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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: not to GLP, follows basic scientific principles

Data source

Reference
Reference Type:
publication
Title:
Effect of dietary manganese level on tissue manganese, iron, copper and zinc concentrations in female rats and their fetuses
Author:
Järvinen R & Ahlström A
Year:
1975
Bibliographic source:
Medical Biology 53: 93-99

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Female rats were maintained, from the time of weaning, on diets containing different levels of Mn. The animals were mated and the offspring collected by caesarean section at day 21 of pregnancy. The number of implantation sites, resorptions and foetuses were recorded. The foetuses were weighed and observations made. In addition the manganese, iron, copper and zinc concentrations in the foetal body and in the liver of pregnant and non-pregnant (control) animals were determined.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Manganese sulphate
- Molecular formula (if other than submission substance): MnSO4.7H20
- Physical state: solid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Orion Yhtyma Oy, Yla- Mankkaa Farm, Mankkaa, Finland
- body weight: 66 g
- Housing: wire bottomed stainless cages
- Diet : ad libitum
- Water :ad libitum
- Acclimation period: 8 weeks before females were placed with males


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Photoperiod (hrs dark / hrs light):12/12



Administration / exposure

Route of administration:
oral: feed
Details on exposure:
DIET PREPARATION
- Mixing appropriate amounts with (Type of food): Suitable amounts of test material were added to the salt mixture used to make up the diets.
- Storage temperature of food: -10° C


Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Details on mating procedure:
10 animals from groups 1, 4 and 5 and 11 animals from groups 2, 3 and 6 were mated with male rats of the same strain that had been kept on a commercial mouse and rat chow. One male was placed overnight with 3 females.
Duration of treatment / exposure:
8-10 weeks
Frequency of treatment:
daily
Duration of test:
approx. 13 weeks
No. of animals per sex per dose:
17 females in each group
Control animals:
yes
Details on study design:
Not reported

Examinations

Maternal examinations:
DETAILED CLINICAL OBSERVATIONS:
- Time schedule: after 21 days blood sample taken and haemoglobin and packed cell volume assessed.
BODY WEIGHT:
- Time schedule for examinations: animals were weighed at the start of the study, week 8 and on gestational day 0 (day of fertilization) and 21

POST-MORTEM EXAMINATIONS:
Maternal: number of implantation sites, resorptions and foetuses were recorded, liver isolated and determination of concentration of Mn, Fe, Cu and Zn was performed.


Ovaries and uterine content:
Not reported
Fetal examinations:
- External examinations: weighed, examination for gross malformations
- Skeletal examinations: skeletal staining
- other: determination of Mn, Fe, Cu, and Zn concentration in body.
Statistics:
Arithmetic means and standard errors were calculated. The significance of differences between the experimental groups was tested by the Student's t-test.
Indices:
Not reported
Historical control data:
Not reported

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
Manganese did not cause gross malformations or bone structure anomalies at the concentrations used in this study

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Remarks:
No effects were noted during the study
Basis for effect level:
other: developmental toxicity
Remarks on result:
not determinable
Remarks:
no NOAEL identified

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There was no impact on foetuses at any of the doses studied

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

No gross malformations or bone structure anomalies could be observed in the foetuses, and the Mn intake of the dams was not found to have influenced essentially the foetal weights and the dry matter and ash contents. The iron content of the livers of both pregnant and non-pregnant female rats fell as the Mn level of the diet increased. The haemoglobin values of dams on the highest levels of dietary Mn were also slightly reduced. The haemoglobin values and packed cell volumes in the non-pregnant rats were not affected by increasing dietary concentrations of Mn.

Table 1 : Body weight gain of female rats during the first eight weeks on diets of different manganese levels, and haemoglobin and packed cell volume values of pregnant (21st) day and non-pregnant rats kept on the different experimental diets (mean ± SE)

 

Group

Mn mg/kg diet

Body weight, g

Weeks on diet

Hb, g/100 mL

PCV, %

0

8

pregnant

non-pregnant

pregnant

non-pregnant

I

4

66 ± 1

238 ± 5

9.8 ± 0.5

14.1 ± 0.3

30 ± 2

43 ± 1

II

24

66 ± 2

235 ± 7

10.4 ± 0.3

14.3 ± 0.1

34 ± 1

43 ± 1

III

54

66 ± 2

235 ± 7

10.2 ± 0.3

14.3 ± 0.2

31 ± 1

43 ± 2

IV

154

66 ± 1

226 ± 6

9.6 ± 0.6

14.1 ± 0.2

29 ± 2

43 ± 1

V

504

66 ± 1

228 ± 6

9.4 ± 0.6

14.0 ± 0.4

30 ± 1

43 ± 1

VI

1004

66 ± 1

221 ± 5

9.4 ± 0.2

13.6 ± 0.6

30 ± 1

41 ± 2

Table 2: Reproductive performance of female rats fed diets of different manganese levels.

Group

Mn mg/kg diet

No. of dams

Body weight gain during pregnancy, g

Implantations per rat

Resorptions

%

Foetuses

Dead

%

Externally normal per rat

I

4

10

117 ± 7

12.6 ± 0.5

10.3

-

11.3 ± 0.7

II

24

11

111 ± 6

11.8 ± 1.1

3.8

-

11.4 ± 1.0

III

54

11

115 ± 5

12.6 ± 0.8

8.6

0.7

11.5 ± 0.7

IV

154

10

110 ± 5

11.6 ± 0.7

11.2

-

10.3 ± 0.8

V

504

10

 99 ± 5

11.9 ± 0.8

12.6

1.7

10.2 ± 0.8

VI

1004

11

110 ± 6

10.5 ± 0.7

8.7

-

 9.5 ± 0.9

Table 3 : Body weight and body dry matter and ash contents of foetuses from dams fed diets of different manganese levels (mean ± SE)

Group

Mn mg/kg diet

Body weight gain during pregnancy, (g)

Dry matter % of bwt

Ash % of dry wt.

I

4

4.63 ± 0.05

13.3 ± 0.1

13.1 ± 0.1

 

II

24

4.72 ± 0.04

13.2 ± 0.1

13.0 ± 0.1

 

III

54

4.73 ± 0.04

13.3 ± 0.1

13.1 ± 0.1

 

IV

154

4.67 ± 0.04

13.2 ± 0.1

13.2 ± 0.2

 

V

504

4.38 ± 0.05

13.0 ± 0.1

13.5 ± 0.3

 

VI

1004

4.75 ± 0.05

13.0 ± 0.1

13.4 ± 0.2

 

Applicant's summary and conclusion

Conclusions:
Manganese content was highest in the offspring of dams given the largest amount of manganese. The manganese level in the maternal diet had the opposite effect on the foetal iron concentration, and the zinc content of foetuses of dams on the highest dietary manganese level was slightly elevated. No gross malformations or bone structure anomalies could be observed in the foetuses, and the manganese intake of the dams was not found to have influenced essentially the foetal weights and the dry matter and ash contents.