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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Subacute Toxicity Studies with Zinc Sulfate in Mice and Rats
Author:
Maita et al.,
Year:
1981
Bibliographic source:
J. Pesticide Sci. 6:327 - 336

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
10 fold intervals were used between the test concentrations instead of 2 - to 4 fold intervals, the applied statistic is not appropriate to analyse dose-response relationships
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Reference substance name:
7446-20-0
EC Number:
616-097-3
Cas Number:
7446-20-0
IUPAC Name:
7446-20-0
Test material form:
solid: crystalline
Details on test material:
- Name of test material (as cited in study report): zinc sulfate heptahydrate
- Physical state: odorless crystal
- Analytical purity: 99.9%

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Shizuoka Agriculture Cooperative Association for Laboratory Animals, Hamamatsu, Japan
- Age at study initiation: 4 weeks
- Housing: 4 animals of the same sex per cage in stainless cages with a wire-meshed bottom
- Diet: pulverized chow, M, Oriental Yeast Co., ad libitum
- Water: ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 1
- Humidity (%): 55 ± 5
- Photoperiod (hrs dark / hrs light): 10/14

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Mixing appropriate amounts with standard diet
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
continuous
Doses / concentrationsopen allclose all
Dose / conc.:
23.2 mg/kg bw/day (actual dose received)
Remarks:
males, calculated from the food intake average (corresponds to 300 ppm)
Dose / conc.:
234 mg/kg bw/day (actual dose received)
Remarks:
males, calculated from the food intake average (corresponds to 3000 ppm)
Dose / conc.:
2 514 mg/kg bw/day (actual dose received)
Remarks:
males, calculated from the food intake average (corresponds to 30000 ppm)
Dose / conc.:
24.5 mg/kg bw/day (actual dose received)
Remarks:
females, calculated from the food intake average (corresponds to 300 ppm)
Dose / conc.:
243 mg/kg bw/day (actual dose received)
Remarks:
females, calculated from the food intake average (corresponds to 3000 ppm)
Dose / conc.:
2 486 mg/kg bw/day (actual dose received)
Remarks:
females, calculated from the food intake average (corresponds to 3000 ppm)
No. of animals per sex per dose:
12
Control animals:
yes, plain diet

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/day/animal: Yes
- Time schedule for examinations: twice a week

WATER CONSUMPTION AND COMPOUND INTAKE : Yes
- Time schedule for examinations: twice a week

HAEMATOLOGY: Yes
- Anaesthetic used for blood collection: Yes (ether anaestesia)
- Parameters checked: Blood was taken from the posterior vena cava by a heparinized syringe to analyse erythrocyte count, haemoglobin, leukocyte count and haematocrit.

CLINICAL CHEMISTRY: Yes
- Parameters checked: Blood was taken from the posterior vena cava by a heparinized syringe to analyse total plasma protein, alkaline phosphatase (AIP), glucose, urea nitrogen (UN), GOT, GPT, cholesterol and calcium.

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
- The following organs were weighed: brain, pituitary, thyroid, heart, thymus, liver, kidney, spleen, adrenals, testes, ovaries and muscels (triceps surae)
HISTOPATHOLOGY: Yes
- The following additional organs were examined: submaxillary glands, lungs, mesentery lymph nodes, pancreas, stomach, small and large intestine, accessory genital organs, bone and bone marrow (sternum, femur). Paraffin sections (3 - 4 µm) were stained with haematoxylin-eosin, periodic Schiff´s reaction and azan for microscopic observations.
Statistics:
Student´s t-test was performed to estimate the statistical differences between control and treated groups.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
A female in the control and high dose group (one animal each per test group) showed suppurative pyelitis. One week after commencement of the experiment, high-dose test animals from both sexes discarded the diet from the food jar by picking it out with their fore-limbs. Since the actual food intake of these animals was not decreased enough to indicate anorexia, the symptom might have been induced by the unpalatability of the diet with its high concentration of ZnSO4 rather than by the specific toxicological effect of the chemical.
Mortality:
mortality observed, treatment-related
Description (incidence):
A female in the control and high dose group (one animal each per test group) were killed in extremis due to suppurative pyelitis. No further moribund animals of either sex were found.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In the high-dose group, a depressed body weight was observed in males (453 g, 463 g, 430 g and 371 g*** for controls, low-, mid- and high-dose animals, respectively) which correlated to retarded growth resulting in smaller body sizes. In contrast, for females, the decrease in body weight reached significant differences compared to control animals only from the 1st up to the 5th week of the study. At the end of the study, no significant effect on body weight was noted (253 g, 257 g, 255 g and 231 g for control, low-, mid- and high-dose animals) (*p < 0.05, **p < 0.01, ****p < 0.001). Thus, a treatment-related effect was only noted for males which is considered as adverse.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
30000 ppm: decreased food intake (non significant)
High-dose animals of both sexes showed a slight, non-significant decrease in food intake. In detail, the average food intake of controls were determined as 24.6 and 15.7 g/rat/day for males and females, respectively, which was reduced to 24.9/16.1 g/rat/day, 23.6/15.6 g/rat/day and 21.3/14.9 g/rat/day in males/females of the low, mid and high-dose group, respectively. For females, the reduced food intake was only recorded from week 1 to 6.
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
30000 ppm: decreased food efficiency average in males (non significant)
In contrast to females where no difference in the food efficiency average was determined between control and test animals, a slight, non-significant dose-dependent decrease in food efficiency average was determined in males of the high-dose group (control: 2.2, low-dose group: 2.2, mid-dose group: 2.0, high-dose group: 1.8).
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
30000 ppm: a slight reduction in water intake was determined for males (non significant)
Males of the high-dose group revealed a slight but non-significant reduction in the water intake average compared to control animals. Specifically, the following values were determined for control, low-, mid- and high-dose groups: 45.5, 43.9, 44.0 and 37.8 mL/day/rat. In contrast, no treatment-related alterations were determined in females ( 36.5, 34.9, 36.2 and 34.2 mL/day/rat for control, low-, mid- and high-dose group animals).
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
3000 ppm: females showed a slight increment of haemoglobin; 30000 ppm: moderate reduction in leukocyte count in both sexes, decreases in haematocrit and heamoglobin concentrations in males
In detail:
A moderate, statistical significant reduction in leukocyte count was shown in both sexes in the high-dose group. The total amount of leukocytes was determined of 7.3, 8.7, 6.2 and 4.7*** E03/mm³ in males and 4.5, 4.6, 4.0 and 3.3*** E03/mm³ for females of control, low-, mid- and high-dose group animals, respectively. However, no change in the differential distribution of leukocytes have been evaluated. Further, males of the high-dose group disclosed a slight but significant decrease in haematocrit (41.8, 41.5, 41.1 and 40.0**% for control, low-, mid- and high-dose animals, respectively) and haemoglobin concentration (14.9, 14.8, 14.6 and 13.9* g/dL for control, low-, mid- and high-dose animals, respectively). In contrast, no significant effects in females have been determined on the haematocrit value. A slight increase in the haemoglobin value was observed for females of the mid-dose group (13.5, 13.6, 14** and 13.2 g/dL for control, low-, mid- and high-dose animals. No changes have been reported for the amount of red blood cells in both genders (*p < 0.05, **p < 0.01, ***p < 0.001). The reduced haemoglobin level in males might be due to depressed iron content in the blood and tissues. However, as this effect was only observed in males and not in females, such a general mechanism of toxicity might rather be questionable.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
significant decreased levels in TP, GOT, GPT, Cholesterol and Calcium in males of different dose groups and Ca in females of the mid- and high-dose group (non adverse)
In detail:
Significant reductive tendencies were seen in male rats in the levels of GOT (87, 77*, 76 and 76 for control, low-, mid- and high-dose groups, respectively), GPT (45, 35*, 34*, 34* for control, low-, mid- and high-dose groups, respectively), total protein (6.8, 6.7, 6.6 and 6.3 g/dL*** for control, low-, mid- and high-dose groups, resepectively), cholesterol (60, 59, 65 and 49 mg/dL* for control, low-, mid- and high-dose groups, respectively) and calcium (10.4, 10.2, 10.0 and 10.0 mg/dL* for control, low-, mid- and high-dose groups, respectively). In females, only calcium levels were altered in the mid- and high-dose group compared to the controls (10.1, 10.1, 9.9* and 9.7 mg/dL *** for control, low-, mid- and high-dose groups, respectively) (*p < 0.05, **p < 0.01, ***p < 0.001). As no correlation was observed between the clinical chemistry and histopathology, the observed effects are not interpreted as adverse.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
30000 ppm: slight or moderate decreases in relative organ weights of the brain, liver and spleen in males; thyroid in females (non adverse)
In detail:
Statistically significant decreased organ weights were determined in males of the high-dose group for the brain (relative organ weight), the pituitary (absolute organ weight), thymus (absolute organ weight), liver (absolute and relative organ weight), the kidney (absolute organ weight), the spleen (absolute and relative organ weight), the gonads (absolute organ weight) and the muscles (absolute organ weight). In high-dose females, significant reduced organ weights were noted for the liver (absolute organ weight) and the spleen (absolute organ weight). Mid-dose females revealed an increase in absolute thyroid weight. As the effects on relative organ weights were concomitantly without histological findings, the observed effects might rather be fortiutous than treatment-related and is not interpreted as adverse.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment-related remarkable lesions were reported for all dose-groups.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Pancreatic lesions, degeneration and necrosis of acinar cells, clarification of centroacinar cells and interstitial fibrosis have been reported for the high-dose group (sex not further specified). No other treatment-related lesions were reported.
Histopathological findings: neoplastic:
no effects observed
Other effects:
not examined
Details on results:
BODY WEIGHT AND WEIGHT GAIN
In the high-dose group, a depressed body weight was observed in males which correlated to retarded growth resulting in smaller body sizes. The food consumption of these animals decreased non-significantly around 24% at most compared to controls. As historical data indicate that a 30% reduced food intake does not cause a reduction in weight gain, this effect is considered as treatment-related. In contrast, for females, the decrease in body weight reached significant differences to control animals only from the 1st up to the 5th week of the study. At the end of the study, no significant effect on body weight was noted. Thus, a treatment-related effect was only noted for males which is considered as adverse.

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
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
Dose descriptor:
LOAEL
Effect level:
2 514 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: body weight; haematology; histopathology; corresponds to 30000 ppm
Key result
Dose descriptor:
NOAEL
Effect level:
243 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: no adverse effects observed in the examined parameters; corresponds to 3000 ppm
Dose descriptor:
LOAEL
Effect level:
2 486 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: body weight; haematology; histopathology; corresponds to 30000 ppm

Target system / organ toxicity

Key result
Critical effects observed:
no

Any other information on results incl. tables

Table 1: Effects induced by zinc sulfate heptahydrate in rats

Endpoint

Effect

Dose group (ppm)

Gender

Male

Female

Body weight (g)

Control

453

253

300

463

257

3000

430

255

30000

371***

231

Haematology

Haematocrit (%)

Control

41.8

39.4

300

41.5

38.9

3000

41.1

40.2

30000

40.0**

38.7

Haemoglobin (g/dL)

Control

14.9

13.5

300

14.8

13.6

3000

14.6

14.0**

30000

13.9*

13.2

Red Blood Cell Count (x10E6/mm³)

Control

6.9

6.4

300

7.0

6.5

3000

6.8

6.6

30000

6.9

6.6

Leukocyte (total (+E03/mm3)

Control

7.3

4.5

300

8.7

4.6

3000

6.2

4.0

30000

4.7***

3.3***

Clinical Chemistry

Total protein (g/dL)

Control

6.8

6.8

300

6.7

6.8

3000

6.6

6.8

30000

6.3***

6.6

GOT (K-unit)

Control

87

93

300

77*

86

3000

76

98

30000

76

87

GPT (K-unit)

Control

45

58

300

35*

42

3000

34*

57

30000

34*

41

Chol (mg/dL)

Control

60

66

300

59

75

3000

65

65

30000

49*

65

Ca (mg/dL)

Control

10.4

10.1

300

10.2

10.1

3000

10.0

9.9*

30000

10.0*

9.7**

Organ Weights (absolute/relative)

brain (g)

Control

1.93/0.43

1.78/0.70

300

2.05/0.44

1.82/0.71

3000

1.97/0.46

1.79/0.70

30000

1.87/0.5***

1.80/0.78

pituitary (mg)

Control

10.5/0.0023

11.5/0.0045

300

10.9/0.0024

11.6/0.0045

3000

11.0/0.0026

11.3/0.0044

30000

8.4***/0.0023

10.3/0.0045

thyroid (mg)

Control

24.2/0.0053

14.8/0.0058

300

28.5/0.0062

17.6/0.0068

3000

24.0/0.0056

17.8*/0.0071

30000

23.3/0.0063

17.2/0.0074

heart (g)

Control

1.31/0.29

0.80/0.32

300

1.35/0.29

0.85/0.33

3000

1.23/0.29

0.84/0.33

30000

1.07/0.29

0.79/0.34

thymus (g)

Control

0.48/0.11

0.40/0.16

300

0.48/0.10

0.42/0.16

3000

0.47/0.11

0.39/0.15

30000

0.39*/0.11

0.35/0.15

liver (g)

Control

16.1/3.55

8.8/3.48

300

17.5/3.80

9.7/3.77

3000

16.0/3.72

9.0/3.53

30000

11.9***/3.20***

7.5*/3.25

kidney (g)

Control

2.93/0.65

1.55/0.61

300

3.16/0.68

1.65/0.64

3000

2.96/0.69

1.58/0.62

30000

2.29***/0.62

1.45/0.63

spleen (g)

Control

0.65/0.14

0.44/0.17

300

0.74/0.16

0.45/0.18

3000

0.69/0.16

0.46/0.18

30000

0.49***/0.13*

0.39*/0.17

adrenal (mg)

Control

48.8/0.011

53.5/0.021

300

46.0/0.010

55.0/0.021

3000

47.3/0.011

52.4/0.021

30000

42.2/0.011

54.7/0.024

gonads (mg)

Control

3000/0.67

67.3/0.027

300

3028/0.66

69.5/0.027

3000

2890/0.68

67.7/0.027

30000

2663*/0.72

71.7/0.031

muscles (g)

Control

2.52/0.56

1.58/0.62

300

2.70/0.58

1.61/0.063

3000

2.43/0.57

1.61/0.63

30000

2.16***/0.58

1.44/0.62

with *p < 0.05, **p < 0.01, ***p < 0.001 

Applicant's summary and conclusion

Conclusions:
Under the test conditions, NOAEL of the test material in rats was determined to be 3000 ppm (approximately equivalent to 234 mg/kg/day in male rats and 243 mg/kg/day in female rats).