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Key value for chemical safety assessment

Effects on fertility

Additional information

The effect of trizinc dicitrate is not expected to differ significantly from the effects of exposure to the zinc ions and citric acid separately once absorbed.Therefore the assessment of this substance will be based on both citric acid and zinc respectively.

Citric acid 

In a non standard repeat dose study by Wright, Hughes (1976), where 5% citric acid was administered in the feed to rats and mice, did not give rise to any reproductive effects. In addition a study by  Bonting (1956) where 1.2% w/w citric acid in feed given daily to male and female rats over a period of 90 weeks did not give rise to any reproductive effects.  Although these studies are not reliable, they help provide supporting evidence that citric acid is not expected to cause reproductive effects.

 

Zinc 

A two-generation reproductive toxicity study of zinc chloride was conducted in rats. F(o) male and female rats were administered 0.00 (control), 7.50 (low), 15.00 (mid) and 30.00 (high) mg/kg/day of ZnCl2. Effects on fertility such as reduced litter size in F1 and F2 generation have been determined only at doses which resulted in toxic effects in the dam (Khan et al. 2007).

A thirteen week reliable screening repeat dose/reproduction feeding study in rats with zinc sulphate reported aNOAEL of 234 mg ZnSO4.7H2O/kg bw (this approximates to 53.5 mg Zn2+/kg bw or 155 mg trizinc dicitrate/kg (bw)*.(Maita et al, 1981,cited in the Zinc metal RAR, 2008).

 

In addition a thirteen week reliable screening repeat dose/reproduction feeding study in mice with zinc sulphate reported aNOAEL of 469 mg ZnSO4.7H2O/kg bw (this approximates to 104 mg Zn2+/kg bw or 302 mg trizinc dicitrate/kg (bw)* (Maita et al., 1981, cited in the Zinc metal RAR, 2008).

 

In addition a review of all available zinc RARs have not provided any additional data related to these endpoints.

 

* Conversion factor = (MW trizinc dicitrate / (MW Zinc x 3) = 547 / (65x3) = 2.9)

This section contains substantially new data.
Short description of key information:
The data from zinc and citric acid will be used to derived data for trizinc dicitrate.
Zinc: (6-18 d, rabbits) The NOAEL is 60 mg/kg bw of unspecified zinc sulphate (≈24 mg or 13.6 mg Zn2+ /kg bw, for the anhydrate which corresponds to 69.6 mg mg Zn2+ /kg bw trizinc dicitrate/kg (bw); or 13.6 mg Zn2+ /kg bw heptahydrate which corresponds to 39.4 mg trizinc dicitrate/kg (bw)repectively*)
(Food and Drugs Research Labs Inc, 1974, cited in Zinc metal RAR, 2008).

Citric acid: Limited studies indicate a lack of effects on the reproductive ability when doses up to 5% citric acid were administered in the diet of rats and mice (Bonting 1956, Wright & Hughes 1976; rel. 4).

Effects on developmental toxicity

Description of key information
 The data from zinc and citric acid will be used to derive data for trizinc dicitrate. ZINC: Teratogenic effects of citric acid in were studied mice, rats, rabbits and hamsters. No teratogenic effects reported (Food and Drugs Research Labs Inc, 1973 and 1974). CITRIC ACID: Teratogenic effects of citric acid in were studied mice, rats, rabbits and hamsters. No teratogenic effects reported (Food and Drugs Research Labs Inc, 1973). 
Additional information

The effect of trizinc dicitrate is not expected to differ significantly from the effects of exposure to the zinc ions and citric acid separately once absorbed. Therefore the assessment of this substance will be based on both citric acid and zinc respectively.

Citric acid

A study by the Food & Drug Research Laboratories (1973) researched the teratogenic effects of citric acid in mice (NOAEL > 241 mg/kg/d), rats (NOAEL > 295 mg/kg/d), rabbits (NOAEL > 425 mg/kg/d), and hamsters (NOAEL > 272 mg/kg/d). There were no reported teratogenic effects in any of the species tested.

Zinc

A study by the Food & Drug Research Laboratories (1973 & 1974 for rabbits) researched the teratogenic effects of zinc sulfate in mice (NOAEL > 30 mg/kg/d), rats (NOAEL > 42,5 mg/kg/d), rabbits (NOAEL > 60 mg/kg/d), and hamsters (NOAEL > 88 mg/kg/d ≈ 35.2 mg Zn2+/kg bw anhydrate which corresponds to 102mg Zn2+/kg bw trizinc dicitrate/kg (bw), or 19.9 mg Zn2+/kg bw heptahydrate which corresponds to 57.7 mg trizinc dicitrate/kg (bw)*). There were no reported teratogenic effects in any of the species tested. * Conversion factor = (MW trizinc dicitrate / (MW Zinc x 3) = 547 / (65x3) = 2.9)

Justification for classification or non-classification