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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labeling and/or risk assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report Date:
2010

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
according to
Guideline:
EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics)
Deviations:
no
Remarks:
The study was conducted according to the guideline in effect at the time of study conduct.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Purity: 84%
Radiolabelling:
no

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc. (Raleigh, North Carolina, U.S.A.).
- Age at study initiation: least 8 weeks old
- Weight at study initiation: males weighed 247.8 g ± 8.15 g and females weighed 181.1 g ± 4.23 g
- Fasting period before dosing: 16 hours
- Housing: housed individually in solid bottom caging with bedding.
- Individual metabolism cages: yes
- Diet: PMI® Nutrition International, LLC Certified Rodent LabDiet® 5002; ad libitum
- Water: tap water, ad libitum
- Acclimation period: 6 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26ºC
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF TEST SUBSTANCE FORMULATION:

- Solvent used: deionized water
- Preparation details: The test substance was weighed into a vial (approximately 178.5 mg) and mixed with deionized water (20 mL). The dose solution was prepared at a nominal concentration of 7.5 mg/mL (adjusted for purity, 84%), with a target dose level of 30 mg/kg body weight (bw) and a dose volume of 4 mL/kg bw. The dosing solution was prepared prior to the day of use and was stored refrigerated at 1-10°C prior to dosing.
- Adjusted for purity: yes
Duration and frequency of treatment / exposure:
once
Doses / concentrations
Remarks:
Doses / Concentrations:
Nominal target dose 30 mg/kg bw ( 7.5 mg/mL in dosing solution)
Measured by LC/MS, was 6.82 mg/mL in dosing solution; calculated dose = male (27.4 ± 0.17 mg/kg bw), female (27.2 ± 0.16 mg/kg bw)
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose level was chosen based on the results of the 28-day daily oral dosing study in rats, where the no-observed-adverse-effect level (NOAEL) was 30 and 300 mg/kg/day for males and females, respectively.
Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, cage washes, liver, fat, G.I. tract and contents, kidney, spleen, whole blood, residual carcass
- Time and frequency of sampling: Urine and feces were collected on dry ice predose and at 0-6 h, 6-12 h, 12-24 h, and every 24 hours until 168 hours post dose. At the end of the experiment (168 hours post dose), rats were killed and tissues collected.
- From how many animals: Samples of urine were pooled across animals for a given time interval where the mean percent of the administered dose (by sex) was ≥5% (males and females: 0-6, 6-12, 12-24, 24-48, and 48-72 hours; feces extract samples were not pooled since the total mean percent of dose for each collection interval (by sex) was <5% of the administered dose.
- Method type(s) for identification: HPLC-MS-MS
- Limits of detection and quantification: The initial LOD was calculated as 3 times the concentration equivalent of the mean noise level. The initial LOQ was based on the lowest calibration standard concentration, which had at least a 10x signal-to-noise ratio. For a sample preparation factor of 1x the initial urine and cage wash sample LOD was 0.1 ng/g and for feces the initial LOD was 0.4 ng/g. For a sample preparation factor of 1x the urine, cage wash, and feces matrices all have an initial LOQ of 2.5 ng/g. The final LOD and LOQ for each sample was determined by multiplying the initial values by the sample preparation factor.



Statistics:
Group data were represented as a mean ± SD.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
The carcass and residual feed were not analyzed for the test substance because analysis of urine, feces and cagewash accounted for the majority of administered dose with an overall recovery of 100% ± 10%.
Details on excretion:
URINE
Following oral administration of the test substance in water, 96.6% ± 1.43%% and 94.6% ± 8.57% of the administered dose (0-12 hours) was accounted for in urine from male and female rats, respectively. At the conclusion of the study (168 hours post-dose), the cumulative amount of the test substance detected in urine was 103% ± 2.73% ± 6.91% and 99.8% ± 6.41% for male and female rats, respectively. Elimination of the test substance via urine accounted for the administered dose for both male and female rats.

FECES:
Following oral administration of the test substance in water, the cumulative amount of the test substance detected in feces over the entire collection period (0-168 hours) was 1.35% ± 1.05% and 0.85% ± 0.58% for male and female rats, respectively. The minor amount of the test substance detected in feces was likely contamination from of urine. Given the high levels of the test substance in urine, and the design of the urine/feces collection system of the metabolism units, feces likely became contaminated with small amounts of urine when contacting surfaces in transit to the feces collection vessel.

For additional results see Table 1 in Other Information on Results

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
Samples of urine evaluated using LC/MS were found to contain only the parent substance. This finding, taken with recovery of the administered dose in urine, confirms that the test substance was rapidly absorbed and eliminated unmetabolized following oral dosing in the rat.

Any other information on results incl. tables

Table 1

Material balance, percent of dose

 

Males

Females

Mean

SD

Mean

SD

Urine

103.0

2.73

99.8

6.41

Feces

1.35

1.05

0.85

0.58

Cage Wash

0.98

0.52

5.03

5.14

Total

105.3

2.19

105.7

1.42

 

Following oral dosing with the test substance in water and a 168 hour post-dose collection period, 105.3% ± 2.19% and 105.7% ± 1.42% of the administered dose was recovered from male and female rats, respectively.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: test substance was rapidly absorbed and eliminated unmetabolized following oral dosing in the rat
This study and the conclusions which are drawn from it fulfill the quality criteria (validity, reliability, repeatability).
test substance was rapidly absorbed and eliminated unmetabolized following oral dosing in the rat
Executive summary:

The absorption, distribution, metabolism, and elimination of the test substance were investigated in the Crl:CD(SD) rat. The test substance was administered in water to 5 male and 5 female rats as a single oral dose at a target dose level of 30 mg /kg bodyweight (bw) and a dose volume of 4 mL/kg bw. Rats were housed individually in metabolism units and urine and feces were collected on dry ice predose and postdose at 0-6 hours, 6-12 hours, 12-24 hours, and every 24 hours until 168 hours post-dose. At 168 hours post-dose, rats were sacrificed. The test substance was quantitated in urine, feces, and cagewash by liquid chromatography tandem mass spectrometry (LC/MS/MS). Urine samples were further evaluated by LC/MS to confirm the identity of the parent analyte and determine if the test substance was eliminated metabolized or unmetabolized.

 

Following oral administration of the test substance in water, 96.6% ± 1.43% and 94.6% ± 8.57% of the administered dose was accounted for in urine (0-12 hours) from male and female rata, respectively. At the conclusion of the study (168 hours post-dose), the total accumulated amount detected in urine was 103% ± 2.73% and 99.8% ± 6.41% of the administered dose for male and female rats, respectively.

 

Elimination of the test substance via urine accounted for a majority of the administered dose for both male and female rats; minor levels of the test substance detected in feces from male ( 1.35% ± 1.05%) and female rats ( 0.85% ± 0.58%) were likely contamination from urine.

 

Cagewash, which is composed of dried excreta (urine and feces), accounted for 0.98% ± 0.52% and 5.03% ± 5.14% of the administered dose for male and female rats, respectively.

 

Following oral dosing with the test substance in water and a 168 hour post-dose collection period, 105.3% ± 2.19% and 105.7% ± 1.42% of the administered dose was recovered from male and female rats, respectively.

  

Samples of urine evaluated using LC/MS were found to contain only the parent substance. This finding, taken with recovery of the administered dose in urine, confirms that the test substance was rapidly absorbed and eliminated unmetabolized following oral dosing in the rat.