2-hydroxyethyl acrylate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

03 Jun 1987 to 10 Dec 1992

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

03 Jun 1987 to 10 Dec 1992

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 427 (Skin Absorption: In Vivo Method)

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD TG 417

GLP compliance:

yes

Specific details on test material used for the study:

- Name of test material (as cited in study report): 2-Hydroxyethyl acrylate
- Source: Sigma Chemical Company, St. Louis, MO (radiolabelled), Epoxy Products Department of The Dow Chemical Company, Freeport, TX (non-radiolabelled)
- Analytical purity: molar purity of 98.3 %, as determined by gas chromatography and infrared analysis (Hermann, 1991)
- Lot/batch No.: 059F9245 (radiolabelled), TB 881212 (non-radiolabelled)
- Radiochemical purity (if radiolabelling): 100 % as determined by high preformance liquid chromatography (HPLC, Analytical Data Sheet 89-397) (upon receipt). The radiochemical purity was evaluated repeatedly throughout the study (Analytical Data Sheets 90-9, 91-5, 90-124, 91-29, 91-33) and ranged from 100 % to 87 %.
- Specific activity (if radiolabelling): 6.3 mCi/mmol (MW 116)
- Locations of the label (if radiolabelling): uniformly labelled 14C-HEA

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 cm X 4 cm) 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 %

Key result

Dose:

12.5 mg/kg bw

Parameter:

percentage

Absorption:

ca. 66 %

Remarks on result:

other: 48 hr

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1992

Report date:

1992

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD TG 427

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

2-hydroxyethyl acrylate

EC Number:

212-454-9

EC Name:

2-hydroxyethyl acrylate

Cas Number:

818-61-1

Molecular formula:

C5H8O3

IUPAC Name:

2-hydroxyethyl acrylate

Test material form:

not specified

Details on test material:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): 2-Hydroxyethyl acrylate
- Source: Sigma Chemical Company, St. Louis, MO (radiolabelled), Epoxy Products Department of The Dow Chemical Company, Freeport, TX (non-radiolabelled)
- Analytical purity: molar purity of 98.3 %, as determined by gas chromatography and infrared analysis (Hermann, 1991)
- Lot/batch No.: 059F9245 (radiolabelled), TB 881212 (non-radiolabelled)
- Radiochemical purity (if radiolabelling): 100 % as determined by high preformance liquid chromatography (HPLC, Analytical Data Sheet 89-397) (upon receipt). The radiochemical purity was evaluated repeatedly throughout the study (Analytical Data Sheets 90-9, 91-5, 90-124, 91-29, 91-33) and ranged from 100 % to 87 %.
- Specific activity (if radiolabelling): 6.3 mCi/mmol (MW 116)
- Locations of the label (if radiolabelling): uniformly labelled 14C-HEA

Radiolabelling:

yes

Test animals

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

Administration / exposure

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

Doses / concentrations

Dose / conc.:

12.5 mg/kg bw/day

Remarks:

corresponding to 15-20 µCi of radioactivity

No. of animals per sex per dose / concentration:

4

Control animals:

no

Details on study design:

After administration or termination of exposure to 14C-HEA, rats from all groups were housed in glass Roth-type metabolism cages. All urine, cage rinse, and feces were collected at specified intervals for up to 48 hr post-dosing or post-exposure and analyzed for radioactivity. In addition, expired organics and 14CO2 were trapped for the 48 hr post-dosing or post-exposure period. Selected samples of urine were analyzed by high performance liquid chromatography (HPLC) to determine 14C metabolic profiles.
The rats were sacrificed 48 hr after administration or exposure to 14C-HEA, and the radioactivity remaining in samples of blood, skin, and the carcass was quantified. For the dermal route of administration, the radioactivity associated with the skin at the dosed site was also determined. in order to determine blood concentration-time profiles, separate groups of animals (different from the groups used to determine the disposition of HEA) were utilized so that expired 14CO2 would not be lost while blood was collected from the animals in the Roth cages.
Radioactivity was quantified with a Beckman LS 3801 or Beckman LS 9000 liquid scintillation Counter (Beckman Instrument Inc., Fullerton, CA).

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.

Results and discussion

Toxicokinetic / pharmacokinetic studies

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.

Metabolite characterisation studies

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.

Any other information on results incl. tables

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.