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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Title:
Metabolism and disposition of [14C]-methylcyclosiloxanes in rats
Author:
Domoradzki JY, Sushynski CM, Sushynski JM, McNett DA, Landingham CV, Plotzke KP
Year:
2017
Bibliographic source:
Toxicology Letters, 279, 98-114
Report Date:
2017

Materials and methods

Objective of study:
metabolism
other: disposition
Test guideline
Qualifier:
equivalent or similar to
Guideline:
EPA OPP 85-1 (Metabolism and Pharmacokinetics)
Version / remarks:
The study was conducted in accordance with EPA Toxic Substance Control Act (EPA-TSCA, 1984) Good Laboratory Practice Standards.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
not specified
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Fischer 344
Details on species / strain selection:
CDF®(Fischer344)/CrlBR rats
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc
- Age at study initiation: approximately 9 weeks of age minimum at dosing
- Weight at study initiation: The mean body weights of female and male rats from the various groups ranged from 150 to 160 g and 200–231 g
- Housing: Animals were housed individually in suspended wire-mesh cages except for the mass balance portion of the study where they were housed in glass Roth-style glass metabolism cages (air flow 500 to 1000 mL/min, 24–48 h acclimation).
- Diet (e.g. ad libitum): Animals were provided LabDiet® Certified Rodent Diet #5002 (PMI Nutrition International, St. Louis, MO) ad libitum.
- Water (e.g. ad libitum): municipal water ad libitum.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18–26 °C
- Humidity: 24–70% relative humidity
- Photoperiod (hrs dark / hrs light): 12-h light/dark cycle

Indwelling jugular vein cannulae, implanted by the animal supplier, were used to facilitate collection of the multiple blood samples collected from each animal (approx. 0.2 mL per time point).
The studies were approved by the Laboratory Animal Care and Use Committee of the lab, fully accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care International.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: D4 administered in dosing solution prepared with a Rodent Liquid Diet (RLD)
Details on exposure:
Single dose exposure
Doses / concentrations
Dose / conc.:
30 other: mg/kg/bw
Remarks:
30 mg 14C-D4/kg bw in a rodent liquid diet vehicle
Details on study design:
Study was conducted with a single oral gavage administration of 30 mg 14C-D4/kg bw in a rodent liquid diet vehicle. Study groups consisted of female and male Fischer 344 rats. Blood (approx. 0.2 mL) was collected at 15, 30, 60 min, and 2, 4, 8, 24, 48, 72, 96, 120, 144 and 168 h post-dosing via a jugular vein cannula. Collection intervals for urine, CO2 and feces were 24 h through 168 h (in addition, urine was collected at 0–12 and 12–24 h) in the mass balance groups. Collection intervals for expired volatiles were: 0–1, 1–2, 2–4, 4–6, 6–12, 12–24, and 24 h intervals through 168 h. Selected tissues and remaining carcasses (including pelt) were collected at 168 h post-dosing. Radioactivity (14C-activity) and parent were measured in collected samples and urine was profiled. Tissues were collected at 2, 6, 12, 24, 48, 72, 120 and 168 h postdosing in the groups to determine tissue kinetics. Tissues collected at these times were adrenals, digestive tract (without contents), perirenal fat, liver, lung, ovaries, spleen, testes and uterus. Radioactivity (14C-activity) and parent were measured in extracted samples.
Details on dosing and sampling:
Preparation of dosing solutions: [14C]D4 was administered in dosing solution prepared with a Rodent Liquid Diet (RLD) product# F6112SP (Bio-Serv, Frenchtown, NJ). The dosing solution was prepared in RLD to deliver approximately 0.29 mCi/kg body weight (bw), with a nominal dose of 30 mg D4/kg bw in 5 mL dosing solution/kg bw.

Test substance administration:
Test substance was administered as a single dose by oral gavage in a RLD vehicle. Dose solutions were administered by oral gavage with a 15 gauge, 100 mm plastic oral feeding tube and syringe at 5 mL/kg bw. Volume was adjusted based upon the most recent individual body weights. The weight of the dose solution administered was determined gravimetrically. The actual mean dose administered ranged from 27.41–30.92 mg/kg in female rats and 26.67–30.04 mg/kg in male rats. Females received a mean range of 41.39–51.38μCi/animal and males received a mean range of 56.70–69.54μCi/animal.
Statistics:
Statistical comparisons between parent and 14C-activity Areaunder- the- Curves (AUCs) were conducted using the Bailer method, Nedelman et al. (1995) and the Satterthwaite approximation method, Nedelman and Jia (1998).

Data analysis and quality assurance:
Calculations of mean and standard deviation (or standard error of the mean) of sample concentrations were performed using Microsoft Excel™ v5, v7,v9 and 2007.Calculations of μg eq were performed using Provantis™Version 8.2 (D4 low dose study).Blood Area-Under the–Curves (AUC)s for parent and radioactivity including statistical analyses were calculated using SAS/STAT software, v8.2 and v9.3. These studies were conducted in accordance with EPA Toxic Substance Control Act (EPA-TSCA, 1984) Good Laboratory Practice Standards.

Results and discussion

Preliminary studies:
Mass balance: dose recovered and disposition:
The mean percentage of the administered dose recovered was 87.01% and 85.86% in female and males rats, respectively. The key elimination pathways were excretion in urine and expiration of volatiles. Urine contained 32.08% and 40.02% of the recovered dose in females and males, respectively. Expired volatiles contained 29.90 and 18.41% of the recovered dose in females and males, respectively. The percentage of the recovered dose in feces accounted for 22.56 and 27.21% of the recovered dose in females and males, respectively. At 168 h, remaining carcass (including pelt) accounted for 10.73% and 8.68% of the recovered radioactivity in females and males, respectively. Absorption of radioactivity, expressed as percent-recovered radioactivity is the summation of radioactivity found in urine, tissues and carcass, expired volatiles, and expired CO2 while the percent found in feces represents unabsorbed dose (assuming no enterohepatic circulation). The percentage absorbed was 77.2% and 72.5% in females and males, respectively following administration of 14C-D4 at 30 mg/kg bw in a RLD vehicle.

Blood kinetics:
For D4 at 30 mg/kg bw in a rodent diet vehicle, parent concentrations were measurable through 72 h and 48 h for females and males, respectively. Radioactivity concentrations were measurable through 168 h for both females and males. The peak blood concentration, Cmax, occurred at 2 h for both D4 and total 14C-activity in females; the peak blood concentrations were at 2 h for D4 and 4 h for total 14C-activity in male animals. Cmax concentrations were similar between females and males.

Calculated AUCs from the blood time course data indicated that 14C-activity was absorbed; AUCs in μg 14C-equivalents D4 × hr/g of blood were similar between females and males. There was a statistically significant difference between AUCs for parent D4 and 14C-activity for females and males. This indicates that metabolites contribute to a portion of the AUC for 14C-activity. A statistically significant difference was observed for parent AUCs between females and males. Terminal half-lives of elimination for either parent D4 or 14C-activity were similar between females and males; however, the elimination of 14C-activity was slower than that for parent.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Following administration of 14C-D4, the mean percentage of the administered dose recovered was 87.01% and 85.86% in female and males rats, respectively. The percentage absorbed was 77.2% and 72.5% in females and males, respectively.
The blood kinetics Cmax was similar between females and males. AUCs in μg 14C-equivalents D4 × hr/g of blood were similar between females and males. Terminal half-lives of elimination for either parent D4 or 14C-activity were similar between females and males.
Details on distribution in tissues:
Tissue distribution and kinetics: parent (D4) and 14C-activity in blood and tissues:
Parent D4 was detected in all tissues with the Cmax in most tissues at 2h post-dosing, except in fat where the highest concentration was observed at 12 and 24h post-dosing for males and females, respectively. Parent D4 was measurable in tissues through 168h post-dosing in all animals.The Cmax of parent D4 in blood was lower than Cmax levels in tissues. Terminal half-lives of elimination (t1/2) of parent D4 were fastest in blood; 20 and 18.7 h for females and males, respectively. Slower t1/2s of elimination in fat were: 233.6 and 166.8 h for females and males, respectively.

14C-Activity D4 was detected in all tissues with the highest concentrations in all tissues at 2h post-dosing, except in fat where the highest concentration was observed at 12h post-dosing. 14C-Activity was measurable in tissues through 168h post-dosing in all animals. In blood the Cmax of 14C-activity was lower than Cmax concentrations in tissues.

The half-lives of elimination (terminal phase) of radioactivity in blood were; 104.5 and 80.6h for females and males, respectively. The slowest t1/2s of eliminations were in perirenal fat; 225.2 and 217.9h for females and males, respectively and in lungs, 311.9 and 212h for females and males, respectively.

Tissue kinetics and metabolism:
Comparisons of calculated 14C-activity AUCs (μg eq*h/g) and parent AUCs (μg*h/g) in female and male tissues revealed the following order from greatest to least: perirenal fat>digestive tract>lung or liver>spleen>blood. The ratio of the AUCs for D4 in tissues to blood was greater than 1 for all tissues. The highest tissue-to-blood AUC ratios were observed in perirenal fat; 240.7 and 189.1, for females and males, respectively. Liver to blood partitioning was 10.4 and 7.6 for females and males, respectively. The percentage of the total radioactivity attributed to metabolites in tissues and blood from females ranged from 9.51% to 83.29% with blood (83.29%) and liver (61.53%) with the greatest percentage of metabolites and the fat (9.51%) with the least percentage of metabolites. Similar percentages of radioactivity attributed to metabolites were observed for males.
Details on excretion:
Radioactivity was measurable through 168h in feces, expired volatiles, urine, and as 14CO2 following single oral gavage administration of D4.
A total of 29.9 and 18.4% of the recovered dose was accounted for in expired volatiles in females and males, respectively. The highest concentrations (14C-activity) measured in expired volatiles was during the 1–2 and 2–4 h collection intervals for females (168 μg eq/h) and males (189μg eq/h, data not shown), respectively.

A total of 32.1 and 40.0% of the recovered dose was accounted for in the urine in females and males, respectively. The highest concentration (14C-activity) in urine was measured at the 12–24h collection interval which was 150 and 253μg eq/g in female and male rats, respectively. A total of 22.6 and 27.2% of the recovered dose were accounted for in feces in females and males, respectively. The highest concentration of 14C-activity in feces was measured at the 0–24h collection interval which was 152 and 173μg eq/g in female and male rats, respectively. Concentrations of parent D4 were measurable through 48h in feces and through 168h in expired volatiles following single oral gavage administration of 14C-D4. The highest concentration of parent in feces was measured at the 0–24h collection interval and was 98.61 and 75.89 μg/g in female and male rats, respectively. The highest amounts measured in expired volatiles were during the 1–2 and 2–4h collection intervals for females (119.28 μg/h) and males (112.60 μg eq/h) respectively. Terminal half-lives of elimination for radioactivity were similar for female and male animals for expired volatiles, urine and feces. Halflives ranged from 50.1 to 63.9h in females and 35.7 to 55.2h in males.
The percentage of the total radioactivity attributed to metabolites in excreta from females following an oral administration of a low dose of D4 ranged from 30.93% to 100.00%: feces (48.26%), expired volatiles (30.93%), and urine (100.00%), with similar results for males.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Urine analysis: metabolite profile: The radioactivity eliminated in the urine consisted entirely of polar metabolites of D4.
The mean percentage of radioactivity that can be attributed to individual metabolites from urine at 0–12, 12–24, and 24–48 h collection intervals following oral administration was 30.0%-39.3% in male and female rats, respectively. Dimethylsilanediol represented the greatest percentage of total urinary radioactivity. The percentages for the three collection intervals ranged from 51 to 59% in female animals and 55 to 65% in male animals. The percentages for methylsilanetriol for the three collection intervals ranged from 20 to 25% in female rats and 16 to 27% in male rats. Dimethyldisiloxane-1, 3, 3, 3-tetrol as a percentage of urinary activity for the three collection intervals ranged from 9.5 to 13.1% in females and 9 to 13% in male animals. The average sum of de-methylated peak percentages (oxidative metabolism) ranged from 30 to 39% for females and males. No gender differences in identified metabolites were noted, except that hexamethyltrisiloxane-1, 5-diol was only present in female animals during the 0–12 and 12–24 h collection intervals.

Fecal analysis: metabolite profile:
Parent D4 represented the major percentage of radioactivity in the fecal samples analysed from the 0–24 h collection interval. 71% of fecal radioactivity was identified as D4 in female rats and 51% in male rats for the 0–24h collection interval. At the same collection interval, 13% and 26% of the radioactivity was attributed to methylsilanetriol in females and males, respectively. In the 24–48h collection interval, less D4 was observed, 41 and 24% in females and males, respectively. However, the percentage of methylsilanetriol was greater in the 24–48h collection interval, 55 and 53% of the total fecal radioactivity in female and male animals, respectively. No gender differences in identified metabolites were noted except dimethyldisiloxane-1, 3, 3, 3-tetrol was not present at the 0–24h collection interval in females.

Conclusion: no bioaccumulation potential.

Applicant's summary and conclusion

Conclusions:
The study showed that a high percentage (77%) of the administered dose is absorbed following oral gavage administration. More of the recovered dose was found in expired volatiles was excreted in urine as metabolites. In addition, a high percentage of the recovered dose was eliminated as metabolites in feces. The data indicated a fast uptake of D4 from the GI tract and high absorption resulting in a greater and rapid metabolism.
Interpretation of results: no bioaccumulation potential based on study results.
Executive summary:

In this ADME study, D4 was assessed in female and male Fischer 344 rats following a single oral gavage administration of 30 mg [14C]D4/kg bw in a RLD vehicle.

Absorption:

Following administration of 14C-D4, the mean percentage of the administered dose recovered was 87.01% and 85.86% in female and males rats, respectively. The percentage absorbed was 77.2% and 72.5% in females and males, respectively.

The blood kinetics Cmax was similar between females and males. AUCs in μg 14C-equivalents D4 × hr/g of blood were similar between females and males. Terminal half-lives of elimination for either parent D4 or 14C-activity were similar between females and males.

Distribution:

Parent D4 was detected in all tissues (except in fat ) with the Cmax in most tissues at 2h post-dosing. Parent D4 was measurable in tissues through 168h post-dosing in all animals. The Cmax of parent D4 in blood was lower than Cmax levels in tissues. Terminal half-lives of elimination (t1/2) of parent D4 were fastest in blood; 20 and 18.7 h for females and males, respectively. Slower t1/2s of elimination in fat were: 233.6 and 166.8 h for females and males, respectively.

Metabolism:

The percentage of the total radioactivity attributed to metabolites in tissues and blood from females ranged from 9.51% to 83.29% with blood (83.29%) and liver (61.53%) with the greatest percentage of metabolites and the fat (9.51%) with the least percentage of metabolites. Similar percentages of radioactivity attributed o metabolites were observed for males. Metabolites found in urine and feces were Dimethylsilanediol (51 - 65%), methylsilanetriol (16- 27%) and Dimethyldisiloxane-1, 3, 3, 3-tetrol (9 - 13.1%). Hexamethyltrisiloxane-1, 5-diol was only noted in females.

Elimination:

A total of 29.9 and 18.4% of the recovered dose was accounted for in expired volatiles in females and males, respectively. A total of 32.1 and 40.0% of the recovered dose was accounted for in the urine in females and males, respectively. A total of 22.6 and 27.2% of the recovered dose were accounted for in feces in females and males, respectively. Terminal half-lives of elimination for radioactivity were similar for female and male animals for expired volatiles, urine and feces. Half lives ranged from 50.1 to 63.9 h in females and 35.7 to 55.2 h in males. The half-lives of elimination (terminal phase) of radioactivity in blood were; 104.5 and 80.6 h for females and males, respectively. The slowest t1/2s of eliminations were in perirenal fat; 225.2 and 217.9 h for females and males, respectively and in lungs, 311.9 and 212 h for females and males, respectively.