene 12:22:66, v/v)
Blood samples (100 µL) for the 14C plasma and red blood cell time-couse determinations were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 30 and 48 hr after the administration of 14C-HEA by the oral route.

Statistics:

The half-lives for the CO2 excretion and the plasma radioactivity were determined from the slope of the line obtained by regression analysis of the excretion time-course obtained from each treatment group. Statistical analysis of the data was limited to the calculation of means and standard deviations where appropriate. Pharmacokinetic analysis (calculation of half-lives, AUC's etc.) were carried out using standard methodologies.

Details on distribution in tissues:

Following oral administration of 14C-HEA, between 91 and 95 % of the administered radioactivity was recovered in the urine, CO2, faeces, tissues and carcass, volatile organics and final cage wash.

Details on excretion:

At the low dose of 2.5 mg 14C-HEA/kg body weight, for the oral route of administration, approximately 43-47 % of the dose was eliminated in the urine, the primary elimination route, whereas 35-36 % of the dose was expired as 14CO2, and the tissues and carcass accounted for between 9-13 % of the dose. Less than 1.5 % of the administered dose of radioactivity was recovered in the faeces and less than 1 % was found in the final cage wash. Less than 0.2 % of the dose was recovered as volatile organics in the expired air.
At the higher dose of 50 mg/kg 14C-HEA/kg body weight, for the oral route of administration, 33-36 % of the dose was eliminated in the urine, whereas 40-45 % of the dose was expired as 14CO2. At this higher dose there was a shift from the urinary pathway as the primary route of elimination to the exhalation of 14CO2 as the primary route of elimination. As with the 2.5 mg/kg dose, the tissues and carcass accounted for 10-13 % of the dose and less than 0.6 % of the recovered radioactivity was in the final cage wash, less than 0.1 % was recovered as volatile organics in the expired air and less than 2.5 % of the dose was recovered in the faeces.
Following the oral route of administration, 0.3-1.5 % of the dose was expired as 14CO2 as early as 15 minutes post-dosing. The peak of CO2 excretion occurred during or before the 4-8 hr collection interval. By 12 hr post-dosing with 2.5 mg/kg for the oral route of administration, 31-32 % of the dose was expired as 14CO2. For this same collection interval following 50 mg/kg oral administration, 41 % of the dose was expired as 14CO2. The exhalation of 14CO2 derived from 14C-HEA appeared to follow first-order kinetics as a biphasic process, except following dermal administration.
Following oral administration, greater than 92 % of the total radioactivity excreted via the urine was excreted during the first 12 hr collection interval.

Metabolites identified:

yes

Details on metabolites:

HPLC analyses were performed on pooled urine specimens from all treatment groups. Recovery from the HPLC System ranged from 90% to 114%. For all treatment groups, the 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 average 14C-HEA doses (mg/kg bw) administered to the oral treatment group ranged from 84 % to 107 % of target. No signs of toxicity were observed following oral administration exposure.

The data show, that once systemically available, HEA is rapidly metabolized and eliminated from the body.

Half-lives:

Following the 2.5 mg/kg and 50 mg/kg oral dose, the half-lives for the terminal phase of elimination via 14CO2 were determined to be approximately 15, and 14 hr, respectively. The half-lives for the initial phase of elimination were 1.9, and 1.8, respectively.

The half life of elimination of radioactivity in the urine following oral administration were 10, and 9 hr for the 2.5 mg/kg bw oral and 50 mg/kg bw oral treatment groups, respectively.

Following the 2.5 mg/kg oral dose, peak plasma concentrations of 14C were seen at the first blood sample collected (15 min post-dosing). However, following the 50 mg/kg oral dose, peak plasma concentrations were not found until 4 hr post-dosing. The plasma data collected past 30 min post-dosing indicated that the plasma radioactivity was eliminated in an apparent monophasic first-order manner. The half-lives of elimination of radioactivity in the plasma were 28, and 26 hr for the following treatment groups: 2.5 mg/kg oral, and 50 mg/kg oral, respectively.

Distribution of radioactivity 48 hr after exposure:

 

Tissues	Oral*
	2.5 mg/kg bw	50 mg/kg bw
Urine	47.11±1.62	33.07±1.51
Faeces	1.33±0.28	2.37±1.26
Tissues & carcass	9.24±1.18	10.19±1.58
14CO2	36.00±1.14	45.47±0.66
Volatile organics	0.22±0.21	0.10±0.08
Cage wash	0.74±0.54	0.39±0.17
Dose site	na	na
Total	94.63±1.39	91.59±1.62

* Percent of dose

Values represent Mean ± SD for 4 animals.

na: not applicable

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results

Reference 8

Endpoint:

dermal absorption in vivo

Type of information:

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

Adequacy of study:

key study

Study period:

03 June 1987 - 10 Dec 1992

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented study report which meets basic scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 427 (Skin Absorption: In Vivo Method)

Version / remarks:

and OECD TG 417

GLP compliance:

yes

Radiolabelling:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories (Kingston, NY; Raleigh, NC)
- Age at study initiation: young adult animals
- Weight at study initiation: approx. 200 g
- Fasting period before study: feed withdrawal approximately 8 hr prior to administration of the 14C-HEA and food was returned about 4 hr post-dosing for all routes of exposure.
- Individual metabolism cages: no data
- Diet (ad libitum): certified rodent chow (Purina Mills Inc., Purina #5002)
- Water (ad libitum): municipal tap water
- Acclimation period: at least one week plus acclimation to glass Roth-type metabolism cages for at least 2 days prior to the administration


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 h / 12 h

Type of coverage:

occlusive

Vehicle:

water

Duration of exposure:

48 hr exposure

Doses:

12.5 mg/kg bw (corresponding to 15-20 µCi of radioactivity)

No. of animals per group:

4

Control animals:

no

Details on study design:

TEST SITE
- Area of exposure: interscapularly and as far anteriorly on the back as possible, 4 cm2
- Type of wrap if used: Immediately after dosing, the dosed area was covered with a piece of teflon@ film (4 an X 4 an) which was secured to the Stomahesive patch/well with surgical adhesive. The dosed area was then wrapped with veterinary bandaging tape.
- Time intervals for shavings or clipplings: before exposure

Signs and symptoms of toxicity:

no effects

Dermal irritation:

no effects

Absorption in different matrices:

- Skin test site: 32.80 ± 6.16 %
- Carcass: 9.19 ± 0.93 %
- Urine: 27.38 ± 3.06 %
- Cage wash: 0.70 ± 0.28 %
- Faeces: 0.59 ± 0.41 %
- Expired air: 26.53 ± 2.73 % (CO2) + 0.36 ± 0.45 % (volatile organics)

Total recovery:

- Total recovery: 97.54 ± 1.06 %

Dose:

12.5 mg/kg bw

Parameter:

percentage

Absorption:

ca. 66 %

Remarks on result:

other: 48 hr

Description of key information

Several in vitro and in vivo experimental studies have been performed on the toxicokinetic behaviour of HPA and HEA

In vitro:

In vitro studies support the rapid elimination of HPA and HEA (ARTF 2018).

In rat liver microsomes HEA and HPA were hydrolyzed to form the metabolite acrylic acid (AA), half-life values of ranging from 30 minutes to 61 minutes.

In whole rat blood, HEA and HPA are rapidly metabolized, shown by a significant and (nearly) complete loss of the parent acrylate. The acrylates formed a single GSH conjugate in the presence of GST. The rate of formation of these GSH conjugates ranged from 1.87 to 2.35 nmol/mg protein/min.

The in vitro half-life of 2-hydroxyethyl acrylate (HEA) in rat blood was approx. 100 sec (BAMM 1992).

 

Overall, these in vitro metabolism results imply that the acrylate esters can be quickly metabolized through hydrolysis to AA and/or glutathione conjugation in vivo, which is in line with the following in vivo data on HPA and HEA.

 

In vivo:

 

A toxicokinetic study with hydroxypropyl acrylate (HPA) showed a fast metabolism in Wistar rats. After one oral dose of HPA, the acrylate itself could not be determined in rat plasma at any time (from 0.17 hours post dosing up to 96 hours post dosing), demonstrating a complete metabolic first pass effect. Consequently, for orally dosed HPA as well as for orally dosed PG, PG is the major entitiy in the systemic circulation. When the plasma concentrations of PG are compared quantitatively for an equimolar target dose of the test substances of 1.54 mmol/kg bw, the maximum plasma concentration was about 3-fold and the internal dose about 50% higher for administered PG compared to HPA. 

After oral HPA gavage the propylene glycol amount could be reduced compared to the equimolar dose of propylene glycol based lower systemic uptake, on direct reaction of the monomer in the stomach, i.e. with glutathione, which is known for this chemistry. 

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). The results of the study indicate that once the chemical becomes systemically available, it is rapidly metabolized and eliminated from the body as either CO₂in the expired air or urinary metabolites. Greater than 70 % of the administered dose of HEA-derived¹⁴C was excreted by 12 hr post-dosing or post-exposure as urinary metabolites and as¹⁴CO₂in the expired air for the oral, ip, and inhalation routes.

No qualitative differences in urinary metabolites between routes were observed, indicating no marked route-dependent differences in the metabolic fate of HEA.

According to the metabolic scheme proposed by BAMM (1992) metabolism occurs by two primary routes, hydrolysis of the ester linkage by carboxylesterase to AA and ethylene glycol, and conjugation with glutathione (GSH); both pathways serve to detoxify HEA. In rats, the metabolism of ethylene glycol proceeds via the alcohol and aldehyde dehydrogenase pathway, finally resulting in the formation of CO₂, and AA on the other hand is rapidly incorporated into the normal cellular metabolism via the propionate degradative pathway. Conjugation of 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.

 

In conclusion, animal studies with HPA and HEA supported be in vitro data 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.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Discussion on toxicokinetics, metabolism and distribution result:

A toxicokinetic study with hydroxypropyl acrylate (HPA) showed a fast metabolism in Wistar rats. After one oral dose of HPA, the acrylate itself could not be determined in rat plasma at any time, demonstrating a complete metabolic first pass effect. Consequently, for orally dosed HPA as well as for orally dosed PG, PG is the major entitiy in the systemic circulation. When the plasma concentrations of PG are compared quantitatively for an equimolar target dose of the test substances of 1.54 mmol/kg bw, the maximum plasma concentration was about 3-fold and the internal dose about 50% higher for administered PG compared to HPA.

After oral HPA gavage the propylene glycol amount could be reduced compared to the equimolar dose of propylene glycol based lower systemic uptake, on direct reaction of the monomer in the stomach, i.e. with glutathione, which is known for this chemistry.

 

In addition the structural analogue 2-hydroxyethyl acrylate (HEA) 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 (BAMM 1992). The results of the study indicate that once the chemical becomes systemically available, it is rapidly metabolized and eliminated from the body as either CO2in the expired air or urinary metabolites. Greater than 70 % of the administered dose of HEA-derived14C was excreted by 12 hr post-dosing or post-exposure as urinary metabolites and as14CO2in the expired air for the oral, ip, and inhalation routes.

No qualitative differences in urinary metabolites between routes were observed, indicating no marked route-dependent differences in the metabolic fate of 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 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 HPA and the oral toxicokinetic study with HPA, similar kinetics for both acrylates are anticipated.

 

Discussion on bioaccumulation potential result:

After oral gavage HPA is rapidly metabolised . Also, the structural analogue 2-hydroxyethyl acrylate was investigated in rats using several routes of exposure.

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 spectrometrywas 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 20μCi), 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 15-20μCi).

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. Greater than 70 % of the administered dose of HEA-derived14C was excreted by 12 hr post-dosing or post-exposure as urinary metabolites and as14CO2in 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 as14CO2 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 as14CO2.

For inhalation 39 % of the 14C-activity recovered at 48 hr was eliminated in the urine and 41 % was expired as14CO2.

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 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 major14C 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 of HPA and HEA 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 2-hydroxypropyl acrylate are anticipated.

 

Discussion on absorption rate:

No reliable studies concerning dermal absorption were identified for hydroxypropyl acrylate. However, the structural analogue 2-hydroxyethyl acrylate was investigated in rats by the dermal route of exposure.

Dermal absorption:

The metabolism, distribution and excretion of uniformly labelled14C-2-hydroxyethyl acrylate was examined in male Fischer 344 rats using dermal application (BAMM 1992). 4 rats were treated under occlusive conditions with14C-HEA at a dose of 12.5 mg/kg body weight (approximately 15-20μCi).

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 as14CO2. 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 HPA, similar adsorption kinetics of hydroxypropyl acrylate are anticipated.