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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:
key study
Study period:
17 September 1980 - 7 January 1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study run to a reliable method but not GLP and no guideline followed. However it has been QA audited.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report Date:
1986

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
not specified
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline
Details on test material:
- Name of test material (as cited in study report): HMX
- Substance type: explosives
- Physical state: white crystalline solid
- Impurities (identity and concentrations): white suspensions containing approximately 20% (w/w) water
- Radiochemical purity (if radiolabelling): 98.3 and 99.4%
- Specific activity (if radiolabelling):26.80 μCi/mmol
- Locations of the label (if radiolabelling): 14C-ring

Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: reputed breeder
- Weight at study initiation: 12 animals/sex were first received and weighed 142g for males and 114 g for females and 5 more animals/sex were received which weghed 150 g for males and 138 g for females
- Fasting period before study: 18 h pre-dose fast
- Housing: individually in glass metabowls specially designed for the separate collection of urine and faeces. After dosing, those animals used in plasma level studies were housed individually in polycarbonate cages with raised mesh floors.
- Individual metabolism cages: yes
- Diet: ad libitum except for an 18 h pre-dose fast
- Water: ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23°C
- Humidity (%): 50-58%

IN-LIFE DATES: From: October 1980 To: June 1981 (these dates include the rat oral TK study, the rat intraveneous TK study and the mouse oral TK study)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
For the low specific activity material 14 C-HMX (49.9 mg) was diluted with HMX (9.86 g) in acetonitrile to yield 9.79 g 14C-HMX of specific activity 0.905 μCi/mg (26.80 μCi/mmol).The target dose level or each animal was 500 mg/g body weight.
Two stock suspensions of 14C-HMX in 0.1% carboxy methyl cellulose (CMC) solution were prepared at concentrations of ca 23.83 mg/ml and 250.02mg/ml

VEHICLE
- Concentration in vehicle: 23.83 mg/ml and 250.02mg/ml
- Amount of vehicle (if gavage): 3 ml


HOMOGENEITY AND STABILITY OF TEST MATERIAL:
The homogeneity of each suspension was maintained throughout the dosing period by use of a magnetic stirrer.
Duration and frequency of treatment / exposure:
Single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
500 mg/kg bw
No. of animals per sex per dose:
16 animals/sex/dose
including 5 animals/sex/dose for collection of faeces and urine samples and 11 animals/sex/dose for collection of blood samples
Control animals:
no
Positive control:
No
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled : urine, faeces, blood, expired CO2 (in 1 male and 1 female), carcass, gastro intestinal tract, and cage washes
- Time and frequency of sampling:
Urine for the periods 0-6, 6-24, 24-48, 48-72 and 72-96 h post-dose
Faeces for the periods 0-24, 24-48, 48-72 and 72-96 h post-dose,
Blood samples were taken at 0.25, 0.5, 1, 2, 4, 6, 24, 48 and 72 h post-dose.
CO2: for a period of 48 h post-dose
Carcass: at sacrifice
Gastro intestinal tract: at sacrifice

UNCHANGED HMX CHARACTERISATION STUDIES
- Tissues and body fluids sampled : urine, faeces
- Time and frequency of sampling: male and female rat 6-24 h faeces and urine collection were separately pooled
- From how many animals: 10 rats, 5 animals/sex/dose, samples were pooled
- Method type(s) for identification: TLC
- Limits of detection and quantification: quantification on TLC was done by scintillation counting (quantitation of radioactivity). A limit of reliable determination of 30 dpm above background count rate

TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable):Selected urine samples were subjected to enzymatic and chemical deconjugation
procedures.
Statistics:
No

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
After 96 h, 85% had been eliminated in the faeces, 4% in the urine and only 0.7% retained in the gastrointestinal tract and carcass. 14CO2 was collected during the first 48 h post dose. In these 2 animals a mean of 0.5% was eliminated as 14CO2.
Type:
distribution
Results:
After 96h, 0.7% was retained in the gastrointestinal tract and carcass.
Type:
metabolism
Results:
The radioactivity eliminated in faeces was excreted as unchanged 14C-HMX.
Type:
excretion
Results:
After 24 h, 64% had been eliminated in the faeces and 2% in the urine. After 48 h, 82% had been eliminated in the faeces and 3% in the urine and 0.5% was eliminated as 14CO2.
Type:
other: Plasma levels
Results:
Plasma levels of radioactivity were very low, peaked slowly to between 6 and 12 μg equiv.ml. (0.07% of administered dose) during the first 6h post dose.During 24h to 72h post dose, plasma levels fell slowly to below the limit of reliable determination.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
A comparison of faeces, urine and plasma levels of radioactivity following oral administration of 14C-HMX to rats suggested that the proportion of 14C-HMX absorbed may be low.
Details on distribution in tissues:
After 96 h post-dose, the carcass had retained 0.55% and the gastro intestinal tract 0.07% of the administered dose
Details on excretion:
Radioactivity was rapidly and significantly eliminated mainly in the faeces. Thus after 96 h, 85% had been eliminated in the faeces and 4% in the urine.
In 2 animals, 14CO2 was collected during the first 8 h post dose. In these 2 animals a mean of 0.5% was eliminated as 14CO2. Examination of the results showed that almost all of the radioactivity eliminated in faeces was excreted as unchanged 14C-HMX.
Toxicokinetic parametersopen allclose all
Toxicokinetic parameters:
Cmax: between 6-12 μg equiv.ml.
Toxicokinetic parameters:
Tmax: 6h post-dose

Metabolite characterisation studies

Metabolites identified:
not measured

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
Following a single oral dose of 500 mg/kg bw 14C-HMX in 0.1% carboxy methyl cellulose (CMC) administered to rats by gavage, radioactivity was rapidly eliminated in the faeces as unchanged HMX. Observed levels in plasma, the carcass and in the urine, however showed that a small proportion of the administered dose had been absorbed.