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Toxicological information

Direct observations: clinical cases, poisoning incidents and other

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Administrative data

direct observations: clinical cases, poisoning incidents and other
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Used in EU risk assessment for zinc metal and zinc compounds. Study well documented, meets generally accepted scientific principles

Data source

Referenceopen allclose all

Reference Type:
Reference Type:
secondary source
Zinc chloride
Bibliographic source:
Risk assessment report, 2nd priority list, Volume 45

Materials and methods

Study type:
study with volunteers
Endpoint addressed:
repeated dose toxicity: oral
GLP compliance:

Test material

Constituent 1
Reference substance name:
EC Number:
EC Name:
Cas Number:
zinc bis(2,3,4,5,6-pentahydroxyhexanoate) (non-preferred name)
Constituent 2
Reference substance name:
Zinc gluconate
Zinc gluconate


Type of population:
Ethical approval:
confirmed and informed consent free of coercion received
Route of exposure:
Reason of exposure:
Exposure assessment:
Medical treatment:

Results and discussion

Any other information on results incl. tables

The authors state that measured indicators of iron status (serum iron, haemoglobin, haematocrit and percent transferrin saturation) were unaffected by dietary treatment (no data presented), with the exception of haemoglobin, which was lower on high zinc than on low zinc in both the low and high copper groups. The drop in haemoglobin occurred especially during the last month of zinc supplementation, possibly due to the frequent blood sampling.

Remarks on the study, reported by Davis et al. (2000) (in EU RAR of zinc metal, zinc chloride and zinc sulphate):

From personal communication with the authors it appears that for ESOD activity the initial equilibration values varied markedly between individuals, and that for women who were assigned to the low copper group ESOD activity was substantially higher than for those assigned to the high copper group. This implicates that for this indicator, the assignment of the subjects to the two groups was suboptimal, which might also be the case for other indicators.

The frequent blood sampling (an average of no more than 235 mL per month was drawn) might have compromised the physiology of the subjects (as was suggested for haemoglobin).

The subjects served as their own controls: values upon both treatments (i.e. low and high zinc administration) were compared with values upon first equilibration. However, as the second treatment is not independent of the first treatment, the study design is not optimal.

Applicant's summary and conclusion

Executive summary:

In the same dietary experiment as described by Davis et al., 2000, also other parameters (i.e. copper-status and iron-status indicators) were investigated to study the effect of moderately excessive and deficient intakes of zinc on copper metabolism and utilization in humans fed low and luxuriant amounts of copper. For that purpose, urine and faeces were collected during the last 78 days of each 90-day dietary period and copper and zinc were determined (in faeces in 6-day composite samples). Once weekly blood was sampled (after overnight fasting for 12 hours), and blood samples were analysed for various copper-status and iron-status indicators. Women fed low copper were in negative copper balance. Zinc intake (low or high) did not alter this. Women fed high copper were put into negative copper balance by low zinc. Upon transition to high zinc, women fed high copper came into positive copper balance, which apparently was the result of a lower amount of dietary copper lost in the faeces; urinary copper was not affected. The zinc balance reflected dietary zinc intake (more positive with increased zinc intake) and was not significantly affected by copper intake. Copper-status indicators were variably affected by dietary treatment. The concentrations of serum ceruloplasmin (enzymatically determined), HDL and VLDL cholesterol, triglycerides and red blood cell zinc did not change statistically significantly with the different dietary treatments. Independent of zinc intake, plasma copper concentrations were significantly lower on low dietary copper than on high dietary copper (P < 0.07). Although plasma copper concentrations were depressed from equilibration values at all dietary treatments, the depression was less for high than for low dietary copper (P < 0.03).

Independent of copper intake, zinc supplementation caused increases in the concentrations of serum ceruloplasmin (immunochemically determined; 4-8%, P < 0.05) and plasma zinc (19-32%, P < 0.0001) and in platelet cytochrome c oxidase activity (on a platelet number basis; 19-27%, P < 0.0007), and decreases in the concentrations of red blood cell copper (8-16%, P < 0.0008) and whole blood glutathione (8-12%, P < 0.009) and in the activities of specific ceruloplasmin (defined as the ratio between enzymatic and immunoreactive ceruloplasmin; 8-11%, P < 0.0003) and erythrocyte glutathione peroxidase (11-15%, P < 0.002). The levels of these indicators were elevated from equilibration values at all dietary treatments, with the exception of serum immunoreactive ceruloplasmin concentration (reduced at all dietary treatments), platelet cytochrome c oxidase activity (reduced at high copper/low zinc), specific ceruloplasmin activity and whole blood glutathione concentration (essentially at equilibration values at low copper/high zinc and high copper/high zinc), and red blood cell copper concentration (essentially at equilibration value at low copper/low zinc and reduced at low copper/high zinc).

Zinc supplementation significantly decreased ESOD activity (5-7%, P < 0.03) as well as the concentrations of total cholesterol (3-4%, P < 0.005) and LDL cholesterol (2-6%, P < 0.003), but not by much. The effect on ESOD was dependent on copper intake (P < 0.0001): compared to equilibration values, ESOD activity decreased on low copper but increased on high copper. Total cholesterol and LDL cholesterol concentrations were significantly higher on low dietary copper than on high dietary copper (P < 0.02 and P < 0.03, respectively). This suggests a dependency on copper intake, but it should be noted that women fed low copper had higher equilibration values for both indicators than women fed high copper.

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