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EC number: 217-775-8 | CAS number: 1951-97-9
- 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
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- two-generation reproductive toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- migrated information: read-across based on grouping of substances (category approach)
- Adequacy of study:
- weight of evidence
- Reliability:
- 4 (not assignable)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- Piperazine (CAS No 110-85-0) is the parent molecule from which piperazine, compound with phosphoric acid or piperazine phosphate (CAS No 1951-97-9) is synthesized. In medicine piperazine is used in the form of the hexahydrate or as the citrate, tartrate, phosphate (1951-97-9) or adipate. Thus, piperazine and piperazine phosphate can be considered as belonging to the same category. No conclusive evidence of reproductive effects have been demonstrated in feeding studies with phosphoric acid or phosphate salts in various species of laboratory animal although limited studies have suggested testicular effects and reduced fertility in rats. No carcinogenic potential was demonstrated in limited feeding studies in rats treated with phosphoric acid or several of its salts, however, in rodents treated orally, several phosphates have been shown to promote the effects of known carcinogens. A wide range of genotoxicity assays (including the Ames bacterial test) have yielded essentially negative results with the acid or its salts. Based on the above, it is has been considered that the properties of piperazine (parent molecule) shall have an important influence on the toxicological properties of piperazine phosphate. Thus, Piperazine (CAS No 110-85-0) has been used as a read across substance, especially for the toxicological end points in this dossier preparation.
Data source
Referenceopen allclose all
- Reference Type:
- other: study report
- Title:
- Piperazine hydrochloride: Dietary two generation reproduction study in the rat.
- Author:
- Wood and Brooks PN
- Year:
- 1 994
- Bibliographic source:
- Report to Akzo Nobel from Safepharm Laboratories Ltd., Derby.
- Reference Type:
- other: study report
- Title:
- European Union Risk Assessment Report : Piperazine
- Author:
- European Chemicals Bureau
- Year:
- 2 005
- Bibliographic source:
- 3rd Priority List Volume: 56;Final Report, 2005
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- GLP compliance:
- not specified
Test material
- Reference substance name:
- Piperazine
- EC Number:
- 203-808-3
- EC Name:
- Piperazine
- Cas Number:
- 110-85-0
- IUPAC Name:
- piperazine
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
Administration / exposure
- Route of administration:
- oral: feed
- Type of inhalation exposure (if applicable):
- not specified
- Vehicle:
- not specified
- Details on exposure:
- The F0 males and females (32 per dose and sex) were dosed for 73 days for males and 17 days for females and paired within their respective dosage groups for up to 21 days.F1 animals were given piperazine in the diet for 80 days.
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- For F0 males and females - 73 days for males and 17 days for females.
F1 animals - for 80 days - Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 5,000, 12,000, or 25,000 ppm (250, 600, or 1,250 mg/kg/day)
Basis:
no data
- No. of animals per sex per dose:
- 32 per dose and sex
- Details on study design:
- Groups of male and female animals were administered 0,5,000, 12,000, or 25,000 ppm (250, 600, or 1,250 mg/kg/day) piperazine dihydrochloride in
the diet throughout maturation, mating, gestation and lactation phases for two successive generations.
Expressed as piperazine base, the doses represent 125,300, and 625 mg/kg/day. The F0 males and females (32 per dose and sex) were dosed for
73 days for males and 17 days for females and paired within their respective dosage groups for up to 21 days. Subsequent exposure to diets continued throughout the breeding, gestation and lactation periods for both generations.
F1 animals were given piperazine in the diet for 80 days, and all animals were observed for sexual development. Males and females were paired for up to 21 days and pregnant females allowed to deliver their offspring that were observed for growth and development. The adult F0 animals as well as the F1 males and females were sacrificed and examined macroscopically post mortem.
Examinations
- Parental animals: Observations and examinations:
- Parental animals were observed daily for clinical signs, and the body weights and food consumption recorded weekly during the maturation phase, which was continued for males after the mating phase. Mated females were weighted and food consumption recorded on specific days post coitum and post partum.
- Litter observations:
- Reduced litter size at birth for both generations (59% and 32% of control values in F1 and F2, respectively)
- Postmortem examinations (parental animals):
- The adult F0 animals was sacrificed and examined macroscopically post mortem.
- Postmortem examinations (offspring):
- The F1 males and females were sacrificed and examined macroscopically post mortem.
Results and discussion
Results: P0 (first parental generation)
Details on results (P0)
At 300 mg/kg/day piperazine base, the effects on body weight gain were smaller, although statistically significant in F0 males (9%), but not in F0 females. In the F1 parental generation, bodyweights were significantly reduced in both males and females from week 2, and there was also a slight reduction in food consumption (F1 females, 9%; F1 males 9%). However, the food conversion ratios were similar to control values. There was no effect on the number of pregnancies, but a statistically significant reduced litter size at birth was noted in both generations.
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 125 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: effects observed mainly on fertility (i.e., reduced pregnancy index and decreased number of implantation sites).
- Remarks on result:
- other: not specified
- Dose descriptor:
- LOAEL
- Effect level:
- 300 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: the effects on body weight gain were smaller, although statistically significant in F0 males (9%), but not in F0 females.
- Remarks on result:
- other: not specified
- Dose descriptor:
- dose level:
- Effect level:
- 625 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: there was clear evidence of toxicity to the adult animals as judged by a statistically significant reduced body weight increase in both sexes for the F0 as well as F1 animals.
- Remarks on result:
- other: not specified
Target system / organ toxicity (P0)
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
Results: F1 generation
Details on results (F1)
for intra-litter onset and duration of landmarks of physical development. On specific days of lactation, reflexological assessment of offspring was performed. These tests included investigation of the surface-righting reflex (day 1 post partum), mid-air righting reflex (day 17 post partum), startle reflex (day 21 post partum) and pupil reflex (day 21 post partum).
Effect levels (F1)
open allclose all
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 125 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: effects observed mainly on fertility (i.e., reduced pregnancy index and decreased number of implantation sites).
- Remarks on result:
- other: not specified
- Dose descriptor:
- LOAEL
- Generation:
- F1
- Effect level:
- 300 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
- Remarks on result:
- other: not specified
- Dose descriptor:
- dose level:
- Generation:
- F1
- Effect level:
- 625 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: there was clear evidence of toxicity to the adult animals as judged by a statistically significant reduced body weight increase in both sexes for the F0 as well as F1 animals.
- Remarks on result:
- other: not specified
Target system / organ toxicity (F1)
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
- Treatment related:
- not specified
Applicant's summary and conclusion
- Conclusions:
- For reproductive effects, a NOAEL of 125 mg/kg/day and a LOAEL of 300 mg/kg/day piperazine base can be established, with decreased litter size as the main effects. The NOAEL for the adult animals is estimated to be 125 mg/kg/day piperazine base, with body weight decreases (<10%) at 300 mg/kg/day in the F1-generation and in males of F0.
- Executive summary:
For reproductive effects, a NOAEL of 125 mg/kg/day and a LOAEL of 300 mg/kg/day piperazine base can be established, with decreased litter size as the main effects. The NOAEL for the adult animals is estimated to be 125 mg/kg/day piperazine base, with body weight decreases (<10%) at 300 mg/kg/day in the F1-generation and in males of F0.
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