Methylhydrazine

Endpoint summary

Link to relevant study record(s)

Reference

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).

Objective of study:

distribution

excretion

metabolism

Qualifier:

no guideline available

GLP compliance:

no

Remarks:

prior to GLP

Radiolabelling:

yes

Remarks:

14C, position not stated

Species:

other: see details below

Details on test animals or test system and environmental conditions:

no data

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

Remarks:

Doses / Concentrations:
see details below

No. of animals per sex per dose / concentration:

see details below

Control animals:

no

Positive control reference chemical:

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.

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

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.

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.

Key value for chemical safety assessment

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

A total of 20 mice, 20 rats, 17 dogs, and 16 monkeys received intraperitoneal injections of 14 C-monomethylhydrazine (MMH) at doses of 22 mg/kg (mice), 15 mg/kg (rats), and 10 mg/kg (monkeys and dogs). At 2, 4, 8, and 24 hours after exposure, representative samples of approximately 20 tissues from each animal were processed for 14C assay using liquid scintillation counting techniques. Both blood and urine samples were simultaneously analyzed by a chemical colorimetric method for unchanged MMH, and the results were correlated with total 14C content. Results of the 14C assays indicated that the mouse, rat, and monkey excreted twice as much as the dog in the first 2 hours, and that all 4 species excreted 25-40% of the total dose by 24 hours after injection. Approximately 50% of the total 14C excretion, at all experimental times, was apparently unchanged MMH as implied by the colorimetric results. Tissue distribution of 1 4C showed the highest concentrations in liver, kidney, bladder, pancreas, and blood serum. Both clinically and pathologically, the dog was apparently much more susceptible than the other species tested to the toxic effects of MMH and to severe kidney damage. [source: see RSS enclosed].

As with hydrazine, MMH affects carbohydrate and amine metabolism. Intensive studies have so far failed to elucidate the mechanism by which MMH affects carbohydrate metabolism (Dost et al., 1973). The inhibition of monoamine oxidase by MMH appears to cause a depressor effect on the cardiovascular system (Weir et al., 1964). [source: review: Proceedings of the fourth annual conference on environmental toxicology held at Fairborn, Ohio, on 16, 17, and 18 October 1973 - Aerospace Medical Research Laboratory - December 1973, N° AMRL-TR-73 -125]