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Description of key information

L-Cystine has been tested in a 93-day study in rats. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

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Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions: article in Japanese has been translated into English
Principles of method if other than guideline:
L-Cystine was tested in a 93-day prolonged oral toxicity test.
Doses of 3000, 600, 300 and 100 mg/kg bw were administered via feeding tube.
The control group was given the vehicle.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 5 weeks
- Weight at study initiation: males 137 +/- 0.7 g, females 125 +/- 0.5 g
- Diet: CA-1 powder
- Water: ad libitum
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 55 +/- 5
Route of administration:
oral: gavage
Vehicle:
other: 5% gum arabic aqueous solution
Details on oral exposure:
Cystine was suspended in 5% gum arabic aqueous solution, which was administered orally once per day for 93 days using a feeding tube in dose of
1 mg/100g of bw.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
The doses were 3000, 600, 300 and 100 mg/kg bw .
Control: same quantity of 5% gum arabic aqueous solution
Duration of treatment / exposure:
93 days
Frequency of treatment:
once per day
No. of animals per sex per dose:
10/sex/dose
Control animals:
yes
Details on study design:
Cystine was suspended in 5% gum arabic aqueous solution, which was administered orally once per day for 93 days using a feeding tube in dose of
1 mg/100g of bw. General symptoms were noted, hematological tests, blood biochemical tests, urine tests and histopathological test were performed.
Positive control:
no
Observations and examinations performed and frequency:
general symptoms (daily), body weight (3 times a week) and food intake quantity (once per week).
Sacrifice and pathology:
by decapitation
Other examinations:
hematological tests (after 93 days)
blood biochemical tests (after 93 days)
urine tests (before decapitation)
histopathological tests (after sacrifice)
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
6 animals (3/sex) in highest dose group
Mortality:
mortality observed, treatment-related
Description (incidence):
6 animals (3/sex) in highest dose group
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
suppressed increase in the highest dose group
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
suppression in the highest dose group
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
no change
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
GOT, GPT, ALP in highest dose group
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
no changes
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
lung, kidney, spleen, pituitary gland
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
no changes
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
liver
Details on results:
General symptoms: no notable change in symptoms were found in the 600 mg/kg and lower group. In the 3000 mg/kg group, there was a decrease
in spontaneous exercise starting on the 5th day, some animals were seen hunched or crouching, and some animals died. The deaths were one each
at 32, 55 and 62 days among the males, a total of 3, and one each at 38, 48 and 62 days among the females, a total of three. The death occured after the animals exhibited a loss of body weight for 1-2 days.
The results of the autopsies showed mild overall swelling of the liver. Bleeding and congestion in the jejunum, ileum and cecum were also found.
Body weight: no particular change was found at 600 mg/kg but suppressed body weight increase was observed in the 3000 mg/kg group starting
around the 10th day for the males and the fifth day for females.
Food and water intake: suppression of food intake was seen from the start throughout the administration period in the 3000 mg/kg female group.
The intake decreased from the start of administration for approximately 6 weeks in the males but normal intake was indicated subsequent to that.
No particular change was found in the water intake.
Hematological tests:
The platelet count decreased in female 3000 mg/kg and 600 mg/kg groups. Decrease in hemoglobin quantity was seen in female 3000 mg/kg group.
The GOT and GPT increased in the female 3000 mg/kg group and the ALP increased in the male and female 3000 mg/kg groups. The glucose
decreased in the male and female 3000 mg/kg groups. The urea nitrogen decreased in the female 600 mg/kg and higher groups. The total
cholesterol increased in the male and female 3000 mg/kg groups. A decrease was seen in the A/G ratio in the female 3000 mg/kg group. The sodium increased in the female 300 mg/kg and higher groups and the calcium increased in the female 3000 mg/kg group.
Urinary tests: no particular changes were found in the protein, pH, glucose, ketone bodies, occult blood reaction, urobilinogen, bilirubin,
or urine output.
Autopsy: no particular macroscopic abnormalities were observed. Congestion was seen in the liver in 2/10 specimens in the female 600 mg/kg
group and 6/7 and 2/7 in the male and female 3000 mg/kg groups, respectively. The spleen had mild tumefaction in nearly all of the animals in the 3000 mg/kg groups, exhibiting a dark red color. Dark red color showed strongly in the kidneys in 2/7 of the males and 4/7 of the females in the
3000 mg/kg groups. An increase was seen in the relative weight of the lungs in the female 300 mg/kg and higher groups. The relative weight of the
kidneys increased in the female 3000 mg/kg group. The relative weight of the liver increased in the male 3000 mg/kg group, though an increase was seen in the absolute weight and relative weight in the female 3000 mg/kg group. The absolute weight and relative weight of the spleen increased in
the male 600 mg/kg and higher groups and in the male 3000 mg/kg group. A decrease was seen in the absolute weight of the pituitary gland in the
female 3000 mg/kg group. These effects were also seen in the control groups and thought to be non-specific reactions due to decapitation.
Histopathological findings: Fibrosis in the Glisson`s sheath periphery was found in three specimens each in the male and female 3000 mg/kg group.
In the histological findings of the animals that died during the experiment due to cystine administration, congestion in the cortex and medulla of the lungs and kidneys was seen in nearly all of the animals. Fibrosis in Glisson`s sheath periphery was seen in the liver and cell vacuolation and focal eosinophileic necrosis in the congested periphery were found as well. Congestion and hemosiderin deposition were observed in the spleen.
Dose descriptor:
NOAEL
Effect level:
ca. 600 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Critical effects observed:
not specified
Conclusions:
The maximum safe doses in rats for 93 day prolonged administration of cystine was 600 mg/kg.
Executive summary:

In the cystine 3000 mg/kg groups, a reduction in food intake and a suppression in body weight increase were seen, and three males and three females died. A decrease in the hemoglobin quantity was seen in the 3000 mg/kg groups. The platelet count decreased, slightly in the female 300 and 600 mg/kg groups, but since no relation to the dosage ws particularly seen, this is not thought to be due to the cystine. No change was found in the cystine 600 mg/kg and lower groups. An increase in GOT, GPT, ALP, and total cholesterol as well as a decrease in the glucose were found in the 3000 mg/kg groups with cystine administration, and these are conjectured to results from a disorder in the liver. While changes in the weight were found in the lungs, kidneys, spleen, pituitary gland in the cystine groups, no histopathological abnormalities whatsowever were found to correspond to any of the weight fluctuations. In general, histopathological findings are said to show that excessive administration of cystine results in a disruption of the cellular metabolic equilibrium, vacuolation and lipidization of the hepatic cells, lipidization and atrophy and vacuolation of the kidneys. In the experiment the weight of the liver increased in the cystine 3000 mg/kg groups and fibrosis of the Glisson`s sheath periphery was found in more than half of the animals, and vacuolation of the congested portion and an eosinophilic necrotic focus were observed in the animals that died during the experiment. These findings are consistent with the blood tests and autopsies.

The maximum safe doses in rats for 93 day prolonged administration of cystine was 600 mg/kg for male and female rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
600 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

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Reference
Endpoint:
repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

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Reference
Endpoint:
repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

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Reference
Endpoint:
repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

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Reference
Endpoint:
repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

A 93-day repeated oral study in rats resulted in a NOAEL of 600 mg/kg bw.

In the cystine 3000 mg/kg groups, a reduction in food intake and a suppression in body weight increase were seen, and three males and three females died. A decrease in the hemoglobin quantity was seen in the 3000 mg/kg groups. The platelet count decreased, slightly in the female 300 and 600 mg/kg groups, but since no relation to the dosage ws particularly seen, this is not thought to be due to the cystine. No change was found in the cystine 600 mg/kg and lower groups. An increase in GOT, GPT, ALP, and total cholesterol as well as a decrease in the glucose were found in the 3000 mg/kg groups with cystine administration, and these are conjectured to results from a disorder in the liver. While changes in the weight were found in the lungs, kidneys, spleen, pituitary gland in the cystine groups, no histopathological abnormalities whatsowever were found to correspond to any of the weight fluctuations. In general, histopathological findings are said to show that excessive administration of cystine results in a disruption of the cellular metabolic equilibrium, vacuolation and lipidization of the hepatic cells, lipidization and atrophy and vacuolation of the kidneys. In the experiment the weight of the liver increased in the cystine 3000 mg/kg groups and fibrosis of the Glisson`s sheath periphery was found in more than half of the animals, and vacuolation of the congested portion and an eosinophilic necrotic focus were observed in the animals that died during the experiment. These findings are consistent with the blood tests and autopsies.The maximum safe doses in rats for 93 day prolonged administration of cystine was 600 mg/kg for male and female rats.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Comparable to guideline study with acceptable restrictions: article in Japanese has been translated into English.

Justification for classification or non-classification

L-Cystine does not need to be classified.