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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: guidelinestudy, GLP
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2003

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
a 14-day recovery period : control and high dose animals
Principles of method if other than guideline:
Guideline for the 28-day repeated dose toxicity test in mammalian species (Chemical Substances Control Law of Japan)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
7803-57-8
Cas Number:
7803-57-8
IUPAC Name:
7803-57-8
Constituent 2
Reference substance name:
hydrazine hydrate
IUPAC Name:
hydrazine hydrate
Details on test material:
IUCLID4 Test substance: other TS: hydrazine monohydrate, purity: 100.15 %

Test animals

Species:
rat
Strain:
other: Crj: CD (SD)IGS
Sex:
male/female
Details on test animals or test system and environmental conditions:
as required by guideline

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
After the 28 day treatment period a 14-day recovery period is reported for the control and the highest test group.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no given
Duration of treatment / exposure:
28 d
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 1, 3, 10, 30 mg/kg bw/day (corresponding to 0, 0.64-19.2 mg/kg bw/d hydrazine)
Basis:

No. of animals per sex per dose:
5 males and 5 females/per dose group including control animals
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: 14 d
Positive control:
no

Examinations

Observations and examinations performed and frequency:
clinical signs, food comsumption, body weight, hematology, blood chemistry, urinalysis
Sacrifice and pathology:
all animals were autopsied
rel and absolute organ weight, gross findings, histopathological findings
Other examinations:
no further information
Statistics:
Appropriate statistical methods were used: eg. non-parametric analysis (no further information)

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):
effects observed, treatment-related
Food efficiency:
effects observed, treatment-related
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
see section remarks on results

Effect levels

Dose descriptor:
NOAEL
Effect level:
3 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: (corresponding to 1.92 mg/kg bw/d) based on adverse effects from 10 mg/kg bw/d onwards including changes in hematology, blood chemistry and changes in liver, spleen and kidneys

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

CLINICAL OBSERVATIONS AND FREQUENCY:
-Mortality:
No deaths were observed
-Clinical signs:
30 mg/kg bw/d:
males+females: wasting, piloerection, salivation;
females: dirty nasal discharge
30 mg/kg bw/d (males and females):
-Body weight gain, food consumption, food efficiency suppressed, reversable during recovery

--HEMATOLOGY (significant changes)
-------males, 30 mg/kg bw:
significant decrease:
HCT: 38.0 % vs 44.8 % of control; recovery in 14 d
HGB: 11.9 g/dL vs 15.1 g/dL of control; recovery in 14 d
MCV: 51.8 µm3 vs 57.3 µm3 of control; recovery in 14 d
MCH: 16.2 pg vs 19.6 pg of control; recovery in 14 d
MCHC: 31.3 % vs 34.2 % of control
PT: 14.4 sec vs 17.5 sec of control; recovery in 14 d
APTT: 19.6 sec 24.2 sec of control; recovery in 14 d
significant increase but recovery in 14 d:
Reticulocytes: 6.2 % vs 2.8 % of control;
Methemoglobin: 0.99 % vs 0.75 % of control;
PLT count: 1786 10³/mm3 vs 1304 10³/mm3 of control
------females,
---from 10 mg/kg bw onwards significant decrease but recovery in 14 d
HCT: 40.5 %, 34.7 % % vs 43.6 % of control;
HGB: 14.0 g/dL, 10.6 g/dL vs 15.3 g/dL of control;
MCH: 18.7 pg, 16.6 pg vs 19.7 pg of control;
---30 mg/kg bw significant dercrease
RBC: 6.43x10[exp6]/mm³ vs 7.77 x10[exp6]/mm³of control; recovery in 14 d
MCHC: 30.7 % vs 35.1 % of control
---30 mg/kg bw significant increase but recovery in 14 d:
Reticulocytes: 9.2 % vs 2.2 % of control;
Methemoglobin: 1.0 % vs 0.52 % of control

--CLINICAL CHEMISTRY (significant changes):
------Male, 30 mg/kg bw but recovery in 14 d
Glucose (mg/dL): 100 vs. 140 of control
BUN (mg/dL): 22.5 vs. 13.7 of control
Tbilirubin (mg/dL): 0.12 vs. 0.04 of control
Albumin (g/dL): 3.86 vs. 3.60 of control
A/G ratio : 2.37 vs. 1.80 of control
Chloride (mmol/L): 104.6 vs. 108 of control
Iphosphate (mg/dL): 9.54 vs. 8.05 of control
AST (U/L): 51 vs. 77 of control
ALT (U/L): 17 vs. 32 of control
------female, at 10 mg/kg bw but recovery in 14 d
AST (U/L): 62 vs. 73 of control
ALT (U/L): 17 vs. 25 of control
------female, 30 mg/kg bw but recovery in 14 d
Glucose (mg/dL): 83 vs. 114 of control
Tbilirubin (mg/dL): 0.11 vs. 0.03 of control
A/G ratio : 2.42 vs. 1.77 of control
Chloride (mmol/L): 102 vs. 108 of control
Calcium (mg/dL): 10.49 vs. 9.74 of control
Iphosphate (mg/dL): 9.81 vs. 7.56 of control

----------GROSS AND HISTOPATHOLOGY
---The absolute weights of
the kidneys were increased or tended to be increased in both sexes of the 10 and 30 mg/kg bw groups; elevation of liver weights in females of the 10 and 30 mg/kg bw groups and of spleen weights in 30 mg /kg bw females was apparent.
---Relative weights of
the liver and kidneys were higher or tended to be higher in both sexes of the 10 and 30 mg/kg bw groups than in controls. liver males: 3.01%,3.5% versus 2.7%, recovery in 14 d liver females: 3.2%,3.9% versus 2.7%, after 14d: 3.2% versus 2.7% kidneys males: 0.84%,1.04 versus 0.76%, recovery in 14 d kidneys females: 0.86%, 0.96% versus 0.79%, after 14 d: 0.85% versus 0.75%
---Macroscopically,
pale colored livers were observed in both sexes of the 30 mg/kg bw group.
---Histopathologically,
fatty change of the hepathocytes was observed in males of the 10 and 30 mg/kg bw groups and in females of all groups including the controls. Pigmentation of the spleen was observed in both sexes of the 30 mg/kg bw group. A higher degree of extramedullary hematopoiesis than normal was observed in both sexes of the 30 mg/kg bw group and in males of the 10 mg/kg bw group.

Applicant's summary and conclusion

Executive summary:

In a subacute toxicity study according to OECD TG 407 hydrazine monohydrate was administered to male and female Crj:CD(SD)IGS rats by gavage at dose levels of 0, 1, 3, 10, 30 mg/kg bw/day diluted in water. Additionally, the control group and the highest dose group were observed during a 14-day recovery period (MHLW 2003). Based on adverse effects from 10 mg/kg bw/d onwards including changes in hematology, blood chemistry and changes in liver, spleen and kidneys the NOAEL is 3 mg/kg bw/day for male and female rats.