Hydrazine

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

There is no Two-Generation reproductive toxicity study available.
Based on the available information from Reproductive Toxicity Screening test (OECD TG 421) and data from repeated dose toxicity, there is no evidence of a specific reproductive toxicity of hydrazine.
Furthermore, hydrazine is classified as a Class 1B Carcinogen and according to the specific rules (Column 2) of Annex XI of Regulation (EC)1907/2006 (REACH) further testing for Reproductive Toxicity (Fertility Assessment or Developmental Toxicity) has not to be considered.

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Quality of whole database:

There is no two -generation study available as required for the respective tonnage band. Hydrazine is classified and labelled as carcinogene (Cat2, carcinogen, R45 (R67/548/EEC); Carcinogenicity Class 1B, H350 (Regulation No. 1272/2008(GHS)). Based on the information given in ANNEX IX and X of REACh Regulation no studies need to be available nor to be performed.
In addition, in a Reproductive Toxicity Screening Test according to OECD 421 there was no evidence of a specifc reproductive toxicity of hydrazine monohydrate.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

There is no two-generation-reproductive toxicity study available.

Hydrazine is classified as a Class 1B Carcinogen and according to the specific rules (Column 2) of Annex XI of Regulation (EC)1907/2006 (REACH) further testing for Reproductive Toxicity (Fertility Assessment or Developmental Toxicity) has not to be considered.

However, in a Reproductive Toxicity Screening Test according to OECD 421 there was no evidence of a specifc reproductive toxicity of hydrazine monohydrate. The NOEL for repeated dose toxicity was 2 mg/kg in that study. There was no effect on fertility index up to the highest dose of 18 mg/kg. In the highest dose of 18 mg/kg, a clearly toxic dose, females could not maintain pregnancy, but there was no respective effect in the next lower dose of 6 mg/kg. Viability index at day 4 as indication of toxicity to the offspring was slightly reduced in the 6 mg/kg group (no effect at 2 mg/kg). In repeated dose toxicity studies there was some evidence of effects on reproductive organs in repeated dose toxicity studies (see section 7.8.3), but respective effects were not obvious in a recent subacute toxicity study (MHWL 2003), which is in line with the result of the Reproductive Toxicity Screening Assay. Therefore. based on the available data there is no reason to expect a specific reproductive toxicity of hydrazine.

As confirmed by recent literature (Mangelsdorf et al 2003, Ulbrich & Palmer 1995, Janer et al 2007a, Dent 2007, Sanbuissho et al. 2009) in rodents histopathological examinations in repeated dose toxicity studies of reproductive tissues are of high value and high sensitivity for evaluation of reproductive toxicity in males and females. Histopathological changes on the reproductive organs in repeated dose toxicity studies are indicative of effects on fertility. With this respect repeated dose toxicity studies should be considered sensitive and sufficient information to evaluate toxicity on fertility if histological examination of the reproductive organs is covered.

Based on the considerations above no further testing is required for the fertility assessment as hydrazine has not shown specific effects on reproductive organs in male and female rats in the lower effect dose range and there was no evidence of a specifc reproductive toxicity of hydrazine monohydrat in a reproductive screening assay.

------

Mangelsdorf. et al., 2003: Some aspects relating to the evaluation of the effects of chemicals on male fertility. Regulatory toxicology and Pharmacology 36, 69-98

Ulbrich & Palmer, 1995: Detection of effects on male reproduction ¿ a literature survey. J am. College of Toxicology 14, 293-327

Janer et al., 2007: A retrospective analysis of the added value of the rat two-generation reproductive toxicity study versus the rat subchronic toxicity study. Reproductive Toxicology 24, 103-113

Dent, 2007: Strength and limitations of using repeated-dose toxicity studies to predict effects on fertility. Regulatory Toxicology and Pharmacology 48, 241-258

Sanbuissho et al., 2009: Collaborative work on evaluation of ovarian toxicity by repeated-dose and fertility studies in female rats. J Tox. Sci. 34:Special Issue SP1-SP22

Short description of key information:
There is no Two-Generation reproductive toxicity study available
Based on the available information from Reproductive Toxicity Screening test (OECD TG 421) and data from repeated dose toxicity, there is no evidence of a specific reproductive toxicity of hydrazine.
Furthermore, hydrazine is classified as a Class 1B Carcinogen and according to the specific rules (Column 2) of Annex XI of Regulation (EC)1907/2006 (REACH) further testing for Reproductive Toxicity (Fertility Assessment or Developmental Toxicity) has not to be considered.

Justification for selection of Effect on fertility via oral route:
There is no two-generation study available as required for the respective tonnage band. Hydrazine is classified and labelled as carcinogene (Carcinogenicity Class 1B, H350 (Regulation No. 1272/2008(GHS)). Based on the information given in ANNEX IX and X of REACH Regulation no studies need to be available nor to be performed.

Effects on developmental toxicity

Description of key information

There is no developmental toxicity study available using a dosing regim which is relevant for the human situation. Furthermore, hydrazine is classified as a Class 1B Carcinogen and according to the specific rules (Column 2) of Annex XI of Regulation (EC)1907/2006 (REACH) further testing for Reproductive Toxicity (Fertility Assessment or Developmental Toxicity) has not to be considered
However, pregnant female rats were intraperitoneal injected with 0, 2.5, 5.0, 10.0 mg/kg/d once daily on gd 9 -16 and sacrificed on gd day 20. The NOAEL (maternal toxicity ) was determined 2.5 mg/kg bw/day; the NOAEL (developmental toxicity) was determined 2.5 mg/kg bw/day based on a dose-related embryolethality from 5.0 mg/kg bw/d onwards. Furthermore, treatmant of dams with 10 mg/kg bw on gd 7-9 resulted in significantly increased number of resorptions per litter, significantly decreased fetal body weight and fetal abnormalities including supernumerary ribs, moderate hydronphrosis and moderate hydrocephalus (Keller 1982).

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Additional information

There is no developmental toxicity study available using a dosing regime which is relevant for the human situation.

However, pregnant female rats were intraperitoneal injected with 0, 2.5, 5.0, 10.0 mg/kg/d once daily on gd 9 -16 and sacrificed on gd day 20. The NOAEL (maternal toxicity ) was determined 2.5 mg/kg bw/day based on reduced weight gain or weight loss during treatment from 5.0 mg/kg bw/d onwards; the NOAEL (developmental toxicity) was determined 2.5 mg/kg bw/day based on a dose-related embryolethality from 5.0 mg/kg bw/d onwards. Furthermore, treatmant of dams with 10 mg/kg bw on gd 7 -9 resulted in significantly increased number of resorptions per litter, significantly decreased fetal body weight and fetal abnormalities including supernumerary ribs, moderate hydronphrosis and moderate hydrocephalus (Keller 1982).

Considering the available study on developmental toxicity in rats developmental toxicity occurs only in the presence of maternal toxicity and mainly at clear toxic dose. Hence, hydrazine was applied as intraperitoneal injection which includes the possibility to hurt the developing organism and on the other hand this application route is not suitable for the human situation. However, regarding the available Reproduction Toxicity Screening Assay (OECD TG 421) using the oral application route, there is no evidence of fetal abnormalities.

Furthermore, hydrazine is classified as a Class 1B Carcinogen and according to the specific rules (Column 2) of Annex X of Regulation (EC)1907/2006 (REACH) further testing for Reproductive Toxicity (Fertility Assessment or Developmental Toxicity) has not to be considered

Justification for selection of Effect on developmental toxicity: via oral route:
There is no developmental study according to OECD TG 414 available using using a dose regim which is relevant for the human situation. Furthermore Hydrazine is classified and labelled as carcinogene (Carcinogenicity Class 1B, H350 (Regulation No. 1272/2008(GHS)) . Based on the information given in ANNEX IX and X of REACH Regulation no further studies need to be available nor to be performed.

Justification for classification or non-classification

The substance is not classified in one of the categories for fertility assessment or developmental toxicity.

Hydrazine has not shown specific effects on reproductive organs in male and female rats in tests with repeated dose toxcicity. Thus, there is no reason for classification.

With regard to developmental toxicity no classification has to be required because developmental effects occur only in the presence of clear maternal toxicity. Thus, the available data are conclusive but not sufficient for classification.