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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
disregarded due to major methodological deficiencies
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
It is uncertain if the test substance is applied unchanged and if the calculated doses are accurate due to the pretreatment procedure. Due to supply problems the experimental feed had to be replaced by standard feed in the 3500 ppm dose group (Exp. 2) for part of the time.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1971

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
A multi-generation feeding test with growing and breeding rats has been conducted to determine the effect of the cysteine-treatment of flour (compared with control flour)used in preparing the bread included in their diets at the level of 77%. Neither 10 times nor 100 times the optimum usage rate of cysteine markedly affected growth, breeding characteristics or post mortem findings in the rats, apart from a slightly greater rate of decline in weaning liveweight from generation to generation at the highest cysteine level, leading to lower liver and kidney weights in male weanling rats of the fifth and sixth generations. Histological evidence from breeding rats of the fifth generation showed no lesions atypical in normal rats and therefore supported the contention that the consumption by rats of bread baked with cysteine- treated flour is without harmful effect over several generations.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
L-Cysteine, hydrochloride, monohydrate
IUPAC Name:
L-Cysteine, hydrochloride, monohydrate
Constituent 2
Reference substance name:
7048-04-6
Cas Number:
7048-04-6
IUPAC Name:
7048-04-6
Test material form:
other: L-Cysteine Hydrochloride Monohydrate added to flour
Details on test material:
L-Cysteine Hydrochloride Monohydrate added to flour in different concentrations.
It is not clear if the L-Cysteine Monohydrate is applied unchanged and if the dose calculation is valid.
There is no information about analytical dose verification.

Test animals

Species:
rat
Strain:
other:
Details on test animals or test system and environmental conditions:
Experiment 1:
C.D. albino females of an inbred Middle Aston strain
Temperature: 20-21°C, food and water ad libitum, wood shavings used for bedding.
Experiment 2:
C.D. Norwegian Hooded females of an inbred Middle Aston strain.
Temperature: 20-21°C, food and water ad libitum, wood shavings used for bedding.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: bread powder in the diet (77% on dry weight basis).
Details on exposure:
Diet preparation:
basic formula: 127kg commercial brad flour containing the added cysteine salt at 0, 35, 350 or 3500 ppm; 77kg water for the lowder levels of
cysteine salt; 2.72 kg bakers' yeast; 2.72 kg sodium chloride and 1.36kg Soyswift
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Identity and concentration of Cysteine Hydrochloride in the feed was not verified. During part of experiment 2 a standard rodent diet was used in place of the experimental bread powder diet due to limited supply. No detailed info about the duration of the supply problem is given.
Details on mating procedure:
Experiment 1: After weaning the mothers and all pups were euthanized; except for two males and three female pups selected at random from each litter which were retained for breeding. Experiment was stopped at the third generation due to poor reproductive characteristics of the strain.
Experiment 2: procedure as in experiment 1. Six-generation-study with reduced number of animals starting at the fourth generation. The experiment was terminated during breeding of the seventh generation.
Duration of treatment / exposure:
Multi-generation feeding experiment, Food and water ad libitum.
Experiment 1: Three generations
Experiment 2: Six generations
Frequency of treatment:
Food and water ad libitum
Duration of test:
Multi-generation feeding experiment
Experiment 1: Three generations
Experiment 2: Six generations
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 35, 350, 3500 ppm
Basis:
other: nominal in flour
Remarks:
Doses / Concentrations:
0, 3500 ppm
Basis:
other: nominal in flour
No. of animals per sex per dose:
Experiment 1: 4 pregnant females per group (control and three dose groups)
Experiment 2: 4 pregnant females per group (control and one dose group)
Control animals:
yes, plain diet
Details on study design:
Number born and litter weight at birth were recorded.
Carcass, liver and kidney weight of all animals were recorded.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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

Results (fetuses)

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

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

A lack of real difference between treatments over six generation was remarked. The principal characteristic of the response measured in the 0 and 3500 ppm groups was the overall rate of change per generation in litter size and weight at birth and at weaning and the rate of change in the size of the carcasses, livers and kidneys of both adults and weanling rats.

There are no significant differences between treatments in the rates of decline. Litter size and weight at birth and number weaned tended in fact to increase with gestation in the 3500 ppm group but this was associated with a slightly greater rate of decline for that group in adult and weanling carcass weights and liver and kidney weights.

No significant differences occurred between the 0 and 3500 ppm treatments for the responses measured in generations 5 and 6 apart from lower liver weights in adult males and lower liver and kidney weights in weanling males receiving the high cysteine treatment. Breeding rats of the fifth generation at about 150 days of age receiving the diet with the highest cysteine treatment were examined histologically. They showed no lesions atypical in normal rats of that age.

Applicant's summary and conclusion

Conclusions:
Cysteine-treated rats did not differ from the control rats in any of the parameters measured .
Executive summary:

The results of two teratogenicity-toxicity experiments were reported by Frape et al .17 Four pregnant, first-generation rats were maintained on diets consisting of 77% bread containing 0, 35, 350, or 3500 ppm cysteine. After weaning, all pups were sacrificed except for 2 males and 3 fenales selected at random from each litter that were retained for breeding. No effects were seen at any dose level on nunber born, litter weight at birth, nunbers weaned or litter weight at weaning. Carcass, liver and kidney weights, and post-mortem examination for gross lesions shvaed no effects at any dose. The retained pups were maintained on the same dietary reginent as their parents . After littering, the sane procedure as for the first generation was adopted and no effects were seen at any dose. In the second experiment, 4 pregnant, first-generation females were naintained on a diet of 77% bread maintaining 0 or 3500 ppm cysteine. Except for retaining more pups for breeding, the same procedure as for the first experiment was earried cut at the weaning of the litters and was continued through the fourth generation. Beginning with the fifth generation, all 4 treatment groups used in the first experiment were esployed and this procedure was continued through the sixth generation .