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Toxicological information

Basic toxicokinetics

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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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report date:
1992

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
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:
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
Doses / concentrationsopen allclose all
Dose / conc.:
2.5 mg/kg bw/day
Dose / conc.:
50 mg/kg bw/day
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.
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 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.

Results and discussion

Toxicokinetic / pharmacokinetic studies

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.

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 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

Applicant's summary and conclusion