Cyclopentane, methoxy-

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 2013-08-02 to 2013-12-12

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Objective of study:

toxicokinetics

Qualifier:

according to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

no

GLP compliance:

yes

Specific details on test material used for the study:

Batch No.: 2820246
Purity: 99.98%

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Vital River Laboratory Animal Technology Co. Ltd
- Age at study initiation: 5 weeks
- Weight at study initiation: female 202.46-236.07 g, male 254.08-287.03 g
- Housing: SPF animal room, group-housed in polycarbonate transparent rat box with 3-5 rats per box
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): purified water, ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25°C
- Humidity (%): 40-70%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle

The basic kinetic characteristics of substance (5mg/kg) by intravenous injection were as follow: The concentration-time curves fit to two compartment open model. According to the parameters calculated by statistical moments, Vz of the test substance was 5.45±3.37L/kg, which was much higher than the total body water content. This indicated systemic distribution with concentration sites. t1/2z was 0.74±0.46h and CLz was 5.37±1.64L/h/kg, which indicated faster elimination of the test substance in rats. No gender difference was found for toxicokinetics characteristics of the test substance.

Toxicokinetic characteristics of the test substance by single oral administration (20mg/kg and 500 mg/kg, 1:25 of dose ratio): Two absorption peaks were found; in some rat samples, three adsorption peaks were found. This indicated the test substance may be absorbed in multiple sites after entered the digestive tract and/or there were hepato-enteric circulation. The first Tmax1 of the two dose groups were 0.23±0.20 and 0.69±0.38h, respectively. The second Tmax2 of the two dose groups were 0.67±0.29 and 5.50±1.00h, respectively. The Tmax was delayed obviously, and increased with dose increase, which indicated the absorption of the test substance was delayed with dose increase by oral administration of the test substance to rats. Mean residue time, MRT0-t were 1.96±0.86 and 6.45±1.82h, respectively, and prolonged obviously with dose increase. AUC0-t were 9360.57±9385.29 ng.h.mL-1 and 355300.83±75806.43 ng.h.mL-1, respectively. The ratio was 1.0:38.0, which was higher than the dose ratio (1:25). tl/2z were 1.39±1.08 and 7.47. In vitro test of liver microsomal metabolism and recombinant enzyme metabolism test could not be conducted.8.87h, respectively, and eliminated decrease with dose increase. Clz were 4.49±3.79 and 1.22±0.60L/h/kg, respectively, and eliminated decrease with dose increase. Results above indicated that characteristics of the test substance by single oral administration (20mg/kg and 500 mg/kg) were nonlinear kinetics and the both absorption saturations and elimination saturations were found. The absorption fraction of the test substance (20 and 500 mg/kg) by gavage was 114.28±109.93% and 115.03±86.32% based on the data analysis of intravenous injection.

Toxicokinetic characteristics of the test substance in repeated dose 7-day study: two absorption peaks were found in both the first and the last administration. Tmax1 of the first and the last administration were 0.23±0.20 and 0.25±0.00h. Cmax1 were 3090.56±2587.74 and 1532.82±731.07ng/mL. Tmax2 of the first and the last administration were 0.67±0.29 and 6.00±2.83h. Cmax2 were 3707.10±2228.66 and 411.42±275.16ng/mL. AUC0-t were 9360.57±9385.29 and 2974.04±1483.45ng.h.mL-1. MRT0-t were 1.96±0.86 and 3.13±0.82h. tl/2z were 1.39±1.08 and 5.92±7.42h. Absorption fraction were 114.28±109.93% and 20.18±13.64%. Furthermore, as the extending of the exposure time, Cmin was not detected. Results indicated that, after exposure to test substance for 7 days, the total exposure levels decreased and the elimination decreased. No accumulation was detected.

After female SD rats with 20mg/kg test substance by single gavage administration with 5min, the concentration of the test substance in digestive tract and its content were very high. This indicated most of the test substance was not absorbed in blood at 5 min. After 30min, the concentration of the test substance in digestive tract and its content decreased a little while the concentration of the test substance in other tissues increased in different degrees. Among these tissues, the highest concentrations were found in fat and ovary. After 6h, the concentration of the test substance in digestive tract and its content was still high and the tissues rich in lipid (fat, uterus, ovary, brain and so on) followed. This indicated the test substance could be concentrated in fat at last. The characteristics of body distribution of the male rat with 20 mg/kg test substance by single gavage administration were the almost the same as that of female rats. High concentration was found in fat. The test substance had a high affinity with the tissues rich in lipid and decreased relatively slowly in fat. Compared with female rats, the test concentration in male rat tissues decreased more slowly after 6h administration.

After SD rats were given test substance by single gavage administration with 20 mg/kg, the excrete amount of test substance in bile, faeces and urine of rats were very low. The results were related to the volatile of test substance. Because the collection of bile, faeces and urine in the test were in open, the test substance in the collected samples volatilized considerably. Therefore, the excretion amount was low.

The processing steps in the plasma protein binding test were many and significantly affected the middle and low concentration groups. Negative values were obtained in the results. However, the measured concentrations of plasma in high concentration group were close to the setting concentrations. It could still represent the binding rate of test substance to plasma protein from different species. The binding rate of 50μg/mL test substance to plasma protein from rat, dog, monkey and human were 95.7%、80.6%、96.1% and 96.3% respectively, which were strong binding affinity.

The test substance could be volatilized quickly at 37℃ of in vitro test. Then, the in vitro test of liver microsomal metabolism and recombinant enzyme metabolism test could not be conducted. For this reason, significant deviation was in the excretion test and in vitro protein binding test.

Conclusions:

Toxicokinetic characteristics of the test substance in rat: Characteristics of the test substance by single oral administration (20mg/kg and 500 mg/kg) was nonlinear kinetics. Multiple absorption peaks indicated the test substance may be absorbed in multiple sites after enters the digestive tract and/or there were hepatoenteral circulation. The both absorption saturations and elimination saturations were found. Absorption fraction of 20 and 500 mg/kg was 114.28±109.93% and 115.03±86.32%. Characteristics of the test substance by intravenous administration was two-compartmental model; The apparent volume of distribution Vz was 5.45±3.37L/kg; The test substance was distributed widely in the whole body and concentration was found. The test substance was eliminated quickly and t1/2z was 0.74±0.46h. After rat exposed to test substance in repeated dose for 7-day, the total exposure levels decreased and the elimination decreased. No accumulation was detected. After rat exposed to test substance by oral administration, the test substance could be concentrated in fat, uterus, ovary, or testis, epididymis (such tissues rich in fat) at last. The test substance could be volatilized quickly. Limited by the test method and conditions, significant deviation was in the excretion test and in vitro protein binding test. In vitro test of liver microsomal metabolism and recombinant enzyme metabolism test could not be conducted.

Description of key information

An OECD 417 study is available. Toxicokinetic characteristics of the test substance in rat: Characteristics of the test substance by single oral administration (20mg/kg and 500 mg/kg) was nonlinear kinetics. Multiple absorption peaks indicated the test substance may be absorbed in multiple sites after enters the digestive tract and/or there were hepatoenteral circulation. The both absorption saturations and elimination saturations were found. Absorption fraction of 20 and 500 mg/kg was 114.28±109.93% and 115.03±86.32%. Characteristics of the test substance by intravenous administration was two-compartmental model; The apparent volume of distribution Vz was 5.45±3.37L/kg; The test substance was distributed widely in the whole body and concentration was found. The test substance was eliminated quickly and t1/2z was 0.74±0.46h. After rat exposed to test substance in repeated dose for 7-day, the total exposure levels decreased and the elimination decreased. No accumulation was detected. After rat exposed to test substance by oral administration, the test substance could be concentrated in fat, uterus, ovary, or testis, epididymis (such tissues rich in fat) at last. The test substance could be volatilized quickly. Limited by the test method and conditions, significant deviation was in the excretion test and in vitro protein binding test. In vitro test of liver microsomal metabolism and recombinant enzyme metabolism test could not be conducted.