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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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report Date:
2017

Materials and methods

Objective of study:
metabolism
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
This non-GLP pharmacokinetic study of both HEMA and HPMA in rats via intravenous (IV) administration was conducted to evaluate the potential quick hydrolysis of both HEMA and HPMA in vivo.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Fischer 344/DuCrj
Details on species / strain selection:
F344/DuCrl rats were selected because of their use in previous toxicological studies for the two test materials (HEMA and HPMA). Rats are a suitable species for the analysis of metabolism of chemicals in vivo. The F344/DuCrl rats are also suitable due to the availability of historical background data, and the reliability of the commercial supplier.
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (Kingston, New York)
- Age at study initiation: 9 weeks
- Weight at study initiation: 191-208 g
- Housing: all animals were single housed in glass Roth-type metabolism cages for
acclimation purposes.
- Diet (e.g. ad libitum): LabDiet Certified Rodent Diet #5002 (PMI Nutrition International,
St. Louis, Missouri) in pelleted form. Feed was provided ad libitum.
- Water (e.g. ad libitum): Municipal water was supplied to all study animals ad libitum throughout the study.
- Acclimation period: Upon arrival, all animals were acclimated to the laboratory for at least two days prior to the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C with a range of 20°C-26°C
- Humidity (%): 50% with a range of 38-78%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
intravenous
Vehicle:
physiological saline
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Appropriate amounts of HEMA or HPMA were added to sterile saline to obtain the appropriate dose of 5 mg/kg bw using aseptic techniques. The amount of dose solution administered was targeted at ~2.5 mL/kg bw and injected over a minimum of 45 seconds which corresponded to injection rates ranging from 0.7 to 0.8 mL/minute based on the averaged body weight of 0.2 kg.
Duration and frequency of treatment / exposure:
once
Doses / concentrations
Dose / conc.:
5 mg/kg bw/day
No. of animals per sex per dose:
2 males
Control animals:
no
Positive control:
no
Details on study design:
- Dose selection rationale: A dose level of 5 mg/kg body weight (bw) for HEMA and 5 mg/kg bw for HPMA was used in this study. These two dose levels are equimolar based on the study design.
Details on dosing and sampling:
TOXICOKINETIC STUDY
- Tissues and body fluids sampled (delete / add / specify): bloodpling:
- Time and frequency of sampling: 5-10-30-60-180 min
- From how many animals: 2, not pooled
- Method type(s) for identification: GC-MS
- Limits of detection and quantification: LOQ: 45.0 ng/mL (HEMA)
Statistics:
Descriptive statistics were used, i.e., mean ± standard deviation, when applicable. All calculations in the database were conducted using Microsoft Excel (Microsoft Corporation, Redmond, Washington) spreadsheets and databases in full precision mode
(15 digits of accuracy). Certain pharmacokinetic parameters were calculated for blood, including AUC (area-under-the-curve), using a pharmacokinetic computer modeling program PK Solutions (v.2.0.6., Summit Research Services, Montrose, Colorado).

Results and discussion

Main ADME results
Type:
metabolism
Results:
Rapid hydrolysis after intavenous administration in rats

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parameters
Key result
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: ca. 1 min
Remarks:
mean

Any other information on results incl. tables

mean T1/2 around 1 min (0.84 and 1.06 min for each animal, respectively)

Applicant's summary and conclusion

Conclusions:
After i.v. administration in rats, HEMA quickly hydrolyses in the order of a few minutes. The estimated half-lives for HEMAwas near 1 minute, indicating that the current study results support the assumption that HEMA was quickly hydrolyzed to its primary metabolites.
Executive summary:

To support the REACH registration for hydroxyethyl methacrylate (HEMA) and hydroxypropyl methacrylate (HPMA), a Read-across approach can be applied if test materials can be quickly hydrolyzed to the methacrylic acid and the corresponding alcohols (glycols) in vivo. This non-GLP pharmacokinetic study of both HEMA and HPMA in rats via intravenous administration was conducted to evaluate the potential

quick hydrolysis of both HEMA and HPMA in vivo.

Two male rats per compound were intravenously administered HEMA or HPMA individually at 5.0 mg/kg dose level with saline as the dose vehicle. After dose administration, blood samples (200 μl) were collected at 5, 10, 30, 60, and 180 minutes into individual glass vials containing ethyl acetate (600 μL) acidified with 1% formic acid. After vortexing, the levels of HEMA and HPMA in the blood samples were

quantitatively analyzed by GC/MS-MS.

The results showed that levels of both HEMA and HPMA dropped rapidly after administration and were not quantifiable by 60 minutes with limit of quantitation (LOQ) of 48.8 ng/mL (HPMA) and 45.0 ng/mL (HEMA). The estimated half-lives for HEMA and HPMA were less than or near 1 minute, indicating that the current study results support the assumption that both HEMA and HPMA were quickly hydrolyzed after intravenous administration in rats.