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Toxicological information

Carcinogenicity

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Description of key information

The effects found in the study are not relevant as different depletion diets are examined. A 14 to 17 months cystine depletion diet in mice results      even in high protein diets in pathologic calcification, primarily in the lungs but also in the aorta and arteries of other organs sectioned. 
The effect of a L-Cystine overdose is not examined and not not discussed.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
disregarded due to major methodological deficiencies
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Unsuitable test system
Principles of method if other than guideline:
Mice were fed different deficiency diets over 14 and 17 months and several organs were subject to histologic studies.
Pathologic calcification as well as a decrease in nephritis and amyloidosis were observed. The incidence of spontaneous pulmonary
tumors was determined, tumors were sectioned.
GLP compliance:
not specified
Species:
mouse
Strain:
other: strain A
Sex:
male/female
Details on test animals and environmental conditions:
Strain A mice, 4-6 weeks old until 14 and 17 months of age.
Four groups: one control and three dose groups.
Route of administration:
oral: feed
Details on exposure:
1. Control group: control Purina dog chow diet (129 mice)
2. high cystine - low protein diet ad libitum (60 mice)
3. high cystine - low protein diet, restricted to the average food consumption of group 4 (95 mice)
4. low cystine - low protein diet (61 mice)

Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
14 and 17 months
Frequency of treatment:
Depletion diet ad libitum or restricted diet (group 3).
Post exposure period:
The mice were killed at 14 to 17 months.
Animals that were found dead before were eliminated from the results.
No. of animals per sex per dose:
345 animals in one control and four dose groups
Control animals:
yes
Details on study design:
At necropsy: observations on the gross organs, histologic sections of lung, heart, aorta, kidneys, testes, ovaries and uterus.
Pulmonary tumors were sectioned, if found.
Positive control:
None
Observations and examinations performed and frequency:
At necropsy: observations on the gross organs, histologic sections of lung, heart, aorta, kidneys, testes, ovaries and uterus.
Pulmonary tumors were sectioned, if found.
Sacrifice and pathology:
All surviving mice were killed after 14 or 17 months.
Statistics:
no data
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
mortality was monitored
Mortality:
mortality observed, treatment-related
Description (incidence):
mortality was monitored
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Clinical biochemistry findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
see study design
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
see study design
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
lung tumors, if found
Relevance of carcinogenic effects / potential:
The effects found in the study are not relevant as different depletion diets are examined. A 14 to 17 months Cystine depletion diet in mice results - even in high protein diets - in pathologic calcification, primarily in the lungs but also in the aorta and arteries of other organs sectioned. Strain A mice develop nephritis in practically 100% of the animals after 12 months of age or older. The deficiency diet seems to inhibit nephritis.
The effect of a L-Cystine overdose is not examined and not not discussed.
The study therefore cannot be used to discuss the carcinogenic potential of high doses of L-Cystine.
Conclusions:
Extensive pathologic calcification was observed in strain A mice 14 and 17 months of age that had been fed a low cystine-low protein diet.
The deficient diets exerted an inhibitory effect on the development of the type of nephritis that commonly occurs in strain A mice.
Throughout the carious groups there was a correlation between the appearance of nephritis and of amyloidosis.
Executive summary:

Extensive pathologic calcification was observed in strain A mice14 and 17 months of age that had been fed a low cystine-low protein diet. The highest degree of calcification occurred in the lungs of certain animals, but it was also observed in the aorta and arteries of the other organs sectioned, including the heart, kidneys, and gonad. With the exception of the testes, the lesion was infrequent and irregular in the organs of strain A mice of the same age, fed the high cystine-low protein diet ad libitum, high cystine-low protein diet restricted, and Purina dog chow. In the arteries of the testes it occurred in males fed all these diets but was more frequent in those fed the high-cystine diets than in those fed dog-chow. The deficient diets exerted an inhibitory effect on the development of the type of nephritis that commonly occurs in strain A mice. Practically all the mice fed Purina dog chow had nephritis, but the incidence was less in those fed the high cystine-low protein diet ad libitum, still less in those fed the high cystine-low protein diet restricted, and least in the animals fed the low cystine-low protein diet. Throughout the carious groups there was a correlation between the appearance of nephritis and of amyloidosis.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
mouse

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Extensive pathologic calcification was observed in strain A mice 14 and 17 months of age that had been fed a low cystine-low protein diet for 14 and 17 months. The deficient diets exerted an inhibitory effect on the development of the type of nephritis that commonly occurs in strain A mice. Throughout the carious groups there was a correlation between the appearance of nephritis and of amyloidosis.


Justification for selection of carcinogenicity via oral route endpoint:
After an extended literature search the only study available is from 1945 and has to be rated as Klimisch 3 due to the unsuitable test system.
As cystine-depletion was examined instead of a cystine overdose, the adverse effects observed in the study don`t need to be considered.

Justification for classification or non-classification

For L-Cystine no experimental study on cancerogenocity is available. There is no indication from the existing studies on CMR- toxicity that L-Cystine has toxicity referring to CMR endpoints. L-Cystine is a natural occurring amino acid present in all living cells. L-Cystine (and L-Cysteine, respectively) is an amino acid that is required for normal functioning of humans. There is sufficient weight of evidence for the absence of reprotoxic effects. There is no indication that the substance is able to induce hyperplasia or pre-neoplastic lesions in subchronic studies. Extensive genotoxicity testing does not raise any concerns for further studies. Additionally L-Cystine (and L-Cysteine respectively) are natural amino acids. It can be stated that amino acids are generally quickly absorbed and utilised in the mammal metabolism and that the amounts used in studies are generally far below the daily intake of an adult European individual (EFSA): as discussed in section 5.1.3. the intake of 2.2 g L-Cysteine which corresponds to approximately 1.1 g L-Cystine is a realistic value for daily intake. The same is for L-Cysteine. Both substances are linked by metabolic pathways and via chemical oxidation. A significant amount of L-Cystine (and L-Cysteine, respectively) is usually taken up via the food.

In usual diet, most amino acids are supplied as constituents of protein and not as free amino acid. Protein intake clearly modifies plasma amino acid levels. However, amino acid concentrations are subject to homeostasis and the plasma concentrations vary within fixed limits and are tightly regulated. Exposure with L-Cystine (and L-Cysteine, respectively) from uses which are covered by this registration would only marginally increase the total daily L-cystine dose (and L-Cysteine dose, respectively) which is taken up via the food. Even if the plasma amino acid concentration would increase/vary by any use such fluctuations are physiological and subject to homeostasis. Therefore it is highly unlikely that L-Cystine (and L-Cysteine, respectively) taken up via any use covered by this registration would result in systemic effects. A repeated dose toxicity studies consistently indicated the very low toxicity of L-Cystine (and L-Cysteine, respectively). Even in very high doses no toxicity is observed and no adverse effects were reported for the reproductive organs. Moreover, L-Cystine (and L-Cysteine, respectively) is an amino acid that is required for normal functioning of humans. The substance is of low toxicological activity. Therefore, reprotoxic effects are not expected for L-Cystine (and L-Cysteine, respectively) and no test is required for this substance. There is sufficient weight of evidence for the absence of reprotoxic effects. Therefore, in accordance with Annex X 8.9.1 column 2 and because of reasons of animal welfare, a study on carcinogenicity is not deemed necessary.