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Diss Factsheets

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

Reference Type:

Materials and methods

Study type:
study with volunteers
Endpoint addressed:
repeated dose toxicity: oral
Principles of method if other than guideline:
Controlled metabolic ward study was performed to evaluate the effect of dietary zinc (and its relation to copper intake) on various indicators of zinc status in humans.
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
Details on test material:
zinc gluconate in beverages served at breakfast, lunch, and dinner (6 mg Zn/day).


Type of population:
Healthy postmenopausal women were admitted to the study after medical, psychological, and nutritional evaluations had established that they had no underlying disease and were emotionally suited for the project. The 25 subjects who completed the study were between the ages of 50 and 76 y (x – ± SD: 64.9 ± 6.7 y) at entry. Subjects had a mean (±SD) height of 159.6 ± 7.6 cm and a mean weight of 65.1 ± 9.5 kg at the beginning of the study. All of the subjects were white.
Ethical approval:
confirmed and informed consent free of coercion received
Route of exposure:
Reason of exposure:
Exposure assessment:
Details on exposure:
Subjects were fed a constant weighed basal diet of conventional foods that was low in copper (0.6 mg, 0.61 ± 0.07 mg by analysis) and zinc (3 mg, 2.96 ± 0.24 mg by analysis), based on an energy content of 8.4 MJ, with a 3-d menu rotation. The diet was supplemented with 492 mg Ca (as calcium carbonate), 23 mg Fe (as ferrous sulfate), 180 mg Mg (as magnesium gluconate), and 10 mg cholecalciferol. Iron was supplemented to compensate for losses through phlebotomy. The diet was adequate in all other known nutrients. The subjects participated in an equilibration period of 10 d in which they received the basal diet supplemented with 1.4 mg Cu (2 mg total) and 6 mg Zn (9 mg total). The women were then randomly divided into 2 groups: 1 group (n = 12) was fed the basal diet supplemented with 0.4 mg Cu and the other group (n = 13) was fed the basal diet supplemented with an additional 2.4 mg Cu/d. The remaining 190 d was divided into two 90-d dietary periods for both groups: the basal diet with no zinc supplement was fed for one 90-d period and the basal diet supplemented with 50 mg Zn/d was fed for the other 90-d period. All of the women were fed the low-zinc diet first. The two 90-d periods were separated by a second equilibration period of 10 d, during which the basal diet supplemented with 1.4 mg Cu/d and 6 mg Zn/d was fed.
- Zinc concentrations of plasma and blood cellular components
- Plasma, erythrocyte and bone-specific alkaline phosphatase activity
- 5'-Nucleotidase activity in plasma, mononuclear cells, and erythrocytes
- Free and total triiodothyronine, free and total thyroxine, and thyroid-stimulating hormone (TSH) level as a measure of thyroid status
- Superoxide dismutase activity in erythrocytes and serum
- Amyloid precursor protein (APP) expression in platelets
- Ethanol tolerance test to determine effect of zinc intake on ethanol metabolism

All the analysis were performed during the last month of each dietary period.
Medical treatment:

Results and discussion

Results of examinations:
- Zinc concentrations: Plasma zinc concentrations were within the normal range for healthy adults (10.7–18.4 mmol/L) throughout the low-zinc
period. In contrast, levels were significantly elevated beginning 1 month after zinc supplementation and remained elevated throughout the zinc supplementation period. 8 of 23 volunteers had plasma zinc concentrations > 18.4 mmol/L at the end of the zinc-supplementation period. Neither erythrocyte nor erythrocyte membrane zinc concentrations responded significantly to changes in dietary zinc.

- Alkaline phosphatase activity: Zinc supplementation significantly increased bone-specific alkaline phosphatase activity (0.40 ± 0.02 compared with 0.32 ± 0.02 µkat/L) and seemed to increase plasma alkaline phosphatase activity (1.66 ± 0.02 compared with 1.57 ± 0.02 µkat/L); however, this difference was not significant. Erythrocyte membrane alkaline phosphatase activity did not change significantly with the different dietary treatments.

- 5'-Nucleotidase activity: Zinc supplementation significantly increased mononuclear white cell 5'-nucleotidase activity (17.90 ± 1.54 compared with 12.16 ± 1.54 U/L) (apparent only for high-copper diet group) and significantly decreased plasma 5'-nucleotidase activity (4.64 ± 0.19 compared with 6.36 ± 0.19 U/L). No change in red blood cell membrane activity.

- Thyroid status: Plasma free thyroxine concentrations were significantly higher and plasma free triiodothyronine concentrations tended to be higher, but not significantly so, during the high-zinc period than during the low-zinc period. However, dietary zinc did not significantly affect total thyroxine or triiodothyronine concentrations.

(See Figure 2 in attached document)

- Superoxide dismutase activity: Extracellular, but not erythrocyte, superoxide dismutase activity was significantly increased by zinc supplementation. This effect was more apparent when subjects were fed the low-copper diet. In contrast, zinc supplementation depressed erythrocyte superoxide dismutase activity (see Fig 1 in attached results tables).

- APP expression: Zinc supplementation significantly depressed platelet APP expression only when subjects were fed the low-copper diet (see Fig 2 in attached full study report).

- Ethanol tolerance test: Ethanol metabolism was not significantly affected by zinc intake. There were no significant differences in the rate of clearance of ethanol or in alcohol dehydrogenase activity among the different dietary treatments.
Effectivity of medical treatment:
Not applicable
Outcome of incidence:
Not applicable

Any other information on results incl. tables

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

In conclusion, changes in dietary zinc and copper affect zinc-status indicators of postmenopausal women, notably, extracellular superoxide dismutase and amyloid precursor proteins.
Executive summary:
Controlled metabolic ward study was performed to evaluate the effect of dietary zinc (and its relation to copper intake) on various indicators of zinc status in humans.


Indicators of zinc status were measured in 25 healthy postmenopausal women aged 64.9 ± 6.7 y. After a 10 d equilibration period, volunteers consumed a diet with either a low (1 mg/d; n = 12) or a high (3 mg/d; n = 13) copper content based on a total energy content of 8.4 MJ. They received the same amount of copper throughout the study. Both groups were fed the basal diet (3 mg Zn/d) with no zinc supplement for one 90-d period, and the diet supplemented with 50 mg Zn/d for another 90 d period.

Zinc supplementation significantly increased extracellular but not erythrocyte superoxide dismutase activity. This increase was more apparent when subjects were fed the low copper diet. Zinc supplementation in combination with the low copper diet significantly decreased amyloid precursor protein expression in platelets. Other indicators of zinc status that were significantly elevated after zinc supplementation were as follows: plasma zinc, and free thyroxine concentrations and mononuclear 5'-nucleotidase (only apparent with high copper-diet), andbone-specific alkaline phosphataseactivities.


In conclusion, changes in dietary zinc and copper affect zinc-status indicators of postmenopausal women, notably, extracellular superoxide dismutase and amyloid precursor proteins.