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Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
The process for gold analysis was undertaken on plasma and urine samples taken from rats on the oral Maximum Tolerated Dose (MTD) study with the test substance.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report date:
2017

Materials and methods

Objective of study:
absorption
Principles of method if other than guideline:
Blood samples were taken into an appropriate anticoagulant from rats at termination of the MTD study and the plasma was separated by centrifugation and stored frozen until anaysis. In addition, overnight urine samples were collected from the same animals and stored frozen until analysis. All sample analysis was undertaken using inductively coupled plasma–mass spectrometry (ICP–MS). ( Nexion 300D PerkinElmer, Waltham, MA ). Samples were analysed in the standard mode.
To 500 µl of the sample ( urine and whole blood ) was added 100 µl HCl 37% and 400 µl HNO3 70%. Samples were then incubated during one hour at 80 °C. After incubation samples were further diluted
with HNO3 0.7% ( 20-fold dilution ). Rhodium was used as internal standard.
GLP compliance:
yes

Test material

Specific details on test material used for the study:
Tetrachloroauric acid (orange liquid)
Radiolabelling:
no

Test animals

Species:
rat
Strain:
other: HsdHan:WIST
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan, Bicester, UK
- Age at study initiation: At least 9 weeks
- Weight at study initiation: N/A
- Housing: 5 per cage
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period: At least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 24
- Humidity (%): 45-65
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 28 October 2013 To: 12 November 2013

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

Dose solutions were prepared freshly each day
Doses / concentrationsopen allclose all
Dose / conc.:
80 mg/kg bw/day (nominal)
Remarks:
Actual dose received was adjusted for density to 168 mg/kg/day
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
Actual dose received was adjusted for density to 210 mg/kg/day
No. of animals per sex per dose / concentration:
5 male and 5 female rats per group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
- Initial dose levels were based on acute studies and subsequent doseselection was based upon the reactions seen at the previous dose level
Details on dosing and sampling:
Animals were dosed each day for 14 consecutive days and at the end of the treatment period overnight urine samples and blood samples were collected from each animal

Results and discussion

Main ADME results
Type:
absorption
Results:
Significant increases in gold content over the controls were measured in both the plasma and urine of rats treated with either 80 (168) or 100 (210) mg/kg/day tetrachloroauric acid

Applicant's summary and conclusion

Conclusions:
Analysis for gold in the urine and plasma of rats treated by daily oral gavage at 80 (actual dose: 168) or 100 (actual dose: 210) mg/kg/day tetrachloroauric acid for 14 days showed significant systemic exposure to gold in comparison with the control animals and that there was no dose relationship at these treatment levels.
Executive summary:

A GLP compliant, non-regulatory Maximum Tolerated Dose study was conducted in rats by the oral gavage route in order to determine suitable dose levels to be used in subsequent repeat dose regulatory studies with the test substance. At the end of the "fixed dose" phase in which animals were dosed for 14 consecutive days at nominal dose levels of 80 and 100 mg/kg/day (Adjusted for density of the solution to 168 and 210 mg/kg/day respectively), overnight urien samples were collected and also blood samples taken from each of the five male and five female rats per group including vehicle controls. Upon analysis of the plasma and urine samples for gold content, it was demonstrated that significant exposure had been achieved at these dose levels although there was no dose dependeny in the gold concentrations between the two treated groups.