Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

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

Data source

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

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Version / remarks:
parts of the guidelines are taken
Qualifier:
equivalent or similar to
Guideline:
EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics)
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Details on test material:
- State of aggregation: liquid/colorless, clear
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals 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

Administration / exposure

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
Doses / concentrationsopen allclose all
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:
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

Results and discussion

Any other information on results incl. tables

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.

Hydroxypropylacrylate: 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 glutathion or stomach content, which is known for this chemistry.

Applicant's summary and conclusion

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.