Hydrazine

Repeated dose toxicity: inhalation

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

Reference

Reference 1

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 2

Reference Type:

study report

Title:

Unnamed

Year:

1981

Reference 3

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 4

Reference Type:

publication

Title:

Unnamed

Year:

1979

Reference 5

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

Test material information

Constituent 1

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

1

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

2

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

3

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)

4

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