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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1971
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see justification
Justification for type of information:
Well documented. Short comings are: small animal number, no definite data on
actual intake of L-Cysteine hydrochloride monohydrate, no purity and no impurities given for the test substance and in results only means given; no min/max no standard deviation given (thus, results are not presented in very detail).
It is important to mention that the substance was applied within the bread baking procedure and heated up to 227°C for 1/2 hour. This may have influenced the stability of the test substance especially as there are comments declaring a decomposition temperature of 175-177.8 °C for L-Cysteine hydrochloride. Nevertheless the documentation is complete enough, so that the influence of the baking process could be evaluated by an additional test if needed.
All in all the study can be jugded as a screening test for the evaluation of the deveolppmental toxicity.
Cross-reference
Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
multi-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
before 1970
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see justification
Justification for type of information:
Well documented study. Short comings are: small animal number, no definite data on actual intake of L-Cysteine hydrochloride monohydrate, no purity and no impurities given for the test substance.
In results: only means given; no min/max no standard deviation given (thus, results are not presented in very detail).
It is important to mention that the substance was applied within the bread baking procedure and
heated up to 227°C for 1/2 hour. This may have influenced the stability of the test substance especially as there are comments declaring a decomposition temperature of 175-177.8 °C for L-Cysteine hydrochloride. Nevertheless the documentation is complete enough, so that the influence of the baking process could be evaluated by an additional test if needed.
Therefore the study can be jugded as a valid screening test for the evaluation of toxic effects on fertility
Principles of method if other than guideline:
L-Cysteine hydrochloride monohydrate was added to flour at levels of 0, 35, 350 and 3500 ppm.
Bread was baked from this flour, dried and milled to a powder, which was added to the rats diet.
Starting with 4 pregnant rats in the control and the highest dosage group the mothers and all pups were slaughtered except for 2 male and 3 female pups selected at random from each litter, which were retained for breeding.
This procedure was continued in the second and third generations, but at the weaning of the fourth generation only 24 males and 48 females were retained for breeding, i.e. 12 males and 24 females on each diet. The same procedure as before was adopted for the sixth generation, using all four dosages, and during the breeding of the seventh generation the experiment was terminated.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: C.D. Norwegian Hooded of an inbred Middle Aston strain
Sex:
female
Details on test animals or test system and environmental conditions:
Starting with pregnant C.D. Norwegian Hooded rats of an inbred Middle Aston strain.
Route of administration:
oral: feed
Details on exposure:
The substance was added to flour in concentrations of 0, 35, 350 and 3500 ppm. With this flour bread was baked. After the baking the bred was sliced, freeze-dried, crushed and milled. This powder was mixed to a diet. The diets contained about 77% of bread crumbs on dry weight
No feed intake is reported. An animal weight of 100 g and a feed intake of 10 g diet per animal and day is used for estimation of the doses. 77% of milled bread was added to the diet. This resulted in an estimated daily intake of L-Cysteine of 0, 2.7, 27 and 270 mg/kg bw..
Details on mating procedure:
For the first generation pregnant rats were used. No data on mating procedure available. 11 weeks after birth the next generation females were mated with males from the same litter. During the breeding of the seventh generation the experiment was terminated.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
6 generations
Frequency of treatment:
daily
Details on study schedule:
L-Cysteine hydrochloride monohydrate was added to flour in concentrations of 0, 35, 350 and 3500 ppm. With this flour bread was baked. After the baking a powder was produced and mixed to a diet.
The test article intake is estimated: An animal weight of 100 g and a daily feed intake of 10 g diet per animal and day is presumed. 77% of milled bread was added to this diet. This resulted in an estimated daily intake of L-Cysteine hydrochoride monohydrate of 0, 2.7, 27 and 270 mg/kg bw..
For the first generation pregnant rats were used. Starting with 4 pregnant rats in the control and the highest dosage group the mothers and all pups were slaughtered after weaning except for 2 male and 3 female pups selected at random from each litter, which were retained for breeding.
11 weeks after birth the next generation females were mated with males from the same litter.
This procedure was continued in the second and third generations, but at the weaning of the fourth generation only 24 males and 48 females were retained for breeding, i.e. 12 males and 24 females on each diet. The same prodceure as before was adopted for the sixth generation, using all 4 dosages, and during the breeding of the seventh generation the experiment was terminated.
Dose / conc.:
3 500 ppm
Remarks:
flour weight
Dose / conc.:
350 ppm
Remarks:
flour weight
Dose / conc.:
35 ppm
Remarks:
flour weight
Dose / conc.:
0 ppm
Remarks:
flour weight
No. of animals per sex per dose:
4
Control animals:
yes
Details on study design:
Estimation of the actual intake of L-Cysteine hydrochloride monohydrate:
feed intake: animal weight: 100g, 10 g diet per animal and day. 77% of milled bread was added to the
diet. This resulted in an estimated daily intake of L-Cysteine of 0, 0.27, 2.7 and 27 mg per animal.
Positive control:
no
Parental animals: Observations and examinations:
examinations for gross lesions
Postmortem examinations (offspring):
examinations for gross lesions
Reproductive indices:
Number born, litter weight at birth, numbers weaned and litter weight at weaning, carcass, liver and kidney weights of all slaughtered aninmals, post mortem examination for gross lesions.
In the 0 and 3500 ppm groups the principal characteristics of the response to the treatment were
measured: 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.
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):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed
Reproductive performance:
no effects observed
Breeding rats of the fifth generation at about 150 days of age and receiving the diet with the highest Lcysteine hydrochloride monohydrate treatment (3500 ppm) were examined histopathologically. They showed no lesions atypical in normal rats of that age
Dose descriptor:
NOAEL
Effect level:
> 270 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
reproductive performance
Critical effects observed:
no
Reproductive performance:
no effects observed
Dose descriptor:
NOAEL
Effect level:
> 270 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
reproductive performance
Critical effects observed:
no
Clinical signs:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Remarks on result:
not determinable due to absence of adverse toxic effects
Critical effects observed:
no
Reproductive effects observed:
not specified

As results only means given; no min/max no standard deviation given.
No treatment related effects were observed (authors: "no obvious adverse effect").

Conclusions:
L-Cysteine hydrochloride monohydrate was added to flour. With this flour bread was baked and from this bread a powder was produced and mixed to the diet. A daily intake of 0, 2.7, 27 and 270 mg/kg bw. was estimated..
Starting with 4 pregnant rats in the control and the highest dosage group a study over 7 generations was conducted.
Although quite well documented the study has short comings as there are: small animal number, no definite data on actual intake of L-cysteine hydrochloride monohydrate, no purity and no impurities given for the test substance and in results: only means, no min/max no standard deviation are given.
Nevertheless the study can be jugded as a valid screening test for the evaluation of the reproduction toxicity.
Up to and including dosages of 270 mg/kg bw. no adverse effects on fertility occurred in the rats
during the experiment even at the high level of L-cysteine hydrochloride monohydrate treatment.
Executive summary:

L-Cysteine hydrochloride monohydrate was added to flour in concentrations of 0, 35, 350 and 3500 ppm. With this flour bread was baked. After the baking the bred was sliced, freeze-dried, crushed and milled. This powder was mixed to a diet. The diets contained about 77% of bread crumbs on dry weight.
Estimation of doses: An animal weight of 100 g and a daily feed intake of 10 g diet per animal and day is estimated. 77% of milled bread was added to this diet. This resulted in an estimated daily intake of L-cysteine hydrochloride monohydrate of 0, 2.7, 27 and 270 mg/kg bw..
For the first generation pregnant rats were used.
Starting with 4 pregnant rats in the control and the highest dosage group the mothers and all pups were slaughtered after weaning except for 2 male and 3 female pups selected at random from each litter, which were retained for breeding.
11 weeks after birth the next generation females were mated with males from the same litter.
This procedure was continued in the second and third generations, but at the weaning of the fourth generation 24 males and 48 females were retained for breeding, i.e. 12 males and 24 females on each diet. The same prodceure as before was adopted for the sixth generation, using all 4 dosages, and during the breeding of the seventh generation the experiment was terminated.
Recorded are number born, litter weight at birth, numbers weaned and litter weight at weaning, carcass, liver and kidney weights of all slaughtered aninmals, post mortem examination for gross lesions. In the 0 and 3500 ppm groups the principal characteristics of the response to the treatment were measured:
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.
Breeding rats of the fifth generation at about 150 days of age and receiving the diet with the highest L-cysteine hydrochloride monohydrate treatment (3500 ppm) were examined histopathologically. They showed no lesions atypical in normal rats of that age.
No adverse effects on fertility occurred in the rats during the experiment even at the high level of Lcysteine hydrochloride monohydrate treatment.


It is important to mention that the substance was applied within the bread baking procedure and heated
up to 227°C for 1/2 hour. This may have influenced the stability of the test substance especially as there
are comments declaring a decomposition temperature of 175-177.8 °C for l-cysteine hydrochloride.
Nevertheless the documentation is complete enough, so that the influence of the baking process could be evaluated by an additional test if needed.

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion

Conclusions:
L-Cysteine hydrochloride monohydrate was added to flour from which bread was baked, milled to a powder. This powder was added to the diet.
A daily intake of 0, 2.7, 27 and 270 mg/kg bw. can be estimated.
Starting with 4 pregnant rats in the control and the highest dosage group the study was conduced
over 7 generations.
Especially the data on litter weight at weaning and the post mortem examination for gross lesions of both adults and weanling rats reveal and the histopathologic examination of the fifth generation can reveal devolopmental toxicity.
No developmental toxicity was observed.