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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Up to 12 week dosing period
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Academic research
Cross-reference
Reason / purpose for cross-reference:
reference to other study
Remarks:
Reference to study that included female reproductive effects
Reference
Endpoint:
developmental toxicity
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
Justification for type of information:
Peer reviewed publication
Academic study not following normal guidelines, but included sufficient detail to cover female reproductive effects and developmental toxicity
Qualifier:
no guideline followed
Principles of method if other than guideline:
From the time of weaning, female rat received 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.
GLP compliance:
no
Remarks:
Pre-dates GLP
Limit test:
no
Specific details on test material used for the study:
Hydrated form. Dose levels considered high enough to negate the presence of water
Species:
rat
Strain:
Sprague-Dawley
Route of administration:
oral: feed
Analytical verification of doses or concentrations:
not specified
Frequency of treatment:
Daily
Duration of test:
From 10 weeks prior to birth
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
4 mg/kg bw/day (nominal)
Dose / conc.:
24 mg/kg bw/day (nominal)
Dose / conc.:
54 mg/kg bw/day (nominal)
Dose / conc.:
504 mg/kg bw/day (nominal)
Dose / conc.:
154 mg/kg bw/day (nominal)
Dose / conc.:
1 004 mg/kg bw/day (nominal)
No. of animals per sex per dose:
17 females in each group
Control animals:
yes, plain diet
Maternal examinations:
General condition, weights, embryonic reabsorption
Clinical signs:
no effects observed
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 examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
dose related
Total litter losses by resorption:
not examined
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Dose descriptor:
NOAEL
Remarks:
Maternal health
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Description (incidence and severity):
No considered significant
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Description (incidence and severity):
No soft-tissue malformations noted
Other effects:
no effects observed
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Abnormalities:
no effects observed
Developmental effects observed:
no
 
Conclusions:
No adverse effects on developmental toxicity
No adverse effects on female fertility

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1998

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
Principles of method if other than guideline:
12 week dosing of males
Observations were made regarding behaviour up to and including mating.
Note that although the study does not meet current regulatory guidelines, there is lot evidence regarding the importance of manganese in the diet and is offered as a food supplement.
GLP compliance:
not specified
Remarks:
Academic research
Limit test:
no
Justification for study design:
Follows accepted scientific principles

Test material

Constituent 1
Chemical structure
Reference substance name:
Manganese sulphate
EC Number:
232-089-9
EC Name:
Manganese sulphate
Cas Number:
7785-87-7
Molecular formula:
MnO4S
IUPAC Name:
Manganese sulphate
Test material form:
solid
Specific details on test material used for the study:
Dihydrate used
The presence of water will not have impacted on the reults

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
Males were dosed for 12 weeks at 1000 ppm in drinking water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Metal content
Duration of treatment / exposure:
12 weeks prior to mating
Frequency of treatment:
Daily; drinking water
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/L drinking water
Remarks:
Estimated 200 mg/kg actual dose
Dose / conc.:
1 000 ppm (nominal)
Remarks:
In drinking water (0.1%)
No. of animals per sex per dose:
10 males and 20 females
Control animals:
other:
Positive control:
No

Examinations

Parental animals: Observations and examinations:
All animals were observed for clinical signs and behaviour.
Oestrous cyclicity (parental animals):
Yes
Postmortem examinations (parental animals):
Not specified
Postmortem examinations (offspring):
Not specified
Reproductive indices:
Yes
Offspring viability indices:
Yes

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
> 200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
not examined
Gross pathological findings:
no effects observed

Effect levels (F1)

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

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
no
Treatment related:
yes

Applicant's summary and conclusion

Conclusions:
The limit study on a single treatment level of manganese sulphate showed no significant effect in fertility or reproduction indices.