Hydrazine

Toxicity to reproduction

Administrative data

Endpoint:

fertility, other

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: guideline study under GLP

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2003

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

hydrazine monohydrate

Cas Number:

7803-57-8

Molecular formula:

H4N2*H2O

IUPAC Name:

hydrazine monohydrate

Constituent 2

Reference substance name:

hydrazine hydrate

IUPAC Name:

hydrazine hydrate

Details on test material:

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:

TEST ANIMALS
- Housing: premating period in groups of of the same sex; mating in cages suitable for this purpose, pregnant females individually
- Diet (e.g. ad libitum): yes
- Water (e.g. ad libitum): yes
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

oral administration by gavage

Details on mating procedure:

according to the respective guideline

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Exposure period: males: 48 d; females: from 14 days before mating to day 3 of lactation
Premating exposure period (males): 14 days
Premating exposure period (females): 14 days
Duration of test: males: 49 days, females: day 4 post partum

Frequency of treatment:

daily

Details on study schedule:

Dosing of both sexes should begin at least 2 weeks prior to mating, after they havbe been acclimated for at least 5 days.
Dosing is continued in both sexes during the mating period
Daily dosing of parental females should continue throughout pregnanty and at least up to including day 3 post partum
Males should further be dosed after the mating periond and then killed
Dams with offspring should be klled on day 4 post partum
The day of birth is defined as day 0 post partum
Femaeles showing no evidence of copulation are killed 24-26 days after the last day of the mating period

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 2, 6, 18 mg/kg bw/day dissolved in water
Basis:
other: with respect to hydrazine: 0, 1.28 - 11.52 mg/kg bw/day

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Details on study design:

see section any other information on material and methods

Positive control:

no

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS:

CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations:
males weekly,
females during pregnancy day 0, 7, 14, and 20
and within 24 hours of partuition and day 4 post partum

FOOD CONSUMPTION yes
WATER CONSUMPTION No data

Oestrous cyclicity (parental animals):

yes

Sperm parameters (parental animals):

no data

Litter observations:

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, no data


GROSS EXAMINATION OF DEAD PUPS:
no data

Postmortem examinations (parental animals):

see section any other information on material and methods
GROSS NECROPSY
yes

ORGAN WEIGHTS
- Male animals:
absolute and relative organ weights: thymus, liver, spleen, kidneys, adrenals, testes, epididymides
- Maternal animals:
absolute and relative organ weights: thymus, liver, spleen, kidneys, adrenals, ovaries
HISTOPATHOLOGY
-Male animals
heart, spleen, thymus, liver, kidney, testis, epididymis, prostate, thyroid gland, adrenal gland skin
- Female animals
spleen, thymus, liver, kidney, uterus, vagina, skin

Postmortem examinations (offspring):

no data

Statistics:

Bartlett's test of homogeneity of variance one-way analysis of variance. Dunnett's test the Kruskal-Wallis test Mann-Whitney U-test Fisher's exact test

Reproductive indices:

Copulation index
Fertility index
Gestation index
Implantation index
Delivery Index

Offspring viability indices:

live birth index
viability index on day 4

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

effects observed, treatment-related

Reproductive function: sperm measures:

not specified

Reproductive performance:

effects observed, treatment-related

Details on results (P0)

CLINICAL SIGNS (PARENTAL ANIMALS)
males and females, 18 and 6 mg/kg bw-group: salivation
females, 18 mg/kg bw-group: lacrimation
AND MORTALITY (PARENTAL ANIMALS)
Males,18 mg/kg b-group: 2/12

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Males, 18 mg/kg bw-group: decrease in body weight and lowered food consumption in the early stage of the administration period
Males, 18 mg/kg bw-group: suppression of body weight gain

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
Irregular cycle: 2 mg/kg bw-group: 1/12; 6 mg/kg bw-group: 0/12; 18 mg/kg bw-group 3/12 versus control: 0/12

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
no data

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Copulation indices and fertility indeces showed no significant difference to the conurrent control

ORGAN WEIGHTS (PARENTAL ANIMALS, only significant changes)
18 mg/kg bw-group, males:
increase in relative liver weight (3.7 g% vs. 3.3 g% of control)
and kidney weight (0.76 g% vs. 0.65 g%)
18 mg/kg bw-group, female:
no data
6 mg/kg bw -group female:
elevated relative liver weights (4.1 g% vs. 3.9 g%), spleen weight (0.23 g% vs. 0.18 g%) and kidney weights (0.7 g% vs. 0.6 g%)

GROSS PATHOLOGY AND HISTOPATHOLOGY (PARENTAL ANIMALS)
18 mg/kg bw (males and females), 6 mg/kg bw (males): pale liver, fatty changes, pigmentation of the spleen

OTHER FINDINGS:
Duration of gestation did not differ from the respective control group
Implantation Index (%):
2 mg/kg bw-group: 85; 6 mg/kg bw-group: 90; 18 mg/kg bw-group 69; versus 80 of control
Gestation Index (%)
2 mg/kg bw-group: 100; 6 mg/kg bw-group: 100; 18 mg/kg bw-group: 0.0% (sign. p<=0.01) versus 100 % of control

Effect levels (P0)

1

Dose descriptor:

other: NOAEL (female reproductive tox)

Effect level:

6 mg/kg bw/day

Sex:

female

Basis for effect level:

other: (with respect to hydrazine:3.84 mg/kg bw/day) in females of the 18 mg-group lethal actions on the embryos were observed

Remarks on result:

other: Generation not specified (migrated information)

2

Dose descriptor:

other: NOAEL (male reproductive tox)

Effect level:

18 mg/kg bw/day

Sex:

male

Basis for effect level:

other: (with respect to hydrazine: 11.52 mg/kg bw/day) The test substance had no effects on reproduction

Remarks on result:

other: Generation not specified (migrated information)

3

Dose descriptor:

NOAEL

Effect level:

2 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: (with respect to hydrazine: 1.28 mg/kg bw/day) general toxicity: based on clinical signs including salivation and lacrimation, body weight development, and histopathological changes in liver kidneys and spleen

Results: F1 generation

General toxicity (F1)

Clinical signs:

effects observed, treatment-related

Mortality / viability:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Histopathological findings:

not specified

Details on results (F1)

VIABILITY (OFFSPRING)
Viability index on day 4 (%).
total:
2 mg/kg bw-group: 99; 6 mg/kg bw-group: 89 (sign p<=0.05); 18 mg/kg bw-group: no data versus 99 % of control
There was no abnormality consedered to be the effect of the test substance on external observation of pups of the 6 mg7kg bw-group but body weights and the viability inded on day 4 of lactation tended to be lower in males and females (no further data available)

There were no gross abnormalities considered to be the effect of the test substance in dead fetuses or offspring necropsied (no further data available).

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

2 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: (with respect of hydrazine: 1.28 mg/kg bw/day) offspring: from 6 mg/kg group viablity index on day 4 and latation tended to be lower in males and females

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

------REPEATED DOSE TOXICITY:
MORTALITY:
18 mg-group: 2/12 males died
CLINCAL SIGNS:
6 mg-group and higher dose groups: salivation in males and females
18 mg-group, females: lacrimation
BODY WEIGHT AND FOOD CONSUMPTION:
Significant decrease in body weight and lowered food consumption were observed in males of the 18 mg group in the early stage of the administration period.
18 mg group, males: significant suppression of body weight
GROSS AND HISTOPATHOLOGICAL EXAMINATION:
18 mg-group, males:
increase in relative liver weight (3.7 g% vs. 3.3 g% of control) and kidney weight (0.76 g% vs. 0.65 g%)
6 mg-group female:
elevated relative liver weights (4.1 g% vs. 3.9 g%), spleen weight (0.23 g% vs. 0.18 g%) and kidney weights (0.7 g% vs. 0.6 g%)
18 mg/kg bw (males and females), 6 mg/kg bw (males): pale liver, fatty changes, pigmentation of the spleen
------REPRODUCTIVE andDEVELOPMENTAL TOXICITY
The test substance had no effect on either copulation or fertility ability.
18 mg-group, dams:
GESTATION INDEX: 0 % vs. 100 % of control;
LIVE BIRTH INDEX: 0 % vs. 97.9 % of control
--- pup data:
6 mg-group:
VIABILITY INDEX ON DAY 4 (males and females):
88.6 % vs. 98.6 % of controls

Applicant's summary and conclusion

Executive summary:

In a preliminary reproduction toxicity study according to OECD TG 421, male and female rats received orally by gavage 0, 2, 6, or 18 mg/kg bw/day hydrazine monohydrate. The NOAEL (general toxicity) is 2 mg/kg bw/d based on clinical signs including salivation and lacrimation, body weight development, and histopathological changes in liver kidneys and spleen. The NOAELs for reproductive and developmental toxicity are considered to be 18 mg/kg bw/d for males because reproductive performance and fertility was not affected by treatment, for females the NOAEL is 6 mg/kg bw/day based on lethal actions on the embryos of the 18 mg/kg bw females; the NOAEL offspring is 2 mg/kg bw/day based on body weight development , viablity index of day 4 of lactation tended to be lower in males and females from 6 mg -group onwards.

Assuming that the hydrazine monohydrate contains 64% hydrazine unhydrous the respective values for hydrazine are

NOAEL (general toxicity): 1.28 mg/kg bw/day

NOAEL (male fertility): 11.52 mg/kg bw/day

NOAEL (female fertility): 3.84 mg/kg bw/day

NOAEL (offspring): 1.28 mg/kg bw/day