Spinflam MF 83 PP-25

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

125 mg/kg bw/day

Study duration:

subchronic

Species:

dog

Quality of whole database:

The assessment is based on official documents issued by OECD, EMA and FDA

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

FURTHER INFORMATION: review of existing data

 

PIPERAZINE

A NOAEL of 25 mg/kg/day of piperazine base for induction of mild hepatic involvement in the Beagle dog can be established; this NOAEL was chosen by EMEA (The European Agency for the Evaluation of Medical products) as the basis for setting an ADI and provisional MRLs for the use of piperazine as a veterinary anthelmintic in pigs and poultry [EMEA, 2001]. However, adequate chronic bioassays are not available, and the fact that none of the systematic experimental studies reported neurotoxic effects is a cause for serious concern. Such effects have been well documented in clinical practice, and have also been described by veterinarians in rabbits, dogs, cats, tigers, horses, the puma, and sea lions. For previously healthy humans, a LOAEL of about 30 mg piperazine base/kg/day can be established for a limited 3-7 day’s treatment period. Since there is little information on effects at lower doses than the therapeutic dose, the 30 mg/kg/day dose should rather be regarded as a ‘low OAEL’ than a true LOAEL. Based on existing data, a NOAEL cannot be established for neurotoxicity induced by piperazine, either in a sensitive animal species or in humans upon long-term exposure. The LOAEL of 30 mg/kg/day for a limited 3-7 days exposure of humans has been used in the risk characterisation. The human neurotoxicity data has been given preference over the dog-based NOAEL cited above. The reasons are the higher relevance of studies in humans (e.g., as regards human sensitivity to the toxic effect) as compared to animal data, and the lower need for assessment factors when basing the risk characterisation on studies in humans as compared to studies in animals. As such, neurotoxicity could also be considered of higher concern than mild hepatic effects. In humans, repeated exposure to piperazine by inhalation may induce chronic bronchitis, but no LOAEL or NOAEL can be established for this endpoint [European Chemicals Bureau, 2005].

 

MELAMINE

Studies with rats, oral administration of melamine with the feed and dosing periods of 14 days to 3 months are available. Additional studies with mice and also other old studies with intraperitoneal administration, and rabbits and dogs were also reported. Summarised findings of the different available studies are: depression of body weight gain and elevated water intake were observed at higher doses of bladder were noted in the studies depending on the dose and the species used. The rat and especially the male rat is more susceptible than the mouse. Ca. 63* and 240 mg/kg/day are regarded as the lowest NOELs from a 13 weeks study and a 28 days study. Long-term studies give a higher NOEL of 126 mg/kg bw in male rats than the 13 weeks study so that no further safety factor has to be applied, when taking NOEL = ca. 63 mg/kg/day also for long-term exposure [NTP, 1983, Melnick et al, 1984 and OECD SIDS, 1998]. The kidney was the main target of melamine toxicity. Melamine precipitated in the nephral tubuli, renal pelvis and urinary bladder of mice and rats. As a consequence, hyperplasia and dysplasia of the bladder epithelium was formed. The pressure effects caused by constriction by precipitates in tubuli also lead to nephral dilatation and fibrotic scars extending from papilla to cortex. Male rats were more susceptible to melamine than female rats and mice [EFSA, 2010].

*The NOAEL/NOEL was not reported into the Melnick et al, neither in the NTP publication; nevertheless, the dose of 750 ppm (63 mg/kg/day) has been judged and reported as NOEL in the OECD SIDS, while it has been judjed and reported as NOAEL in the WHO, 1987 and in the EFSA, 2010.

 

PHOSPHATES

Repeated dose toxicity studies by the oral route demonstrated that Sodium Tripolyphosphate (STPP) induce retarded growth, anaemia and renal calcification at 2 % and higher. In a 2-year study, no toxic effect was observed at the doses of 15 mg/kg/day and 225 mg/kg/d (0.5 % assuming a 0.4 kg rat eats 18 g food/d). Thus, the NOEL was estimated at 225 mg/kg/d, based on the dose at which no histopathological effects were observed on kidneys. Similar effects were observed with all types of inorganic condensed phosphates. These results are consistent with the use of STPP and other phosphate derivatives as food additives, and GRAS (Generally Recognised As Safe) status in the United States (FDA, 2001). STPP is also an authorised food additive in Europe, E451(i) (EC, 1995). However, the use of STPP as a food additive is considered minor as compared with its use in household detergents [HERA, 2003].

 

CONCLUSION

According to the previous assessment, the NOAEL of piperazine was set at 25 mg/Kg for piperazine, due to mild effect on hepatic function and the NOEL of melamine to 63 mg/Kg due to precipitation in the urinary tract.

According to the analytical characterisation, it can be considered that DG HF 2000 may contain up to 10% of free melamine and maximum 20% of piperazine. Based on this composition, piperazine is the limiting factor for the risk assessment, with corresponding NOAEL of 125 mg/Kg for DG HF 2000.

Reference

EC (1995) European Parliament and Council Directive No. 95/2/EC of 20 February 1995 on food additives other than colours and sweeteners, Annex IV, Other permitted additives, OJ No L 61, 18. 3. 1995, p. 1.

EMEA, 2001. Committee for Veterinary Medicinal Products. EMEA/MRL/771/00-FINAL. Piperazine Summary Report. The European Agency for the Evaluation of Medicinal Products.

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.

FDA (2001) Substances Generally Recognized As Safe - Multiple Purpose GRAS Food Substances, Sodium tripolyphosphate, Ref. 182.1810, Code of Federal Regulations Title 21, Volume 3, Subpart B, part 182. (http://www.cfsan.fda.gov/~dms/eafus.html).

Human & Environmental Risk Assessment (HERA) on ingredients of European household cleaning products. Sodium Tripolyphosphate (STPP) CAS: 7758-29-4. Draft, June 2003.

Melnick R.L. et al., Urolithiasis and bladder carcinogenicity of melamine in rodents, Toxicol.Appl.Pharmacol. 72, 292-303, 1984.

National Toxicology Program (NTP), 1983. Carcinogenesis bioassay of melamine (CAS No. 108-78-1) in F344/N rats and B6C3F1 mice (feed study). NTP-81-86 NIH Publication No. 83-2501 NTP TR 245 - U.S. Department of health and human service

OECD SIDS, 1998. Melamine CAS N°: 108-78-1. UNEP Publications.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Assessment is performed through the evaluation of the toxicity of the single constituent of DG HF 2000.

Justification for classification or non-classification

According to the CLP regulation (EC 1272/2008), 3.9 Specific target organ toxicity - repeated exposure section, substances are classified as specific target organ toxicants following repeated exposure by the use of expert judgement, on the basis of the weight of all evidence available, including the use of recommended guidance values which take into account the duration of exposure and the dose/concentration which produced the effect(s), and are placed in one of two categories, depending upon the nature and severity of the effect(s) observed.

Classification in Category 2 is applicable, when significant toxic effects observed in a 90-day repeated-dose study conducted in experimental animals are seen to occur within the guidance value ranges as: oral (rat): 10 < C ≤ 100 mg/kg bw/day.