Amines, C10-14-tert-alkyl

Repeated dose toxicity: oral

Administrative data

Endpoint:

repeated dose toxicity: oral, other

Remarks:

Gastroplus modelling of repeated oral exposure to rats for 90 days

Type of information:

other: In silico predictive model

Adequacy of study:

supporting 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

Materials and methods

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

Limit test:

no

Test material

Specific details on test material used for the study:

Not applicable - method is an in silico predictive model

Test animals

Species:

other: Not applicable - method is an in silico predictive 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:

oral: feed

Details on route of administration:

Simulation of dietary administration

Vehicle:

other: Not applicable - report is an in silico rat model of gastric absorption

Details on oral exposure:

Simulated oral dietary exposure for a period of 90 Days

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

Simulated oral dietary exposurefor a period of 90 days

Frequency of treatment:

Simulated dietary exposure for a period of 90 days

No. of animals per sex per dose:

Not applicable

Details on study design:

In silico predictive model of gastric absorption

Positive control:

Not applicable

Results and discussion

Results of examinations

Clinical signs:

not examined

Mortality:

not examined

Body weight and weight changes:

not examined

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Applicant's summary and conclusion

Conclusions:

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.

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.