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Diss Factsheets

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
reproductive toxicity, other
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:
Effects of Excess Thiamine and Pyridoxine on Growth and Reproduction in Rats
Author:
Morrison, A.B. and Sarett H.P.
Year:
1959
Bibliographic source:
J. Nutrition 69:111-116

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study was conducted to determine whether excess amounts of thiamine hydrochloride affected growth and reproductive performance in female rats. The female rats of the control group were fed with a basal diet containing 1.5 mg thiamine hydrochloride per 1 kg of diet. For the treatment group the feed was supplemented with 50 times of this level, resulting in a diet containing 75 mg/kg food. Records were kept of the amounts of food and water consumed by each rat, and the animals were weighed individually at weekly intervals. After an exposure duration of 12 weeks, the animals were mated with stock males of proven fertility. As soon as possible after each hitter was born, the number and weight of the young were recorded. When necessary, the number of young per litter was reduced to 8 at 5 days of age.
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Thiamine hydrochloride
EC Number:
200-641-8
EC Name:
Thiamine hydrochloride
Cas Number:
67-03-8
Molecular formula:
C12H17N4OS.ClH.Cl
IUPAC Name:
3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride hydrochloride

Test animals

Species:
rat
Strain:
other: McCollum-Wisconsin
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 19 - 21 days
- Weight at study initiation: 50 g
- Housing: The animals were individually housed in screen-bottom cages.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on mating procedure:
Females were mated with stock males of proven fertility.
Analytical verification of doses or concentrations:
no
Frequency of treatment:
(P) Females: 12 weeks before mating, during mating, during resulting pregnancies and until lactation day 21, through weaning of their F1 offspring.
(F1) Males and Females: 19 - 21 days, until weaning
Details on study schedule:
- Age at mating of the mated animals in the study: approximately 15 weeks
Doses / concentrationsopen allclose all
Dose / conc.:
75 mg/kg diet
Remarks:
basal diet contained 1.5 mg thiamine hydrochloride per kg food and was supplemented with 50 times of this level, resulting in a diet containing 75 mg/kg food.
Dose / conc.:
9 mg/kg bw/day (nominal)
Remarks:
a default factor of 0.12 for rats was used for converting test substance concentrations in feed (mg/kg) into daily dose (mg/kg bw per day) as described in a scientific opinion from EFSA (EFSA Journal 2012;10(3):2579).
No. of animals per sex per dose:
12
Control animals:
yes, plain diet

Examinations

Parental animals: Observations and examinations:
BODY WEIGHT: Yes, the body weight of the female rats were recorded weekly.

FOOD CONSUMPTION AND FOOD EFFICIENCY:
Amounts of food consumed by each rat were recorded.

WATER CONSUMPTION:
Amounts of water consumed by each rat were recorded.
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 5 postpartum: when neccesary, the number of young per litter was reduced to 8

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: as soon as possible after each litter was born, the number and weight of the pups were recorded. Thereafter, weight gain was recorded on lactation day 21 again. Postnatal mortality was determined on lactation day 5 and 21, respectively.
Postmortem examinations (parental animals):
SACRIFICE
- Maternal animals: All surviving animals were sacrificed by intraperitoneal injection of Nembutal solution after the F1 generation had reached 21 days of age.

GROSS NECROPSY
- Gross necropsy consisted of the examination of liver, kidneys and adrenals. These organs were removed and weighted. In addition, the livers of each treatment group were pooled and analyzed for solids, total lipids and thiamine content.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Control: 1/12 females died.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
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
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Remarks:
calculated
Effect level:
9 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No adverse effects were observed at the dose level of 75 mg/kg of diet
Remarks on result:
other: a default factor of 0.12 for rats was used for converting test substance concentrations in feed (mg/kg) into daily dose (mg/kg bw per day) as described in a scientific opinion from EFSA (EFSA Journal 2012;10(3):2579).

Target system / organ toxicity (P0)

Key result
Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
Control: 98% survived from day 0 to day 5 and 73% survived from day 0 to day 21
75 mg/kg diet: 96% survived from day 0 to day 5 and 76% survived from day 0 to day 21

There was no difference between the survival rates of control and treatment group, therefore the effect was considered to be non-treatment related.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
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
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
Other effects:
not examined

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Remarks:
calculated
Generation:
F1
Effect level:
9 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects were observed in the F1 generation
Remarks on result:
other: a default factor of 0.12 for rats was used for converting test substance concentrations in feed (mg/kg) into daily dose (mg/kg bw per day), as described in a scientific opinion from EFSA (EFSA Journal 2012;10(3):2579).

Target system / organ toxicity (F1)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
The source substance had no effect on reproductive performance.