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EC number: 206-114-9 | CAS number: 302-01-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
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- Nanomaterial pour density
- Nanomaterial photocatalytic activity
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- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Carcinogenicity
Administrative data
Description of key information
In a drinking water study, male and female rats received 0, 2, 10, 50 mg
hydrazine/l water over the whole period of life. With respect to body
weight development, mortality or tumour development 2 mg hydrazine/l was
tolerated without effects, 10 mg/l leads to reduced body weight
development and 50 mg/l leads not to reduction of survival time but to a
reduction in body weight gain of about 20 % . At this toxic dose male
and female rats showed an increase in benign liver tumours and
addionally, female rats an increase in maligne liver cell tumours
(Steinhoff 1988). There is a longterm inhalation study on rats, mice,
hamsters 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).
Neoplastic lesions were observed
- in male and female rats from 1 ppm (1.33 mg/m³) onwards based on
increase in benigne and maligne nasal tumours in male and females and
thyroid carcinomas in males
- in female mice at 1 ppm (1.33 mg/m³) based on increase in lung adenoma
development
- in male hamsters at 5 ppm(6.65 mg/m³) based on increase in benign
nasal polyps
By comparison, the lowest concentration of 0.066 mg/m³ (0.05 ppm) is
taken as a worst case LOAEC for local irritation.
Key value for chemical safety assessment
Carcinogenicity: via oral route
Link to relevant study records
- Endpoint:
- carcinogenicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: no individual animal data shown
- Reason / purpose for cross-reference:
- reference to same study
- Principles of method if other than guideline:
- Oral application of different concentrations in drinking water over the entire lifespan, examination for effects.
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- animal age: 6 weeks,
housing : individually
room temperature: 23 °C
rel humidity: 70 %
diet ad libitum - Route of administration:
- oral: drinking water
- Vehicle:
- water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
they were prepared every second day
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- every 4 weeks a check was performed (further details not given)
- Duration of treatment / exposure:
- lifetime: until spontaneous death
- Frequency of treatment:
- daily ad libitum
- Post exposure period:
- no
- Remarks:
- Doses / Concentrations:
0, 2, 10, 50 mg/l
Basis:
other: calculated as hydrazine in water - No. of animals per sex per dose:
- 50
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Post-exposure period: no
- Positive control:
- no
- Observations and examinations performed and frequency:
- body weight weekly, survival time, drinking water consumption of test animals
- Sacrifice and pathology:
- All animals were autopsied macrroscopic findings recorded:
Wet weight of brain, heartn lungs, liverm spleen, kidneys testes, adrenals, ovaries
histologicalexamination: adrenals, bladder , brain, epididymis, esophagus, eyes, femur, heart, intestines, kidneys, larynx, liver, lungs, mammary
gland, mesentery, nasopharynx, omentum, ovaries, pancreas, pituitary, prostate, salivary glands, seminal vesicles, skeletal muscels, skin, spinal cord with marrow, spleen, sternum, submaxillary gland with lymph nodes, testes, thymus if possiblem thyroid, tongue, trachea, uterus - Other examinations:
- no data
- Statistics:
- yes, method not mentioned
- 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 examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- effects observed, treatment-related
- Details on results:
- see section remarks on results
- Dose descriptor:
- other: Carcinogenicity
- Effect level:
- ca. 50 mg/L drinking water
- Sex:
- male/female
- Basis for effect level:
- other: based on occurrence of small, usually beningn liver cell tumours
- Remarks on result:
- other: Effect type: carcinogenicity (migrated information)
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 2 mg/L drinking water
- Remarks on result:
- other: Effect type: toxicity (migrated information)
- Executive summary:
In a drinking water study, male and female rats received 0, 2, 10, 50 mg hydrazine/l water over the whole period of life. With respect ot body weight development, mortality or tumour development 2 mg hydrazine/l was tolerated without effects, 10 mg/l leads to reduced body weight development and 50 mg/l leads not to reduction of survival time but to a reduction in body weight gain of about 20 % . At this toxic dose male and female rats showed an increase in benign liver tumours and addionally, female rats an increase in maligne liver cell tumours (Steinhoff 1988).
Reference
see also chapter 7.5.1 for toxicological results.
Carcinogenicity: There is an increase in the number of uterine
tumours in female rats (highest concentration : 17/50(36 %) versus
8/50(16 %)in the controls and 117/326 = 36 % in the historical controls)
Thus, these tumours give no indication of a carcinogenic effect of
hydrazine liver cell tumours: 50 mg/l: significant increase in benign
(males and
females) and malignant (only females) liver cell tumours No tumours were
found in the control groups. Type of tumours 2 ppm-group (males): 1
hepatocellular adenoma and 1 haemangioma
10 ppm-group(males): 1 hepatocellular adenoma, 1 hepatocellular
carcinoma, 1 cholangioma 50 ppm-group (males and females) 8
hepatocellular adenomas, 2 hepatocellular carcinomas, 1 cirrhotic
carcinoma 3 cholangiomas (14.6% liver cell tumours [historical control
range: 0-2.7%]) Number of rats with tumours conc: 2 - 10 - 50 versus
concurrent(historical) control: benign liver tumours males: 1/49, 1/50,
4/49 versus 0/50 (4/326) females: 0/50, 0/50, 4/47 versus 0/50 (3/326)
malign liver tumours males: 0/49, 1/50, 0/49 versus 0/50 (2/326)
females: 0/50, 0/50, 3/47 versus 0/50 (0/326).
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- LOAEL
- 3 mg/kg bw/day
- Study duration:
- chronic
- Species:
- rat
- Quality of whole database:
- Although individual animal data are not shown this is the only reliable oral rat study providing sufficient information to be worth to be mentioned. In this publication of the drinking water study tumours are reported to occur only at the highest dose of 50 mg/l (ca 3 mg/kg bw/d) in a late phase of life time in the presence of marked toxicity. Based on this considerations and taking into account that oral application is not the predominant route of exposure against hydrazine this information will not be considered with respect to threshold evaluations.
Carcinogenicity: via inhalation route
Link to relevant study records
- Endpoint:
- carcinogenicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: refers mostly to the guidelines of today
- Reason / purpose for cross-reference:
- reference to same study
- Principles of method if other than guideline:
- Other exposure of rat, mouse, hamster, dog for 1 year; see section any other information on material and methods.
- GLP compliance:
- not specified
- 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 - Route of administration:
- inhalation
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- other: air
- Details on 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 months
- Frequency of treatment:
- 6 h per day; 5 days per week; no exposures on holidays (no further data)
- Post exposure period:
- life time
- 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: rats 18, mice 15, hamsters 12, dogs 38 months
- 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
- 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 examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- 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 section remarks on results
- Dose descriptor:
- conc. level:
- Effect level:
- 1 ppm
- Sex:
- male/female
- Basis for effect level:
- other: rat. increase in benigne and maligne nasal tumours in male and females, thyroid carcinomas in males
- Remarks on result:
- other:
- Remarks:
- Effect type: other: tumour development (migrated information)
- Dose descriptor:
- conc. level:
- Effect level:
- 1 ppm
- Sex:
- female
- Basis for effect level:
- other: mouse: increase in lung adenoma development
- Remarks on result:
- other:
- Remarks:
- Effect type: other: tumour development (migrated information)
- Dose descriptor:
- conc. level:
- Effect level:
- 5 ppm
- Sex:
- male
- Basis for effect level:
- other: hamster: increase in benign nasal polyps
- Remarks on result:
- other:
- Remarks:
- Effect type: other: tumour development (migrated information)
- Dose descriptor:
- conc. level:
- Effect level:
- 0.25 ppm
- Sex:
- female
- Basis for effect level:
- other: dog: 1 hemangioma and 1 papillary carcinoma of the anus.
- Remarks on result:
- other:
- Remarks:
- Effect type: other: tumour development (migrated information)
- 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).
Neoplastic lesions were observed
- in male and female rats from 1 ppm (1.33 mg/m³) onwards based on increase in benigne and maligne nasal tumours in male and females and thyroid carcinomas in males
- in female mice at 1 ppm (1.33 mg/m³) based on increase in lung adenoma development
- in male hamsters at 5 ppm(6.65 mg/m³) based on increase in benign nasal polyps
- in dogs at 0.025 ppm : 1 hemangioma and 1 papillary carcinoma of the anus evaluated as no consistent pathological effect..
Reference
Variance in exposure concentration mainly +/-10%; 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 tumor incidences different from controls:
hamsters: 0.25 - 1.0 - 5 ppm versus control benign nasal polyps
0/154 - 1/146 - 16/160 versus 1/181;
rats: 0.05 - 0.25 - 1.0 - 5.0 ppm versus control benign epithelial tumors of the nasal cavity
males: 2/99 - 2/99 - 10/98 - 66/99 versus 0/149
females: 1/99 - 0/100 - 4/97 - 31/98 versus 0/147
malignant tumors of the same type
males: 1/99 - 0/99 - 1/98 - 6/99 versus 0/149
females: 0/99 - 0/100 - 0/97 - 5/98 versus 0/147
thyroid adenocarcinomas
males: 6/99 - 5/99 - 9/98 - 13/99 versus 7/149
at 5 ppm 13/99 (male) versus 7/149;
mice: 0.05 - 0.25 - 1.0 ppm versus controls
pulmonary adenomas
females: 3/364 - 5/382 - 12/379 versus 4/373;
1 dog of the 0.25 ppm group showed 1 hemangioma and 1 papillary
carcinoma of the anus.
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- LOAEC
- 0.066 mg/m³
- Study duration:
- chronic
- Species:
- rat
- Quality of whole database:
- This is a reliable long term study using the most appropriate route of exposure and is therefore evaluated with Klimisch Score 2.
Carcinogenicity: via dermal route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
Under Regulation No. 1272/2008 (GHS) the substance is classified in Carcinogenicity Class 1B; Hazard Statement H350: May cause cancer.
Additional information
Oral route
In the long-term drinking water study in rats under this particular severe experimental condition of exposure during the total lifetime, hydrazine induced increased liver tumours, at the highest the toxic - concentration of about 3 mg/kg bw/day (no effect at the next lower dose of 0.7 mg/kg bw/day). The majority of the liver tumours were benign thus demonstrating that hydrazine showed only a weak carcinogenic effect (Steinhoff 1988). In contrast, the 2 year drinking water study in mice revealed no increase in tumour incidence up to the highest dose tested (Steinhoff et al. 1990).
There are several publications discussing the mechanism of action of hydrazine in rat and mouse suggesting a dose-dependent increase in liver DNA methylation after single and repeated oral administration. In this context it is discussed that treatment with hydrazine disturb the balance of methylation and demethylation on N-7 and O-6 of guanine by inhibiting the demethylation which would result in accumulation of the methylated purines in the liver DNA (see also DFG 1989). Dose-response studies in rats revealed a single oral dose of 0.1 mg/kg as a starting dose for effects on liver DNA methylation (borderline effect, clear effects with 10 mg/kg; van Delft 1997; clear effect at 30 mg/kg; Becker et al. 1981). After the third of four oral doses of 3 mg/kg increase of 7-methylguanine was observed as trace and readily detectable after 4 treatments (Becker et al. 1981). Evidence of liver toxicity was shown at 2.5 mg/kg (exposure for 1-10 days; decrease of GSH, increase of triglycerides; Jenner & Timbrell 1992) and 3 mg/kg (3-4 doses; Becker et al. 1981). Therefore it is plausible that the liver tumours after long-term high dose exposure are secondary to liver toxicity and alteration of the balance of methylation and demethylation.
Inhalation route
In the above described inhalation study the local irritant, hydrazine, induced in hamsters and in rats, but not in mice, tumours only of the epithelium of the nasal cavity starting at 1.3 mg/m³. In contrast, the LOAEC in rats based on irritational effects in the nose, the larynx and trachea was much lower (0.066 mg/m³).As it is known that this tissue is highly sensitive to the local effects of carcinogens in rodents, it is difficult to extrapolate the results of this study to the human situation. It seems to provide evidence for a low carcinogenic potential of hydrazine (DFG 1989)
Dermal route
There are no data available using the dermal route
Human information
There are epidemiological studies available investigating the association between hydrazine exposure and tumour development.(Cordier 1993, Ritz 1996). Although they are of limited validity (small numbers of participants, only estimated exposure information and the lack of discussion of confounding factors they did not reveal an indication of a causal association between human exposure to hydrazine and the development of cancer. Recently, Ritz (2006) published the results of an additional epidemiological study on the association between hydrazine exposure and lung cancer mortality in aerospace workers. Whereas this study of aerospace workers give some evidence of an association between hydrazine exposure and lung cancer mortality, a variety of limitations mentioned in the paper limits the overall evaluation and relevance for the assessment of hydrazine: at first, Ritz defined as "Hydrazine" a mixture of hydrazine, 1-methylhydrazine and 1,1 -dimethylhydrazine of unknown ratio. Most importantly, however, the exposure assessment is based on a job-exposure matrix adjusted for other carcinogens e.g trichloroethylene but without specific measurements and potential confounding factors as e.g. smoking could only be partly included in the assessment. In the same cohort an association between mineral oil exposure and eg lung cancer risk was reported (Zhao et al (2005), Am J Indust Med 48, 249 -258). In contrast to this publication, in the meantime, data are available from the hydrazine producing industry (Arkema 2003) that show that under the circumstances of hydrazine production a limited epidemiological study do not reveal an indication of a carcinogenic response in humans under historic working conditons. These data are confirmed in a very recent follow-up study (Arkema 2014) which covers a longer follow-up period than the 2003 study and involves the integration of new workers into the cohort: no evidence of relationship between hydrazine exposure and cancer is observed.
Conclusion
Hydrazine is classified as animal carcinogen. Irrespective of this classification, the database is not fully conclusive regarding the mode of action that leads to the tumour response in animal studies, e.g. the carcinogenic effects of hydrazine have been shown only with maximally tolerated unambiguously toxic doses or locally irritating concentrations. Tumour responses are limited to the first site of contact in inhalation studies (nasal cavity) or the first organ of systemic availability after oral dosing (liver), respectively. Studies on the mode of action led to the conclusion that for the oral intake it is plausible that the liver tumours after long-term high dose exposure are secondary to liver toxicity and alteration of the balance of DNA methylation and demethylation. Regarding the local effects after inhalation exposure from the dose-response assessment (irritation threshold much lower than the concentration leading to tumours) it can be derived that that a direct cytotoxic mechanisms is most probably dominant.
Genotoxicity seems not to be a major cause for the tumour responses as for primary genotoxic carcinogens multiorgan tumour responses with a wide tissue distribution is typical, instead of a local first site of contact/first organ of systemic availability. Therefore, even if some role of genotoxicity at very high doses cannot be excluded, based on the available data the overall weight of evidence points to a non-genotoxic mechanism for the tumour responses in animal experiments. Local toxicity is regarded to be of main importance with tumour development as secondary response
That reflection of the database led industry initially to propose to strengthen the database with a testing proposal to examine the irritation threshold after repeated inhalation with the aim to define the most sensitive level of the respiratory tract after repeated exposure, as well as the threshold for irritation after repeated exposure and on the respective dose-response relationship.
Based on responses received from the Competent Authorities that proposal was revised taking into consideration the following aspects:
• Within the activity of the EU Commission for an amendment of Directive 2004/37/EC on carcinogens and mutagens the proposal to set the 8hr TWA for Hydrazine (0.013 mg/m3) as a Binding Limit Value was agreed by the Advisory Committee on Safety and Health at Work (Opinion Doc. 2011/12).
• After implementation such a Binding Limit Value will be the corner stone for the risk management and it is expected that a more in depth knowledge on the Mode of Action most probably will not influence that Binding Limit Value.
• This view was supported by the responses from Member States to the testing proposal
• The scientific and regulatory value for further toxicological testing needs to be weighted with animal welfare considerations.
Based on these considerations the testing proposal for a short-term repeated dose toxicity study via the inhalation route was deleted.”
Justification for selection of carcinogenicity via oral route
endpoint:
Although individual animal data are not shown this is the only
reliable study providing sufficient information to be worth to be
mentioned
Justification for selection of carcinogenicity via inhalation route
endpoint:
This is a reliable long term study using the most appropriate route
of exposure and is therefore evaluated with Klimisch Score 2
Carcinogenicity: via inhalation route (target organ): respiratory:
nose
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