Exo-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl acrylate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

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

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2019

Report date:

2019

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Three male rats per compound were intravenously administered IBOA at target concentration 7.5 mg/kg (36 µmol/kg), using Intralipid 20% as the dose vehicle. After dose administration, blood samples (~200 μL) were collected at 5, 10, 30, 60, and 180 minutes into individual pre-weighed glass vials containing ethyl acetate (600 μL) acidified with 10% trifluoroacetic acid (TFA). After vortexing and subsequent centrifugation, the blood extracts underwent quantitative analysis for IBOA by gas chromatography tandem mass spectrometry (GC/MS-MS).

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Exo-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl acrylate

EC Number:

227-561-6

EC Name:

Exo-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl acrylate

Cas Number:

5888-33-5

Molecular formula:

C13H20O2

IUPAC Name:

(1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl prop-2-enoate

Test material form:

liquid

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Fischer 344/DuCrj

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (Kingston, New York)
- Age at study initiation: 9-12 weeks
- Weight at study initiation: 183-196 g
- Housing: singly in glass Roth-type metabolism cages
- Diet (e.g. ad libitum): LabDiet Certified Rodent Diet #5002 (PMI Nutrition International, St. Louis, Missouri) in pelleted form, ad libitum
- Water (e.g. ad libitum): Municipal water, ad libitum
- Acclimation period: 7d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C with a range of 20°C-26°C
- Humidity (%): 50% with a range of 30-70%
- Photoperiod (hrs dark / hrs light): 12-hour light/dark (on at 6:00 a.m. and off at 6:00 p.m.)

Administration / exposure

Route of administration:

intravenous

Vehicle:

other: Intralipid 20%

Details on exposure:

Appropriate amounts of the test substance were added to sterile pharmaceutical grade Intralipid 20% using aseptic technique to obtain the appropriate concentration. The amount of dose solution administered was targeted at 2.5 mL/kg bw and injected over ~1minute to correspond to an injection rate of ~0.5 mL/min. The dose was stored at ambient temperature (19-25°C) and used within 24 hours of preparation.

Duration and frequency of treatment / exposure:

single iv treatment

Doses / concentrations

Dose / conc.:

7.5 mg/kg bw/day (nominal)

Remarks:

corresponds to 36 µmol/kg

No. of animals per sex per dose / concentration:

3 males

Control animals:

yes, concurrent vehicle

other: another isobornyl ester (isobornyl acetate, IBOAC) was tested for its toxikokinetic properties for comparison reasons (rad-across background)

Positive control reference chemical:

no

Details on study design:

- Dose selection rationale: previous studies of this type have used similar equimolar ratios

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY
- Tissues and body fluids sampled: blood
- Time and frequency of sampling: 5, 10, 30, 60 and 180 minutes post-dosing

Statistics:

Descriptive statistics were used, i.e., mean ± standard deviation, where applicable. All descriptive statistic calculations were conducted using Microsoft Excel (Microsoft Corporation, Redmond, Washington) spreadsheets in full precision mode (15 digits of accuracy). Pharmacokinetic parameters that were calculated for blood used the pharmacokinetic computer modeling program PK Plus (v. 9.6, Simulation Plus, Inc., Lancaster, California, United States of America).

Results and discussion

Preliminary studies:

The solubility of both IBOAC and IBOA was tested up to 10 mg/mL in saline and Intralipid 20%. Both test materials were insoluble at this concentration in saline but were soluble in Intralipid 20%; thus they were prepared using the latter vehicle .

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parameters

Toxicokinetic parameters 1

Key result

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 1.2494 min-1

Remarks:

relevant for the vast majority of applied test substance

Toxicokinetic parameters 2

Key result

Test no.:

#1

Toxicokinetic parameters:

other: <1.0% of the corresponding administered dose remains in the blood 10 minutes post-intravenous administration

Toxicokinetic parameters 3

Test no.:

#1

Toxicokinetic parameters:

AUC: 383.7 µg-min/g

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

The resulting blood time course showed that the substance was quickly hydrolyzed with less than 1.0% of the corresponding administered dose remaining in the blood 10 minutes post-intravenous administration and around 0.1% remaining 180 minutes post-intravenous administration. Further pharmacokinetic analysis of the blood concentrations of the substance showed that both compounds were biphasic (alpha [α] and beta [β] phases; i.e. a two-compartment model) in which there is a dominant initial distribution and hydrolysis step (i.e. t_½α) with a subsequent phase of further hydrolysis and elimination (i.e. t_½β). The initial distribution and hydrolysis step had an average calculated t_½αvalue of 1.25 min^-1and accounts for metabolic fate of the vast majority of applied test substance quantities. The secondary hydrolysis and elimination phase (t_½β) had an average value of 120 min^-. The cause of the beta-phase associated with the minor portion of the test substance's kinetics is currently unclear and may be of limited relevance to normal physiology. The average area under the curve (AUC_0-t) value was 384 µg-min/g, respectively.

Applicant's summary and conclusion

Conclusions:

Overall, the analysis of the blood pharmacokinetics indicated that the parent test material is rapidly removed from blood circulation (i.e. blood compartment)in vivoin a very similar manner. Hence, these data support a pharmacokinetics-based Read-Across for IBOAC and IBOA.

Executive summary:

This non-GLP pharmacokinetic study of isobornyl acetate (IBOAC) and isobornyl acrylate (IBOA) in rats via intravenous administration evaluated the hydrolysis and pharmacokinetic characteristics as measured by the rate of parent (IBOAC or IBOA) disappearance. The purpose of this study was to evaluate whether these data can be used in a pharmacokinetics-based Read-Across approach similar to several other well-studied (meth)acrylates.

Three male rats per compound were intravenously administered either IBOAC or IBOA at target concentrations 7.0 mg/kg (36 µmol/kg) or 7.5 mg/kg (36 µmol/kg), respectively, using Intralipid 20% as the dose vehicle. After dose administration, blood samples (~200 μL) were collected at 5, 10, 30, 60, and 180 minutes into individual pre-weighed glass vials containing ethyl acetate (600 μL) acidified with 10% trifluoroacetic acid (TFA). After vortexing and subsequent centrifugation, the blood extracts underwent quantitative analysis for either IBOAC or IBOA by gas chromatography tandem mass spectrometry (GC/MS-MS).

The resulting blood time course showed that both substances were quickly hydrolyzed with less than 1.0% of the corresponding administered dose remaining in the blood 10 minutes post-intravenous administration and around 0.1% remaining 180 minutes post-intravenous administration. Further pharmacokinetic analysis of the blood concentrations of both IBOAC and IBOA showed that both compounds were biphasic (alpha [α] and beta [β] phases; i.e. a two-compartment model) in which there is a dominant initial distribution and hydrolysis step (i.e. t_½α) with a subsequent phase of further hydrolysis and elimination (i.e. t_½β). The initial distribution and hydrolysis step had average calculated t_½αvalues of 0.866 and 1.25 min^-1for IBOAC and IBOA, respectively, and accounts for metabolic fate of the vast majority of applied test substance quantities. The secondary hydrolysis and elimination phase (t_½β) had average values of 55.1 and 119.5 min^-1for IBOAC and IBOA, respectively. The cause of the beta-phase associated with the minor portion of IBOAC and IBOMA kinetics is currently unclear and may be of limited relevance to normal physiology. The average area under the curve (AUC_0-t) values for IBOAC and IBOA were 363 and 384 µg-min/g, respectively.