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Diss Factsheets

Administrative data

Description of key information

Repeated dose toxicity: oral: Key study: The NOEL for Zinc acetate anhydrous was 133.77 mg/kg bw/day in female rats (test method similar to OECD guideline 408).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1988
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No specific test guideline was reported; however, the study is performed in similar way as described in OECD 408 guideline.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
(Only female rats were used)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Interfauna Iberica, Barcelona, Spain
- Weight at study initiation: 70-90 g
- Housing: Animals were placed in individual metabolism cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
VEHICLE
The vehicle is water, but sugar was added to reduce the aversive effect of the zinc in the water.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
The solutions were prepared weekly.
Duration of treatment / exposure:
A period of three months.
Frequency of treatment:
The rats were exposed to test substance continously.
Remarks:
Doses / Concentrations:
160 mg/kg body weight/day
Basis:
nominal in water
Remarks:
Doses / Concentrations:
320 mg/kg body weight/day
Basis:
nominal in water
Remarks:
Doses / Concentrations:
640 mg/kg body weight/day
Basis:
nominal in water
No. of animals per sex per dose:
10 female animals per each dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: 1/5, 1/2.5, and 1/1.25 of acute oral dose.
Positive control:
No positive controls were used.
Observations and examinations performed and frequency:
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded prior to treatment and weekly throughout the study.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: daily
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of experiment
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: Forty
- Parameters checked in table were examined.

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: The zinc concentration in organs and tissues was determined.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
Determination of zinc concentration in organs and tissues.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
effects observed, treatment-related
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
not specified
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
During the total 3-month treatment period same outstanding changes were found as regards to appearance, mortality and behaviour between the rats receiving the higher doses of zinc acetate (640 mg/kg bw/day) and the controls, Treated rats showed a tendency towards apathy and two animals in this group died throughout the study. Food consumption as well as the amount of feces excreted were about equal in all groups. There was no effect on weight gain caused by treatment.
With regard to the nutricional parameters measured, the drinking water ingested and the volume of urine excreted were always significantly lower for the 640 mg/kg bw/day group. Nevertheless, the animals receiving 160 and 320 mg/kg bw/day did not show significant differences in any of the nutritional parameters studied.
Dose descriptor:
NOEL
Effect level:
133.77 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: overall effects (Estimated results for Zinc Acetate anhydrous)
Critical effects observed:
not specified

No treatment-related effects on organ weights or organ/body weight ratios were observed during the study (Table 1, P>0,05),

Table 1:        Fresh weights of organs from rats receiving zinc acetate in their drinking water for three months

 

 

Dose (mg/kg/day)

 

 

0

160

320

640

Brain

1,88± 0,11

1,83± 0,12

1,74± 0,15

1,72± 0,24

Heart

0,86± 0,10

0,76± 0,13

0,84± 0,09

0,66± 0,17

Lungs

1,44± 0,29

1,51± 0,37

1,39± 0,20

1,03± 0,14

Spleen

0,48± 0,24

0,46± 0,11

0,51± 0,15

0,29± 0,24

Liver

8,56± 0,75

8,33± 1,32

7,50± 1,29

5,02± 1,97

Kidneys

1,81± 0,17

1,71± 0,11

1,73± 0,21

1,61± 0,46

Results are presented as arithmetic means, No significant differences could be de detected by the Student's t test,

The Table 2 summarizes the hematological and plasma analyses carried out in the treatment and control animals after three months of treatment. The concentrations of urea and creatinina and plasma were significantly higher for the animals receiving 640 mg/kg/day zinc acetate than the control rats.

Table 2: Hematological and clinical chemical parameters* in rats dosed with zinc acetate for three months.

Dose (mg/kg/day)

 

0

160

320

640

Hematocrit

(%) 46,7± 4,9

41,0± 12,7

43,5± 3,5

39,0± 11,8

Hemoglobin

 

 

 

 

(g/100 ml)

12,2± 0,7

14,5± 1,0

14,1± 2,7

10,3± 1,9

Glucose

 

 

 

 

(mg/10O ml)

163,5± 9,9

142,3± 29,1

156,3± 29,1

142,3± 8,5

GOT (U/l)

118,9± 22,1

96,6± 47,5

113,2± 25,5

141,6± 8,1

G.PT (U/l)

40,1± 10,9

50,4± 15,1

51,9± 7,0

42,1± 6,1

ALP (U/l)

136,9± 37,9

227,0± 19,8

228,4± 23,5

236,7± 38,7

Urea

 

 

 

 

(mg/100 ml)

39,5± 5,2

40,5± 11,4

35,5± 3,1

59,2± 4,2**

Creatinine

 

 

 

 

(mg/100 ml)

0,7± 0,21

1,7± 1,22

0,6± 0,24

4,4± 0,70**

The concentration of zinc in the tissues of rats are shown in Table 3. The highest concentrations were found in bone, liver and kidneys as well as in blood. A significant relationship between dose received and tissue concentrations can be seen. The most several histological lesions were observed in kidneys.

Table 3: Zinc concentrations* in organs and tissues of rats receiving zinc acetate for three months.

Dose (mg/kg/day)

 

0

160

320

640

Brain

9.5 ± 1.9

9,4± 3,2

13,5± 1,8

15,4± 2,8

Liver

20,3±5,3

24,7± 5,7

47,6± 8,4*

59,9± 7,0**

Kidneys

15,0± 11,09

20,6± 4,9

41,1± 4,9**

38,3± 3,2**

Spleen

15,6± 12.05

15,9± 3,4

22,0± 3,6

36,4± 6,0*

Heart

10,5± 11,7

11,3± 1.8

16,8± 1,1*

21,9± 2,5**

Lungs

12,7± 12,4

14,2± 3,6

20,2± 1,3

20.7± 2,8

Bone

92,3± 121,3

127,3± 39,7

326,3± 47,6**

330,6± 58,6**

Muscle

14.5± 13,2

13,9± 1,6

18,0 ± 1.3

30,0± 9,1

Blood

3.4± 12,0

4,2± 1,7

16,3 ± 2,3**

21,1± 3,0***

 aZinc concentrations are expresed as µg/fresh weight, *P>0.05, **P<0.01, ***P<0.001 by the Student's t test 

Conclusions:
The results of the assay have demostrated for zinc acetate anhydrous a toxicological no observable-effect level (NOEL) of 133.77 mg/kg bw/day in female rats.
Executive summary:

The repeated dose of zinc acetate 90-days oral toxicity study in rodents was carried out using 40 females Sprague-Dawley rats which were exposed to dihydrated zinc acetate in drinking water at concentrations of 0, 160, 320, and 640 mg/kg bw/day continuously during 3 months.

For animals receiving 640 mg/kg bw/day of zinc acetate the volume of urine excreted and the drinking water taken in were always lower than in the other groups. Concentrations of urea and creatinina in plasma were significantly higher for the animals of this group. The highest concentration of zinc was found in the bone, liver, and kidneys as well as in blood.

The results of the assay have demonstrated a toxicological no observable-effect level (NOEL) for zinc acetate anhydrous of 133.77 mg/kg bw/day in female rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
133.77 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

Repeated dose toxicity: oral:

Key study: Experimental results with Zinc Acetate dihydrate. Test method was similar to OECD guideline 408.

The repeated dose of zinc acetate 90-days oral toxicity study in rodents was carried out using 40 females Sprague-Dawley rats which were exposed to dihydrated zinc acetate in drinking water at concentrations of 0, 160, 320, and 640 mg/kg bw/day continuously during 3 months. The NOEL for Zinc acetate anhydrous was estimated as 133.77 mg/kg bw/day in female rats.

Justification for classification or non-classification

Repeated dose toxicity:

Oral: NOEL > 100 mg/kg bw/day: non- classification.