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Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
repeated dose toxicity: inhalation
Remarks:
other: 1 Year exposure and add observation period lifelong
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: evaluation of histopatological changes only
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Long-Term Inhalation Toxicity of Hydrazine.
Author:
Vernot EH, MacEwen JD, Bruner RH, Haun CC, Kinkead ER, Prentice DE, Hall A, Schmidt RE, Eason RL, Hubbard GB, Young JT . (1985).
Year:
1985
Bibliographic source:
Fundam. Appl. Toxicol. 5, 1050-1064
Reference Type:
study report
Title:
Unnamed
Year:
1981
Reference Type:
other: abstract
Title:
Chronic inhalation toxicity of hydrazine. Oncogenic effects
Author:
MacEwen, JD, Vernot ER, Haun CC
Year:
1980
Bibliographic source:
Proc. Am. Ass. Cancer Res. 21, 74
Reference Type:
publication
Title:
Unnamed
Year:
1979
Reference Type:
other: Review
Title:
Unnamed
Year:
1978
Report date:
1978

Materials and methods

Principles of method if other than guideline:
Method: exposure of rat, mouse, hamster, dog for 1 year and post exposure observation for 18 months (rat), 15 months (mouse), 12 months (hamster) and 38 months (dog), respectively.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Hydrazine
EC Number:
206-114-9
EC Name:
Hydrazine
Cas Number:
302-01-2
Molecular formula:
H4N2
IUPAC Name:
hydrazine
Details on test material:
IUCLID4 Test substance: hydrazine
purity= 97% nominal

Test animals

Species:
other: rat, mouse, hamster, dog
Strain:
other: F344 rat; C57BL/6 mouse, Golden Syrian hamster, Beagle dogs
Sex:
male/female
Details on test animals or test system and environmental conditions:
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 50
-

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: air
Remarks on MMAD:
MMAD / GSD: no data
Details on inhalation exposure:
inhalation exposures were conducted 6 hr/day, 5 days/week for 1 year without exposures on weekend and holidays
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Technico Autoanalyser proportioning pump and colorimeter
Duration of treatment / exposure:
12 mo
Frequency of treatment:
6 h per d, 5 d a week, not during holidays (not specified)
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.05 - 5.0 ppm (0, 0.066-6.65 mg/m³)
Basis:

No. of animals per sex per dose:
100 male and 100 female rats/conc. 0.066, 0.33, 1.33, 6.65 mg/m³: post exposure observation: 18 months
400 female mice/conc.0.066, 0.33, 1.33 mg/m³; post exposure observation: 15 months
200 male hamsters/conc. 0.33, 1.33, 6.65 mg/m³ post exposure observation: 12 months
4 males and 4 female dogs/conc. 0.33. 1.33 mg/m³ post exposure observation: 38 months
Control animals:
yes, concurrent no treatment
Details on study design:
Post-exposure period: 12 mo hamsters, 18 mo rats, 15 mo mice, 38 mo dogs
Positive control:
no

Examinations

Observations and examinations performed and frequency:
clinical signs of toxicology body weight development biweekly (10 mice/cage as cage groups),
hematology and clinical chemistry of dogs biweekly,
Sacrifice and pathology:
all animals that died or were killed during the study were necropsied: external examination and complete histopathological examination
Other examinations:
no further data
Statistics:
yes: t-test, Fisher's exact test,

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
see remarks on results

Effect levels

open allclose all
Dose descriptor:
LOAEC
Effect level:
0.066 mg/m³ air
Sex:
male/female
Basis for effect level:
other: Rat: based on inflammatory changes and squamous metaplasia in the nose, larynx and trachea most prominent at the highest test dose
Dose descriptor:
LOAEC
Effect level:
0.33 mg/m³ air
Sex:
male
Basis for effect level:
other: hamster: based on generalized amyloidosis in the liver, kidneys, thyroid and adrenal glands significantly greater frequency than in control animals
Dose descriptor:
NOAEC
Effect level:
0.33 mg/m³ air
Sex:
male/female
Basis for effect level:
other: dog: based on focal areas of highly vacuolated liver cells and a corresponding elevation in SGPT (data not shown)
Dose descriptor:
NOAEC
Effect level:
6.65 mg/m³ air
Sex:
female
Basis for effect level:
other: mouse: no non-neoplastic lesions

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Variance in exposure concentration mainly +/-10%; neoplastic lesions see chapter carcinogenicity; significantly reduced body weight gain in male and female rats (but not dose-dependent), most
significant in male rats at 5 ppm, in male hamsters at all doses during exposure (only at 5 ppm in the final mo); no effects on weight gain in female mice; mortality in mice and rats not significant different from controls, in unexposed hamsters lowered number of deaths during exposure compared to all treated hamsters (no data about significance); histopathology of rodents found dead or sacrified at termination of post exposure period (10% of surviving rats were nercopsied after 12 mo post exposure period) showed following alterations, significantly different from controls:
hamsters: liver amyloidosis and hemosiderosis, bile duct hyperplasia, spleen amyloidosis, lymphadenitis, kidney interstitial and glomerular amyloidosis, adrenal amyloidosis, senile atrophy of the testis;
female rats: tracheal inflammation, hepatic hyperplasia at 1 and 5 ppm; only significant in high dose group: nasal squamous and epithelial metaplasia, inflammation and squamous metaplasia of the larynx, tracheal squamous metaplasia, lymph node hyperplasia, glomerulonephritis, cystic endometrial hyperplasia, endometritis, salpingitis, atrophy of ovar;
male rats: myocardial degeneration; only significant in high dose group: nasal meta- and hyperplasia, laryngeal squamous metaplasia, interstitial hyperplasia of the testis; no significant histopathological alterations in mice and dogs; no further treatment related, significant effects in dogs.

Applicant's summary and conclusion

Executive summary:

There is a longterm study on rats, mice, hamsters and dogs which is reported in brief. The used concentration for rats ranged between 0.05 and 5 ppm (0.066 -6.65 mg/m³) hydrazine, for mice between 0.05 and 1.0 ppm (0.066-1.33 mg/m³) and for hamsters between 0.25 and 5.0 ppm (0.33-6.65 mg/m³) The exposure period was 6 h per day, 5 days per week for 1 year (but not during holidays, not specified) followed by a lifelong post exposure observation period (MacEwen 1981, Vernot 1985). With respect to the non-neoplastic lesions

in rats the LOAEC is 0.066 mg/m³ based on dose-dependent increase in inflammatory changes and

squamous metaplasia in the nose, larynx and trachea

in hamster the LOAEC is 0.33 mg/m³ based on generalized amyloidosis in the liverm , kidneys,thyroid and adrenal glands significantly greater frequency than in control animals

in dogs the NOAEC is 0.33 mg/m³ based on focal areas of highly vacuolated liver cells and a corresponding elevation in SGPT (data not shown)

in mouse the NOAEC is 6.65 mg/m³ because no non-neoplasic lesions were reported