Hydrazine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - workers

Hydrazine (CAS 302-01-2)_Hazard assessment conclusion

WORKER

Actual EU Regulation:

According to DIRECTIVE (EU) 2017/2398 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 12 December 2017  amending Directive 2004/37/EC on the protection of workers from the risks related to exposure to carcinogens or mutagens at work the binding limit value for occupational exposure is 0.013 mg/m³.

The Binding Limit Value is 0.013 mg/m³ whereas the LOAEC for irritation at the respiratory tract based on the available data is 0.066 mg/m³ (MacEwen 1981, Vernot 1985) and therefore higher than the Binding Limit Value. By that, even if there are uncertainties regarding the no effect level for irritation it is assumed that the Binding Limit Value covers also the aspect of non-neoplastic lesions including local irritation.”

SCOEL 2016

Based on the assessment of SCOEL (2016), “the relevant toxicological endpoint for hydrazine is carcinogenicity. In addition, it is a potent contact sensitizer; allergic contact eczema caused by hydrazine has been described in numerous publications from different branches of industry. Evidence on respiratory sensitization is lacking”.

Inhalation hazard:

“When tested by oral administration, it has produced mainly lung and liver tumors in rats, mice and hamsters. The most useful information comes from the long-term inhalation studies in rodents, and is related to the upper respiratory tract. In mice, exposed in a preliminary study for 6 months at 0.2, 1, or 5 ppm, there was an increased incidence of pulmonary tumors in all groups. A subsequent inhalation study in rats, mice, dogs and hamsters (6h/d; 5d/wk at 0.05 ppm [rats, mice], 0.25, 1.0 ppm and 5 ppm [rats, mice, hamsters, dogs] for 1 year with a follow-up for life span or 38 months revealed an increased incidence of benign and malignant nasal tumors at 1 and 5 ppm in rats. At 0.05 ppm, the incidence of nasal tumors in rats was slightly, but not significantly, higher than in the controls. An increased incidence of benign nasal polyps was observed in hamsters at 5 ppm. In addition, hamsters exposed at 0.25 ppm showed pathological degenerative changes, including amyloidosis. An increased incidence of pulmonary adenomas was observed at 1 ppm in mice.

While there is sufficient evidence of carcinogenicity in animals, the evidence of hydrazine carcinogenicity in humans has been recently evaluated as being limited. There are some data available on the carcinogenic effect in exposed aerospace workers, in particular to an increased risk of lung cancer. This would be compatible with the aforementioned experimental data from experimental animals.

Hydrazine has been characterised as genotoxic. Studies into the mode of action have revealed an indirect mechanism of genotoxicity, involving reaction with endogenous formaldehyde and ultimate formation of a DNA-methylating agent.

In principle, the systemic genotoxicity of hydrazine, based on such an indirect mechanism, may be characterised by a threshold at low exposure levels (when hydrazine-induced DNA methylation becomes insignificant vs. the normal methylation background). However, the critical target upon occupational inhalation exposure is the respiratory tract, and specific studies into the local mode of carcinogenic action, as well as appropriate toxicokinetic modellings, are lacking. Hydrazine is categorised into the SCOEL carcinogen group B, as a genotoxic carcinogen, for which the existence of a threshold cannot be sufficiently supported at present. In this situation, the derivation of a health-based OEL is not possible at the present time. Therefore, SCOEL has decided to perform a dose-response analysis of the data on upper respiratory tract tumors from a long-term inhalation study of hydrazine in rats, mice, hamsters and dogs and derive risk numbers”.

“Derived Limit Values/dose-response analysis (SCOEL 2016)

The long term inhalation study of hydrazine in rats, mice, hamsters and dogs demonstrated that the nasal epithelium of rats and hamsters was most sensitive to the tumorigenic activity of hydrazine following inhalation exposure. Especially the data on neoplastic lesions in male and female rats were suitable for dose-response modelling. BMD modeling of the neoplastic lesions observed in male and female rats revealed BMD10 values for malignant neoplasms which varied between 5.67 and 22.33 ppm. Based on these data it was concluded that a BMD10 of 5.67 ppm (corresponding to 7.6 mg/m³), based on malignant thyroid tumors, would provide an adequate point of departure for definition of risk numbers.

Using this value the following risk numbers were derived:

A tumor risk of 1 : 10 at 7.6 mg/m3 (equal to 5.67 ppm)

A tumor risk of 1 : 1000 at 76 μg/m3 (equal to 0.057 ppm)

A tumor risk of 1 : 10 000 at 7.6 μg/m3 (equal to 0.0057 ppm)

A tumor risk of 1 : 106 at 0.08 μg/m3 (equal to 0.000057 ppm)

Skin notation

The available data on skin absorption and systemic effects seen in animals following dermal contact warrant a “skin notation”.”

SCOEL 2016:

In the report of SCOEL (2016) (SCOEL/REC/164 – Hydrazine – Recommendation from the scientific committee on occupational Exposure limits (Sept. 2016) “ hydrazine is categorised into the SCOEL carcinogen group B, as a genotoxic carcinogen, for which the existence of a threshold cannot be sufficiently supported at present. In this situation, the derivation of a health-based OEL is not possible at the present time”.

“EXISTING OCCUPATIONAL EXPOSURE LIMITS (SCOEL 2016)

OEL's do exist in various EU Member States as well as outside the EU due to national regulations. These OEL's are presented in the following table as examples and the list should not be considered as exhaustive (SCOEL/REC/164 – Hydrazine – Recommendation from the scientific committee on occupational Exposure limits (Sept. 2016)”.

Overview of existing OELs for hydrazine

EU	TWA (8 hrs)		STEL (15 min)		Remarks	References
	ppm	mg/m³	ppm	mg/m³
Austria	0.1	0.13	0.4	0.52	TRK, i.e. TMW and KZW, skin not.	AU GKV (2011)
Belgium	0.01	0.013			8 hrs TGG (TWA), skin not.	BE KB (2014)
Denmark	0.01	0.013	0.02	0.026		DK DWEA (2011)
Germany (AGS)	0.017$ 0.0017&	0.022$ 0.0022&			4:1000 risk number (draft) 4:10000 risk number (draft)	DE BAUA (2016)
Finland	0.1	0.13	0.3	0.4		FI MSAH 2012
France	0.1	0.1				FR INRF (2012)
Hungary				0.13		HU MHSFA (2000)
Ireland	0.01	0.01				IE HSA (2016)
Latvia		0.1				DE IFA (2015)
Norway	0.01	0.01				NO NLIA (2011)
Spain	0.01	0.13			inhalable aerosol	ES INSHT (2011)
UK	0.02	0.03	0.1	0.013	TWA	UK HSE (2011)

•       STEL = Short Term Exposure Limit (usually 15 minutes average).

•        TGG [TijdGewogen Gemiddelde] = TWA.

•        TMW [Tagesmittelwer] = TWA; KZW [Kurzzeitwert] = STEL.

•        TRK [Technische RichtKonzentration] = indicative concentration. Used when no 'safe' exposure level can be derived. Value based on     technical feasibility.

•        TWA = Time-Weighted Average (usually 8 hours average).

•        TWAEV = Time-Weighted Average Exposure Value = TWA.

•        VME [Valeur Moyenne d'Exposition] = TWA.

•        $ Workplace exposure concentration corresponding to the proposed tolerable cancer risk.

•        & Workplace exposure concentration corresponding to the proposed preliminary acceptable cancer risk.

Hazard assessment conclusion

Under Regulation No. 1272/2008 (GHS) the substance is classified in Carcinogenicity Class 1B; Hazard Statement H350: May cause cancer.

The derivation of a valid health-based DNEL /DMEL is not possible based on the available studies.

According to ECHA Guidance on information requirements and chemical safety assessment Part E: Risk characterization (May 2016) in cases ‘when neither a DMEL nor a DNEL can be set for a carcinogen, because no suitable (semi-)quantitative animal or human data are available to establish relevant dose descriptors. In such circumstances, a qualitative assessment should be performed. Carcinogens classified in Category 1A and 1B, are allocated to the high hazard band on the basis that exposure to such substances should be strictly contained because they may cause serious health effects based on sufficient evidence of carcinogenicity derived from human or animal data and for which a dose threshold is not usually identifiable for many of these carcinogens. Non-genotoxic carcinogens which are classified in Category 2 in CLP are in principle allocated to the moderate hazard band, because they are regarded to represent a lower concern than Category 1A and 1B carcinogens according to CLP as there may be only limited evidence of carcinogenicity based on human or animal data. On the other hand, if the mode of action or carcinogenic potency remains unclear then these Category 2 carcinogens according to CLP could be assigned to the high hazard band, on a case by case basis’.

Due to the classification as Carc. 1B (H350) under Regulation No. 1272/2008 (GHS) an allocation of hydrazine to the high hazard band for the hazard via inhalation and dermal route (systemic and local effects for long term and short term exposure) seems justified.

‘With the strict control needed for mutagens (Cat 1A, 1B or 2 in CLP) and carcinogens classified in Category 1A, 1B or in Category 2 if potent, according to CLP, the RMMs/OCs aimed at avoidance of exposure will likely be sufficient to also cover for other relevant effects for which DNELs can be derived, for all routes of exposure. In that case, a qualitative risk characterisation will suffice, and there is no need to conduct a quantitative risk characterisation’ (ECHA Guidance on information requirements and chemical safety assessment Part E: Risk characterization (May 2016).

Overall Conclusion:

The derivation of a valid health-based DNEL /DMEL is not possible based on the available studies.         Based on the assessment of SCOEL (2016), the relevant systemic toxicological endpoint for hydrazine is carcinogenicity. Under Regulation No. 1272/2008 (GHS) the substance is classified in Carcinogenicity Class 1B; Hazard Statement H350: May cause cancer.  

According to ECHA Guidance on information requirements and chemical safety assessment Part E: Risk characterization (May 2016) in cases ‘when neither a DMEL nor a DNEL can be set for a carcinogen, a qualitative assessment should be performed. Carcinogens classified in Category 1A and 1B, are allocated to the high hazard band.

According to DIRECTIVE (EU) 2017/2398 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 12 December 2017  amending Directive 2004/37/EC on the protection of workers from the risks related to exposure to carcinogens or mutagens at work the binding limit value for occupational exposure is 0.013 mg/m³.

Dermal hazard:

DNEL (short term)

Hydrazine is a caustic, fuming hygroscopic liquid at ordinary temperature and pressure (WHO1987).

There is no repeated dose toxicity study available using the dermal route.

According to SCOEL 2016 absorption via the skin is likely “Skin notation: The available data on skin absorption and systemic effects seen in animals following dermal contact warrant a “skin notation“.”

According to ECHA Guidance on information requirements and chemical safety assessment Part E: Risk characterization (May 2016) in cases ‘when neither a DMEL nor a DNEL can be set for a carcinogen, a qualitative assessment should be performed. Carcinogens classified in Category 1A and 1B, are allocated to the high hazard band.

Reproduction Toxicity

Fertility

There is no 2-generation toxicity study available.

For estimation the likelihood of the impairment of fertility the available Screening Reproductive Toxicity study can be taken as surrogate. After oral intake the resulting NOAEL (male fertility) is 11.52 mg/kg bw/day, NOAEL (female fertility) is 3.84 mg/kg bw/day, calculated in terms of hydrazine unaqueous.

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. The NOAEL is 3 mg hydrazine monohydrate/kg bw/day for male and female rats based on changes in hematology, blood chemistry and absolute and relative weight increase in liver, spleen and kidneys and histopathologically fatty change of hepatocytes starting at 10 mg/kg.

Since these NOAELs are higher than the NOAEL for the oral repeated dose toxicity, it can be assumed that hydrazine is not a reproductive toxicant.

Developmental toxicity

Considering the available study on developmental toxicity in rats (i.p.: 2.5-10 mg/kg bw, gd 9-16) developmental toxicity occurs only in the presence of maternal toxicity NOAEL (maternal) 2.5 mg/kg bw/day  and it can be concluded that hydrazine is not a reproductive toxicant.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Explanation for the modification of the dose descriptor starting point:

Hazard described in the worker section. No exposure to general population.

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Explanation for the modification of the dose descriptor starting point:

Hazard described in the worker section. No exposure to general population.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

The substance is not used in the public domain and exposure of consumers is thus not to be expected.