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Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
significant methodological deficiencies
Remarks:
Group size was not appropriate (10 to 11 pregnant rats, 20 pregnant rats were required with a minimum requirement of 16 pregnant rats if mortality occurs). Food consumption not recorded. Necropsy of dams incomplete (uterus and liver were examined), foetal data incomplete (litter size, sex, soft tissue defects missing). Purity of test material not stated.

Data source

Reference
Reference Type:
publication
Title:
Effect of the dietary manganese level on tissue manganese, iron, copper and zinc concentrations in female rats and their fetuses
Author:
R. Järvinen and A. Ahlström
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 fed with manganese sulphate heptahydrate containing diets and mated after 8 weeks of exposure with males receiving normal rat diet. Pregnant females were sacrificed at day 21 of pregnancy. Maternal livers and uterus were examined as well as fetuses. Additionally, mineral contents (manganese, iron, copper and zinc) in fetuses and in livers of pregnant and non-pregnant females were analysed.
GLP compliance:
not specified
Remarks:
not specified in publication
Limit test:
no

Test material

Constituent 1
Reference substance name:
manganese(2+);sulfate;heptahydrate
Cas Number:
13492-24-5
Molecular formula:
H14MnO11S
IUPAC Name:
manganese(2+);sulfate;heptahydrate
Test material form:
not specified
Details on test material:
not specified
Specific details on test material used for the study:
not specified

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Orion Yhtymä Oy, Ylä-Mankkaa Farm, Mankkaa, Finland
- Age at study initiation: not specified
- Weight at study initiation:
Group I: 66 ± 1 g
Group II: 66 ± 2 g
Group III: 66 ± 2 g
Group IV: 66 ± 1 g
Group V: 66 ± 1 g
Group VI: 66 ± 1 g
- Fasting period before study: not specified
- Housing:
housed individually in in wire-bottom stainless steel cages
- Diet ad libitum:
females: low-manganese basal diet (16 % protein, 9 % fat, 65 % carbohydrate, 4.1 kcal/g, 4.3 % average moisture)
Males: commercial mouse and rat chow (Orion Yhtymä Oy, Ylä-Mankkaa Farm, Mankkaa, Finland)
- Water ad libitum: tap water
- Acclimation period: not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): not specified
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Experimental diets were prepared by adding to the salt mixture suitable quantities of manganese sulphate heptahydrate. Experimental diets were prepared in 15-kg portions in a Horbart mixer and stored in plastic containers.

DIET PREPARATION
- Rate of preparation of diet (frequency): not specified
- Mixing appropriate amounts with (Type of food): low-manganese basal diet (16 % protein, 9 % fat, 65 % carbohydrate, 4.1 kcal/g, 4.3 % average moisture)
- Storage temperature of food: -10 °C
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused: 10 females from groups I, IV and V and 11 females from group II, III and VI were mated.
- M/F ratio per cage: 1 male and 3 females
- Length of cohabitation: overnight
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
8 to 11 weeks
Frequency of treatment:
daily
Duration of test:
not specified
Doses / concentrationsopen allclose all
Dose / conc.:
24 mg/kg diet
Remarks:
based on element (mg Mn/kg dry diet)
Dose / conc.:
54 mg/kg diet
Remarks:
based on element (mg Mn/kg dry diet)
Dose / conc.:
154 mg/kg diet
Remarks:
based on element (mg Mn/kg dry diet)
Dose / conc.:
504 mg/kg diet
Remarks:
based on element (mg Mn/kg dry diet)
Dose / conc.:
1 004 mg/kg diet
Remarks:
based on element (mg Mn/kg dry diet)
No. of animals per sex per dose:
17 females/group
thereof were 10-11 females mated and 6-7 females served as non-pregnant controls (treated like pregnant females)
Control animals:
yes, plain diet
other: non-pregnant females in all dose groups
Details on study design:
- Dose selection rationale:
Doses were selected based on optimum manganese level for rat growth that was stated as 40 mg/kg dry diet.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: weekly and additionally on days 0 and 21 of pregnancy

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: uterus, livers
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of resorptions: Yes
- Number of fetuses: Yes
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: No data
- Skeletal examinations: 5 fetuses
- Head examinations: No data

OTHER:
- fetuses were weighed individually
- 30 fetuses fom each group were analyzed for the dry matter content
- 8-10 fetuses from each group were analyzed for the ash content
- pooled samples of two fetuses from each litter were used for mineral analyses
Statistics:
From the analytical data arithmetic means and standard errors (SE) were calculated. The significance of differences between the experimental groups was tested by the Student's t-test.
Indices:
No data
Historical control data:
No data

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
not specified
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
hemoglobin concentration was significantly lower in pregnant females of group VI (1004 mg Mn/kg dry diet) compared to groups II and III (24 and 54 mg Mn/kg dry diet, respectively).
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
The manganese content in liver was increased in pregnant females compared to non-pregnant females in a dose dependant manner. Manganese intake had no effect on manganese concentrations in livers of non-pregnant females.The liver iron content decreased with increasing manganese intake, this effect was more pronounced in non-pregnant females than in pregnant females. The liver copper content was elevated only in pregnant females of the high dose group. Liver zinc content was not affected by manganese intake.

Maternal developmental toxicity

Number of abortions:
not specified
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed

Effect levels (maternal animals)

Remarks on result:
not determinable due to absence of adverse toxic effects

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Reduction in number of live offspring:
not specified
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
not specified
Details on embryotoxic / teratogenic effects:
Manganese contents in fetuses only slightly increased and reflected manganese intake of the dams.

Effect levels (fetuses)

Remarks on result:
not determinable due to adverse toxic effects at highest dose / concentration tested

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Female rats were fed with manganese sulphate heptahydrate containing diets and mated after 8 weeks of exposure with males receiving normal rat diet. Pregnant females were sacrificed at day 21 of pregnancy. Maternal livers and uterus were examined as well as fetuses. Additionally, mineral contents (manganese, iron, copper and zinc) in fetuses and in livers of pregnant and non-pregnant females were analysed. No adverse effects were observed in all animals. The manganese content in liver was increased in pregnant females compared to non-pregnant females in a dose dependant manner. Manganese intake had no effect on manganese concentrations in livers of non-pregnant females.The liver iron content decreased with increasing manganese intake, this effect was more pronounced in non-pregnant females than in pregnant females. The liver copper content was elevated only in pregnant females of the high dose group. Liver zinc content was not affected by manganese intake. Manganese contents in fetuses only slightly increased and reflected manganese intake of the dams.