Dizinc pyrophosphate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No data regarding effects on reproducitve toxicity are available for dizinc pyrophosphate. Reliable data are available from zinc chloride (CAS 7646 -85 -7). The zinc ion is considered to be the toxicologically relevant element and thus a read across to zinc chloride is reliable.

Oral, rat:

LOAEL systemic toxicity (zinc chloride) = 7.5 mg/kg bw/day

NOAEL reproductive toxicity (zinc chloride) = 15 mg/kg bw/day

Link to relevant study records

Reference

Endpoint:

two-generation reproductive toxicity

Type of information:

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

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

Limit test:

no

Key result

Dose descriptor:

LOAEL

Remarks:

systemic

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Key result

Dose descriptor:

NOAEL

Remarks:

reproductive

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Critical effects observed:

not specified

Key result

Dose descriptor:

LOAEL

Remarks:

systemic

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Key result

Dose descriptor:

NOAEL

Remarks:

reproductive

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Critical effects observed:

not specified

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

body weight and weight gain

Key result

Critical effects observed:

no

Key result

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

body weight and weight gain

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

yes

Lowest effective dose / conc.:

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

Treatment related:

yes

Relation to other toxic effects:

reproductive effects as a secondary non-specific consequence of other toxic effects

Dose response relationship:

yes

Relevant for humans:

no

Conclusions:

Under the test conditions, adminsitration of the source substance zinc chloride to adult male and female rats throughout maturation, mating, gestation and early lactation resulted in significant systemic toxicity effects as reduced body weight on adults in all dose levels. Reproductive toxicity effects and effects on pups were only seen at the highest dose group (30 mg/kg bw/day). Therefore, a systemic NOAEL could not be determined and a systemic LOAEL of 7.5 mg/kg bw/day was set. For reproducitive toxicity a NOAEL of 15 mg/kg bw/day is concluded.

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 reproductive toxicity potential.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

15 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2) and consistent studies from reference 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, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive toxicity

Justification for read-across

There are no data available on reproductive 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 chloride (CAS 7646 -85 -7). The zinc ion is considered to be the toxicologically relevant element and thus a read across to zinc sulfate is reliable.

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

Zinc is necessary for normal growth and development (e.g. gene expression, metabolism of vitamins including folate, retinol) and therefore it is not surprisingly that a zinc deficiency can cause foetal damage as reported in animals (Walsh et al., 1994; ATSDR, 1994). Both human and animal data show that zinc deficiency will also lead to delayed sexual maturation and to impairment of reproductive capacity (WHO, 1996).

A two-generation study similar to OECD 416 in rats with zinc chloride is availabe in order to evaluate the reproductive toxicity potential (Khan, 2007). Male and female rats were administered zinc chloride via gavage at the doses of 7.5, 15.0 and 30.0 mg/kg bw/day over two successive generations. Control group animals received deionised water. There were no significant changes observed in the clinical pathology parameters after zinc chloride exposure to two generations of rats. The results in this study suggest very mild effec of zinc exposure on the erythrocytes (decreased packed cell volume (PCV)) in both P0 and P1 male and female rats. The PCV change was not of sufficient magnitude in either sex to have adversely affected reproductive performance. In this study, there seemed to be a trend toward elevated values of amylase, alkaline phosphatase and glucose in mid/ and high-dose males of both generations. Amylase and glucose are both associated with the pancreas. Although not statistically significant, these parameters appeared to be elevated in the zinc chloride treated groups and were propably manifestations of very mild pancreatic effect. Alkaline phosphatase is a zinc-dependent enzyme and slight (not significant) elevation in the zinc chloride treated groups would be exptected. This elevation probably had no adverse effect. The total body weight gain in zinc chloride treated males of both generations showed a significant reduction compared to their controls. However, the total body weight gain of zinc chloride treated females of both generations did not show any significant difference compared to their controls. This lack of significant zinc chloride treatment effect on total body weight gain of females suggested that toxicity from the test substance was not at a high level. The post-partum dam weight of P0 and P1 rats in all dose groups were significantly different from their control groups. The absolute and relative kidney, liver, spleen, seminal vesicles weights of P0 males and kidney, liver, spleen, adrenal, testis, prostrate, and seminal vesicle weights of P1 males were significantly reduced after 15 and 30 mg/kg bw/day of zinc chloride exposure during pre-mating and mating periods. The absolute and relative spleen and uterus of P0 females were signficantly reduced after 15 and 30 mg/kg bw/day of zinc chloride exposure during pre-mating and mating, gestation and lactation periods. Histopathological evaluation of the tissues in rats in both generations revealed prostatic acinar atrophy and inflammation in the reproductive system and the hematopoietic-lymphoreticluar system (splenic lymphoid depletion and hemosiderosis and thymic atrophy) of 30 mg/kg bw/day zinc chloride treated groups. So effects in organ weights at the mid-dose level could not be attributed to histopathological or clinical pathology and thus are considered to be not adverse. Zinc chloride exposure caused significant reduction in fertility of both generations, F1 pups viability (days 0 and 4) and litter size (F2) in high-dose group rats. Body weight gain of F1 and F2 pups on day 21 in the high-dose group was significantly reduced when compared to the control groups.

Under the test conditions, adminsitration of zinc chloride to adult male and female rats throughout maturation, mating, gestation and early lactation resulted in significant systemic toxicity effects as reduced body weight on adults in all dose levels. Reproductive toxicity effects and effects on pups were only seen at the highest dose group (30 mg/kg bw/day). Therefore, a systemic NOAEL could not be determined and a systemic LOAEL of 7.5 mg/kg bw/day was set. For reproductive toxicity a NOAEL of 15 mg/kg bw/day is concluded. 15 mg zinc chloride/kg bw/day corresponds to 7.2 mg zinc/kg bw/day.

In the SIDS for zincs category which includes six zinc substances including zinc metal, zinc oxide, zinc distearate, zinc chloride, zinc sulphate and trizinc bis(orthophosphate) the following conclusion on reproductive toxicity is given: Available data in experimental animals on zinc excess indicate that adverse effects on fertility and fetal development may occur at dose levels (200 mg Zn2+/kg bw/day) at which other effects such as perturbation of parental and fetal copper homeostasis are evident. The only available data in humans indicate that additional zinc up to 0.3 mg Zn2+/kg bw/day during pregnancy did not result in adverse reproductive or developmental effects. In analogy with the findings in animals, where reproductive toxicity was observed at higher dose levels than those at which other effects were already present, it was considered unlikely that in humans reproductive effects will occur at exposure levels at which clinical signs are not manifest.

This conclusion is in line with the findings observed in the 2 -generation study with zinc chloride. Thus, as dizinc pyrophosphate would also fit in this category no reproductive toxicity potential is assumed for dizinc pyrophoshpate as well.

References:

ATSDR (1994). Toxicological profile for zinc (update). Agency for Toxic Substances and Disease Registry, Atlanta.

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

Walsh CT, Sandstead HH, Prasad AS, Newberne PM and Fraker PJ (1994). Zinc: Health effects and research priorities for the 1990s. Environ. Health Perspect 102, 5-46.

WHO (1996). Zinc. In: Trace Elements in Human Nutrition and Health. WHO, Geneva, Chapter 5.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

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