Registration Dossier
Registration Dossier
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EC number: 442-080-3 | CAS number: -
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 625 mg/kg bw/day
- Species:
- rat
- Quality of whole database:
- The effect level is the NOAEL estimated for piperazine in official documents (RAR) for inclusion in annex VI as repr. Cat 2 (H351fd). This is a precautionary principle, as piperazine is less than 20% in DGHF 2000
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
FURTHER INFORMATION: review of existing data
PIPERAZINE
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. Classification Repr. Cat 3; R62-63 is suggested for piperazine [European Chemicals Bureau, 2005].
MELAMINE
No indication of an effect to the reproductive organs was obtained from the repeated dose and chronic toxicity studies: mammary glands, ovaries, prostate, seminal vesicles, testes and uterus were examined macroscopically and microscopically in 13-weeks and in chronic toxicity studies with rats and mice and were found to be unaffected by melamine at each of the doses used. The lowest NOEL for general toxicity in these studies was ca. 63 mg/kg/day [OECD SIDS, 1998 and EFSA, 2010].
PHOSPHATES
Studies reported briefly in the literature indicated no evidence of reproductive effects for Sodium Tripolyphosphate (STPP) and several other inorganic phosphates. These results are also supported by data on two other inorganic condensed phosphates and monovalent orthophosphoric acid, which tends to support the absence of reproductive effects of STPP, and inorganic phosphates in general [HERA, 2003].
MELAMINE POLYPHOSPHATE
Estimated based on analogy to structurally similar compound and professional judgment. There were no data for melamine polyphosphate located. Experimental data for the melamine component also support a low hazard designation [EPA, 2014].
PIPERAZINE PYROPHOSPHATE
There were no treatment-related macroscopic or microscopic effects on mammary glands, ovaries, prostate, seminal vesicles, testes and uterus in rats and mice in a 13-week study on substituted amine phosphate component (Measured for the free base); nevertheless, this study was judged as not adequate to assess the reproductive toxicity for the substituted amine phosphate mixture or substituted amine phosphate component of the mixture [EPA, 2014].
CONCLUSION
The NOEL of piperazine is 125mg/Kg, with reduced litter size in rats at the higher dose of 300mg/kg. This effect was considered relevant and in fact piperazine is inserted in Annex VI of the CLP and classified as suspected of damaging fertility and the unborn child (Repr. Cat. 2 H351fd). In vitro tests demonstrated that piperazine has a specific effect on oocytes and sperm, while DGHF 2000 is only cytotoxic. In spite the fact that piperazine is one of the constituent of DGHF 2000, the biological impact may be different with the effect of piperazine shielded by the phosphate, even though it is not clear whether the bond between polyphosphates and piperazine is mainly ionic or even covalent. The difference between piperazine as a mono-constituent substance and piprazine as one of the constituent of DGHF 2000 is demonstrated also in the area of skin sensitisation, as DGHF 2000 was tested on guinea pigs with clear negative result while piperazine is classified as H317, skin sensitiser. This is the demonstration that beyond the chemical composition, biovailability of piperazine in DGHF 2000 is limited. However, for precautionary principle, the NOEL estimated for piperazine (125 mg/Kg) is used for DGHF 2000.
Reference
Environmental Protection Agency (EPA) United States. An Alternatives Assessment for the Flame Retardant Decabromodiphenyl Ether (DecaBDE). Final report. January 2014.
European Chemicals Bureau; Joint Research Centre (2005). European Union Risk Assessment Report. Piperazine CAS 110-85-0 EC: 203-808-3. 3rd Priority List Volume: 56. Office for Official Publications of the European Communities, 2005.
European Food Safety Authority (EFSA), 2010. Scientific Opinion on Melamine in Food and Feed. EFSA Panel on Contaminants in the Food Chain (CONTAM) and EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF). European Food Safety Authority (EFSA), Parma, Italy. EFSA Journal 2010; 8(4):1573.
Human & Environmental Risk Assessment (HERA) on ingredients of European household cleaning products. Sodium Tripolyphosphate (STPP) CAS: 7758-29-4. Draft, June 2003.
OECD SIDS, 1998. Melamine CAS N°: 108-78-1. UNEP Publications.
Effects on developmental toxicity
Description of key information
Assessment is based on th ecomparison with the two most relevant consituent (piperazine end melamine), as the phophate and polyphosphate are not at concerning
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 125 mg/kg bw/day
- Species:
- rat
- Quality of whole database:
- The effect level is the NOEL estimated for piperazine in official documents (RAR) for inclusion in annex VI as repr. Cat 2 (H351fd). THis is a precautionary principle, as piperazine is less than 20% in DGHF 2000
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
FURTHER INFORMATION: review of existing data
PIPERAZINE
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. Classification Repr. Cat 3; R62-63 is suggested for piperazine [European Chemicals Bureau, 2005].
MELAMINE
No indication of an effect to the reproductive organs was obtained from the repeated dose and chronic toxicity studies: mammary glands, ovaries, prostate, seminal vesicles, testes and uterus were examined macroscopically and microscopically in 13-weeks and in chronic toxicity studies with rats and mice and were found to be unaffected by melamine at each of the doses used. The lowest NOEL for general toxicity in these studies was ca. 63 mg/kg/day [OECD SIDS, 1998 and EFSA, 2010].
PHOSPHATES
Studies reported briefly in the literature indicated no evidence of reproductive effects for Sodium Tripolyphosphate (STPP) and several other inorganic phosphates. These results are also supported by data on two other inorganic condensed phosphates and monovalent orthophosphoric acid, which tends to support the absence of reproductive effects of STPP, and inorganic phosphates in general [HERA, 2003].
MELAMINE POLYPHOSPHATE
Estimated based on analogy to structurally similar compound and professional judgment. There were no data for melamine polyphosphate located. Experimental data for the melamine component also support a low hazard designation [EPA, 2014].
PIPERAZINE PYROPHOSPHATE
There were no treatment-related macroscopic or microscopic effects on mammary glands, ovaries, prostate, seminal vesicles, testes and uterus in rats and mice in a 13-week study on substituted amine phosphate component (Measured for the free base); nevertheless, this study was judged as not adequate to assess the reproductive toxicity for the substituted amine phosphate mixture or substituted amine phosphate component of the mixture [EPA, 2014].
CONCLUSION
The NOEL of piperazine is 125mg/Kg, with reduced litter size in rats at the higher dose of 300mg/kg. This effect was considered relevant and in fact piperazine is inserted in Annex VI of the CLP and classified as suspected of damaging fertility and the unborn child (Repr. Cat. 2 H351fd). In vitro test on bovine embryo development, demonstrated a different kinetics between the two substance. DGHF 2000 has a more severe cytotoxic effect, but the activity of piparzine is more specific. In spite the fact that piperazine is one of the constituent of DGHF 2000, the biological impact may be different with the effect of piperazine shielded by the phosphate, even though it is not clear whether the bond between polyphosphates and piperazine is mainly ionic or even covalent. The difference between piperazine as a mono-constituent substance and piprazine as one of the constituent of DGHF 2000 is demonstrated also in the area of skin sensitisation, as DGHF 2000 was tested on guinea pigs with clear negative result while piperazine is classified as H317, skin sensitiser. This is the demonstration that beyond the chemical composition, biovailability of piperazine in DGHF 2000 is limited. However, for precautionary principle, the NOEL estimated for piperazine (125 mg/Kg) is used for DGHF 2000.
Reference
Environmental Protection Agency (EPA) United States. An Alternatives Assessment for the Flame Retardant Decabromodiphenyl Ether (DecaBDE). Final report. January 2014.
European Chemicals Bureau; Joint Research Centre (2005). European Union Risk Assessment Report. Piperazine CAS 110-85-0 EC: 203-808-3. 3rd Priority List Volume: 56. Office for Official Publications of the European Communities, 2005.
European Food Safety Authority (EFSA), 2010. Scientific Opinion on Melamine in Food and Feed. EFSA Panel on Contaminants in the Food Chain (CONTAM) and EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF). European Food Safety Authority (EFSA), Parma, Italy. EFSA Journal 2010; 8(4):1573.
Human & Environmental Risk Assessment (HERA) on ingredients of European household cleaning products. Sodium Tripolyphosphate (STPP) CAS: 7758-29-4. Draft, June 2003.
OECD SIDS, 1998. Melamine CAS N°: 108-78-1. UNEP Publications.
Justification for classification or non-classification
According to the CLP Regulation (EC 1272/2008), 3.7 Reproductive toxicity section, reproductive toxicity includes adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring.
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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