Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
Gastroplus modelling of repeated oral exposure to rats for 90 days
Type of information:
other: In silico predictive model
Adequacy of study:
key study
Study period:
April-July 2020
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Justification for type of information:
Information on oral absorption and other major pharmacokinetic parameters is provided in support of data waiving arguments for in vitro micronucleus assay and repeat dose oral toxicity studies

Data source

Materials and methods

Objective of study:
bioaccessibility (or bioavailability)
Principles of method if other than guideline:
For the predictions of Fa%, F%, Css, and AUC 0-2160 hr of the representative major components of PRIMENE 81-R following 90-day repeated dietary exposures in rats, a PBPK model was utilized in GastroPlus (version 9.7). This PBPK model contains 13 compartments (lung, adipose, muscle, liver, spleen, heart, brain, kidney, skin, reproductive organs, red marrow, yellow marrow, and the rest of the body). In this PBPK simulation, the oral dose formulation type was defined to be a suspension (equivalent to the dietary type in the defined PBPK model) with particle size of 25 μm mean radius
GLP compliance:
not specified

Test material

Specific details on test material used for the study:
Not applicable - method is an in silico predictive model
Radiolabelling:
no

Test animals

Species:
other: Not applicable - in silico rat model
Strain:
not specified
Remarks:
In silico rat model
Details on species / strain selection:
Not applicable - report is an in silico rat model of gastric absorption
Sex:
not specified
Details on test animals or test system and environmental conditions:
Not applicable - report is an in silico rat model of gastric absorption

Administration / exposure

Route of administration:
not specified
Vehicle:
not specified
Remarks:
Not applicable - report is an in silico rat model of gastric absorption
Details on exposure:
Not applicable - report is an in silico rat model of gastric absorption
Duration and frequency of treatment / exposure:
Not applicable - report is an in silico rat model of gastric absorption
No. of animals per sex per dose / concentration:
Not applicable - report is an in silico rat model of gastric absorption
Control animals:
not specified

Results and discussion

Applicant's summary and conclusion

Executive summary:

PRIMENE™ 81-R (Amines, C10-C14-tert-Alkyl) is a mixture containing major components with alkyl carbon number ranged from C10 to C14. Experimental data on oral absorption in rats either from single or repeated oral exposures (such as repeated 90-day dietary exposure) is not available for this mixture. Therefore, the oral bioavailability, other major pharmacokinetic parameters, and metabolic clearance data of the major representative 20 components of the mixture were estimated via the widely accepted QSAR programs, ADMET predictor (v9.5, Simulations Plus Inc, Lancaster, CA, USA), and GastroPlus (v9.7, Simulations Plus Inc, Lancaster, CA, USA).

Using the parameters for a repeated 90-day oral dietary exposure to a fed rat (0.25 kg) at dose level of 107 mg/kg/day (mkd), the predicted fractional absorption (Fa%), bioavailability (F%), and maximum steady-state plasma concentration (Css ), area under curve (AUC) values, and rat liver microsomal clearance (CYP-RLM-CLint) of the representative 20 components by GastroPlus were determined.

Overall, the predicted Fa%, F%, Css, AUC, and CYP-RLM-CLint for these major components were in the ranges of 97.60-99.81%, 16.10-34.97%, 0.646-1.092 μg/mL, 493-999 μg.h/mL, and 196.602-435.343 μl/min/mg RLM protein, respectively.

According to the predicted values of Fa%, F%, Css, and AUC, all these representative components of PRIMENE 81-R are bioavailable in rats, and the predicted CYP-RLM-CLint values indicate that all these representative components can be metabolized via cytochrome p450 (CYP). The predicted plasma time-courses of the representative components indicated no apparent bioaccumulation of any of the representative major components of PRIMENE 81-R upon repeated-day exposures at the dose level of 107 mkd.

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