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Toxicological information

Toxicity to reproduction

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Administrative data

multi-generation reproductive toxicity
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
disregarded due to major methodological deficiencies
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
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 Type:

Materials and methods

Test guideline
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:

Test material

Constituent 1
Reference substance name:
L-Cysteine, hydrochloride, monohydrate
L-Cysteine, hydrochloride, monohydrate
Constituent 2
Reference substance name:
Cas Number:
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

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
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
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.
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.
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
Details on study schedule:
Multi-generation feeding experiment
Experiment 1: Three generations
Experiment 2: Six generations
Doses / concentrationsopen allclose all
Doses / Concentrations:
0, 35, 350, 3500 ppm

Doses / Concentrations:
0, 3500 ppm

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.
Positive control:

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

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.