Dizinc pyrophosphate

Endpoint summary

Description of key information

No data regarding effects on repeated dose toxicity are available for dizinc pyrophosphate. Reliable data are available from zinc sulfate heptahydrate (CAS 7446 -20 -0). The zinc ion is considered to be the toxicologically relevant element and thus a read across to zinc sulfate heptahydrate is reliable.

Oral, rat: NOAEL (zinc sulfate heptahydrate) = 234 and 243 mg/kg bw/day for males and females, respectively. This corresponds to 53.5 mg Zn2 +/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Remarks:

Summary of available data used for the endpoint assessment of the target substance

Adequacy of study:

key study

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

rat

Effect level:

234 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: no adverse effects observed in the examined parameters

Key result

Critical effects observed:

no

Conclusions:

Under the test conditions, the NOAEL of the source substance zinc sulfate heptahydrate in rats and mice was determined to be approximately 234 mg/kg/day in male rats and 243 mg/kg/day in female rats and 458 mg/kg bw/day in male mice and 478 mg/kg bw/day in female mice. Zinc is considered to be the toxic element therefore the NOAEL is found to be 53.5 mg Zn2+/kg bw/day based on these studies.

Executive summary:

As explained in the analogue justification, zinc is considered to be the toxic element. Therefore, it is considered that the target and the source substances are unlikely to lead to differences in repeated dose toxicity potential.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

234 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2) and consistent studies from source substances. Read-across is based on the basic assumption that the ionic species of the target substance are the determining factors for biological activity. The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

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

Repeated dose toxicity

Justification for read-across

There are no data available on repeated dose toxicity of dizinc pyrophoshpate. In accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5 read-across from appropriate substances is conducted to fulfill the standard information requirements set out in Regulation (EC) No 1907/2006, Annex VII, 8.5.

According to Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across) “to avoid the need to test every substance for every endpoint”.

Reliable data are available from zinc sulfate heptahydrate (CAS 7446 -20 -0). The zinc ion is considered to be the toxicologically relevant element and thus a read across to zinc sulfate heptahydrate is reliable.

A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Repeated dose toxicity after oral administration

Rat:

The subchronic toxicity of zinc sulfate heptahydrate was determined by Maita et al. in ICR mice and Wistar rats. For both rodent species, a test design similar to the OECD guideline 408 was applied (Maita et al., 1981). Specifically, 12 animals per sex and dose group were exposed continuously to doses of 300, 3000 or 30000 ppm zinc sulfate heptahydrate (ZnSO4.7 H2O, CAS 7446-20-0) over 13 weeks. To evaluate the adversity of observed effects, a control group was included and historical data were considered. Parameters monitored included clinical signs of toxicity, mortality, body weight, food and water consumption, food efficiency and absolute and relative organ weights. Further, haematology, clinical chemistry and pathology were performed.

Based on food intake, rats were exposed to 23.2/24.5, 234/243, and 2514/2486 mg/kg bw/day for males/females, respectively, corresponding 300, 3000 or 30000 ppm ZnSO4.7 H2O/kg food (Maita et al., 1981). No treatment-related effects on clinical signs or mortality have been observed. Despite the females in the control and high-dose group (one animal each per group) that were killed in extremis due to suppurative pyelitis (not considered as substance-related), no further moribund animals of either sex were found. In the high-dose group, a depressed body weight was observed in males (453 g vs 371 g) which correlated to retarded growth. Haematological analyses revealed a moderate reduction in leucocyte counts in both sexes of the high-dose groups (males: from 7.3.103/mm³ vs 4.7.103/mm³; females: from 4.5.103/mm³ vs 3.3.103/mm³). Compared to controls, males also showed slightly decreased haematocrit (42 to 40%) and haemoglobin concentration (14.9 g/dL vs 13.9 g/dL). Moreover, high-dose males revealed slightly decreased values for total protein (6.8 to 6.3 g/dL), calcium (10.4 mg/dL vs 10.0 mg/dL) and cholesterol values (60 to 49 mg/dL). For GPT, slight but significant decreased amounts were detected in all dose groups ranging from 45 K-units in the control to 34 K-units in high-dose animals. Calcium levels were altered in the mid- and high-dose group compared to the controls (10.1 mg/dL vs, 9.9 mg/dL and 9.7 mg/dL).

Relative organ weights were slightly but significantly altered in the brain (0.43% vs 0.5%), the liver (3.55% vs 3.2%) and the spleen (0.14 vs 0.13%) in high- dose males.

No treatment-related remarkable lesions were reported for all dose-groups after gross pathology. Histopathology showed pancreatic damage including degeneration, necrosis of acinar cells, clarification of centroacinar cells and interstitial fibrosis in high-dose animals. Similar to the observations in mice, no effects on the reproductive organs (i.e. ovaries, testes, accessory sex organs) were reported. In conclusion, a NOAEL of 234 and 243 mg ZnSO4.7 H2O/kg bw/day for male and female rats, respectively was determined which corresponds to approximately 53.5 mg Zn2+/kg bw/day (Maita et al.,1981).

Mouse:

ICR mice were exposed to corresponding concentrations of 42.7/46.4, 458/479 and 4,927/4,878 mg/kg bw for males/females. No treatment-related effects on clinical signs have been observed in the control and lower dose-groups. In contrast, 4 males and 1 female of the high-dose group showed depressed spontaneous motility and were found dead or killed in extremis resulting in mortality rates of 33.3% and 8.3% in males and females, respectively. Histological findings of these animals revealed impairment of the urinary tract and regressive changes in the exocrine gland of the pancreas. Further, a dose-dependent decrease in body weight was observed for both genders reaching statistically significance for the high-dose groups (males: 47.2, 47.7, 45.3 and 38.6***g; females: 45.2, 46.5, 44.6 and 32.7*** g for control, low-, mid- and high-dose groups) which was correlated to a retarded growth. No treatment-related alterations were observed in food and water consumption over the whole study period for all test groups. Only the high-dose group animals showed moderately lower values in haematocrit (males: from 42% in controls to 29% in high-dose animals; females: from 44% in controls to 31% in high-dose animals) and haemoglobin concentrations (males and females: 14 to 10 g/dl). Further, the leukocyte count decreased moderately in males from 4.8 x 103/mm³ in controls to 3.6 x 103/mm³ in high-dose animals whereas a slight increase was determined in females of the mid-dose group (3.5 x 103/mm3 vs 3.1 x 103/mm3). Mice of both sexes in the high-dose group showed moderate decreases in total protein, glucose and cholesterol whereas alkaline phosphatase and urea nitrogen were increased. Further, high-dose females showed reduced ALAT and increased calcium levels whereas ASAT was increased in high-dose males. In the high-dose group, significant alterations were determined in the relative weight of the following organs in both genders: brain, thyroid, heart and spleen. Moreover, high-dose females showed significant alterations in the weight of the kidney and spleen. For adrenals, relative weight changes were detected also in the mid-dose groups for both genders. Gross pathology showed marked emaciation, ischemic discoloration of the kidney and thyroid, atrophy of the pancreas, edematous thickening of the upper small intestine and slight splenomegaly in high-dose animals. Moreover, several cases of forestomach ulcer were observed. Histopathological findings include treatment-related lesions in the pancreas, the upper intestine, stomach, spleen and kidney of high-dose group animals. No treatment-related effects were found on the reproductive organs (e.g. ovaries, testes, accessory sex organs). Based on the above mentioned findings, the NOAEL in this study is 458 and 479 mg ZnSO4.7 H2O/kg bw/day for males and females, respectively, corresponding to approximately 104 mg Zn2+/kg/bw/day (Maita et al., 1981).

Assessment of repeated dose toxicity of zinc

Zinc compounds are recognised as zinc category in the OECD HPV program [1]. The zinc category includes six compounds (zinc metal, zinc oxide, zinc distearate, zinc chloride, zinc sulphate, and trizinc bis(orthophosphate). Available data show that zinc salts have moderate effects upon acute oral application and may be irritating to skin and eyes. The repeated dose toxicity of zinc was evaluated in the SIDS for zinc [1]. In repeated dose toxicity studies with rats and mice, oral zinc exposure resulted in copper deficiency and pathological changes in the pancreas and the spleen as the most sensitive effects, with a NOAEL of 13.3 mg Zn2+/kg bw/day. In studies with human volunteers, women appeared to be more sensitive than men to the effects of repeated zinc supplementation. In women, supplementation at a level of 150 mg Zn2+/day (2.5 mg/kg bw/day, based on a body weight of 60 kg; LOAEL) resulted in clinical signs such as headache, nausea and gastric discomfort, and in indications for disturbance of copper homeostasis. The NOAEL in women supplemented with zinc was 50 mg Zn2+/day (0.83 mg/kg bw/day). The background intake of zinc via food is approximately 10 mg/day. [1] In summary, the following effect levels are observed for zinc as described in the SIDS [1]:

NOAEL (rat) = 13.3 mg Zn2+/kg bw/day

LOAEL (human) = 2.5 mg Zn2+/kg bw/day

NOAEL (human) = 0.83 mg Zn2+/kg bw/day.

These effect levels are lower than found for the zinc sulfate heptahydrate (NOAEL = 53.5 mg Zn2 +/kg bw/day). Therefore, it has to be assumed that dizinc pyrophosphate has a NOAEL for repeated dose between 0.83 and 53.5 mg Zn2+/kg bw/day. Nevertheless, zinc salts are not classified regarding repeated dose toxicity and the estimated effect levels would not lead to a classification regarding repeated dose toxicity. However, the uncertainty will be considered when deriving a DNEL for dizinc pyrophosphate.

To cover these uncertainties the human NOAEL for Zn2+ was used to derive a DNEL which also covers these possible effects of zinc. Recalculating the effect levels to dizinc pyrophosphate in respect to the molecular weight (MW dizinc pyrophosphate = 304.76 g/mol and atomic weight Zn = 65.39 g/mol) leads to the following effect levels for dizinc pyrophosphate:

NOAEL (human) = 1.93 mg/kg bw/day.

Conclusion

In conclusion, repeated dose toxicity of dizinc pyrophosphate is sufficiently covered by available data of structural analogues. A NOAEL of 53.5 mg Zn2+/kg bw was derived after subchronic exposure for zinc sulfate heptahydrate in rats. For the human population, a LOAEL of 150 mg Zn2+/kg bw/day was derived for zinc sulphate. Considering that Zn2+ represents an essential trace element necessary for several biological processes within the human body and a maximum allowable daily intake of 50 mg zinc per day, no classification is required for the zinc component as the derived LOAEL is well above the recommended daily intake level. Thus, based on the available animal and human data on read-across surrogate substance, low toxicity of dizinc pyrophosphate is considered after repeated dose exposures. 

References not included in IUCLID:

[1] SIDS initial assessment profile, (2005);http://webnet.oecd.org/Hpv/UI/handler.axd?id=fddec5fa-9727-413a-9d67-41c2154cd362

Justification for classification or non-classification

Based on read-across, the available data on repeated dose toxicity indicate that dizinc pyrophosphate does not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC.