Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Non-GLP. Some inconsistencies between summary and results. Unknown recovery due to several non-sampled matrices (air, carcass, feces).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Report Date:
1967

Materials and methods

Objective of study:
distribution
excretion
metabolism
Test guideline
Qualifier:
no guideline available
GLP compliance:
no
Remarks:
prior to GLP

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 14C-monomethylhydrazine
- specific activity of 3.1 µc/mM (60 µc/mL)
- no other details given
Radiolabelling:
yes
Remarks:
14C, position not stated

Test animals

Species:
other: see details below
Details on test animals and environmental conditions:
no data

Administration / exposure

Route of administration:
intraperitoneal
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The material is water soluble, and aqueous dilutions were prepared fresh immediately prior to use
All animals were fasted overnight and weighed just prior to use.

HOMOGENEITY AND STABILITY OF TEST MATERIAL:
not applicable (fresh solutions)

no other details
Duration and frequency of treatment / exposure:
single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
see details below
No. of animals per sex per dose:
see details below
Control animals:
no
Positive control:
no
Details on study design:
- Dose selection rationale: doses were varied according to species based on preliminary dose response studies
- Rationale for animal assignment (if not random): no data
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)

Groups of 4 or 5 animals each were injected with 14C-MMH and maintained in individual metabolism cages (or chairs, in the case of monkeys) for 2, 4, 8, or 24 hours.
Excreted urine was collected for each experimental period, and bladder urine was obtained at necropsy. Each animal was processed individually, except for the mice which were pooled in groups of 5 to obtain sufficient tissue material for analysis.
All animals were killed by pentobarbital sodium anesthesia and exsanguination. Blood samples were collected at this time. Necropsies were performed immediately, and whole organs were removed, weighed, and processed for liquid scintillation 1 4C counting.
Digestion of tissue samples, 100 to 150 mg, in 3 ml Hydroxide of Hyamine-lOX R was accomplished by overnight maintenance in a 56 C waterbath.
Blood serum samples were analyzed for MMH by colorimetry; urine volumes were recorded and samples were likewise analyzed by a slight modification of the same technique.
Efforts to analyze tissue samples for MMH content were unsuccessful. Therefore, distribution results for MMH in tissues are given solely in terms of 14C radioactivity.
Serially collected blood samples from some dogs and monkeys were also analyzed for methemoglobin by the method of Hainline.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
not applicable (injection)
Details on distribution in tissues:
The same four tissues had the highest concentrations of 14 C, in all four species: blood serum, liver, kidneys and bladder.
In every tissue analyzed, the dog and mouse showed the highest values at 4 h, the monkey showed its highest values at 2 hours and in the rat there was no apparent consistent pattern relative to time.
Appreciable amounts still present in the tissues at 24 hours after exposure, but with a clear decline over these 24h (except in mice where it was less clear).
Details on excretion:
Urine: high concentration in monkey urine at 2 hours and in dog urine at 4 hours.
Total percent excreted in urine at 24h: 26% in dog, 31% in monkey, 40% in rat, 9% in mice (inconsistent result in mice). The most rapid excretion was in mice.
No analysis of feces or exhaled air was attempted

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
approximately 50% of what is excreted is unchanged monomethylhydrazine. Also in blood the results of 14C dosing were higher than those of specific MMH levels.

Applicant's summary and conclusion

Conclusions:
Bioaccumulation potential cannot be judged based on study results unknown total recovery, expired air and feces not assayed
MMH evidenced a metabolism both in blood and excreted urine (about 50% was unchanged MMH).
Important excretion in urine occured in rats, monkeys, dogs and mice.
In all species the highest concentrations were in liver, kidney, bladder, pancreas, and blood serum.