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EC number: 204-886-1 | CAS number: 128-44-9
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Carcinogenicity
Administrative data
Description of key information
Key study. Carcinogenicity study (24 years) in monkeys (non-GLP). The test item at a dose of 25 mg/kg bw/d did not produce any adverse effect administered in the diet of three species of monkeys beginning at birth and continuing for nearly the entire lifetime of the animals. Therefore, the test item is deemed non-carcinogenic.
Key value for chemical safety assessment
Carcinogenicity: via oral route
Link to relevant study records
- Endpoint:
- carcinogenicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1970-1995
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Qualifier:
- no guideline followed
- GLP compliance:
- not specified
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Fisher Scientific Company. - Species:
- monkey
- Strain:
- other: Macaca fascicularis (cynomolgus), Macaca mulatta (rhesus), and Cercopithecus aethiops (African green).
- Details on species / strain selection:
- Monkeys were selected at the time of inception of this study in 1970 from those available in a monkey colony consisting of three species. A total of 20 monkeys were treated. They included 6 African green, 7 rhesus, 6 cynomolgus, and 1 hybrid rhesus male × cynomolgus female monkey.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 24h
- Diet: The animals were given a diet consisting of high-protein Purina monkey chow (5045 Standard), with a vitamin spread on sandwiches and apples.
- Water: ad libitum.
ENVIRONMENTAL CONDITIONS
The monkeys were cared for according to the standards established by the Association for Assessment and Accreditation for Laboratory Animal Care (AAALAC). The experimental protocols used were approved by the Animal Sciences Branch of the National Cancer Institute and reviewed on an annual basis. - Route of administration:
- oral: feed
- Details on exposure:
- DIET PREPARATION
- For newborn monkeys, sodium saccharin was added to the Similac formula at the time of feeding.
- When the monkeys were 6 months old, the compound was incorporated into a vitamin mixture that was given to the monkeys as a vitamin sandwich on a slice of bread. The mixture consisted of powdered dry milk (5 pounds), Parvo (a folic acid supplement, 4 ounces, 20% with starch; Roche Agricultural Products), Cecon (a vitamin C supplement, 300 mL; Abbott Laboratories, Chicago, IL), molasses (2 L), and water (500 mL). The vitamin mixture was spread onto bread (1 teaspoon per slice of bread), after which the dose of sodium saccharin was added on top of the spread and the bread was folded in half to form a sandwich and then fed to the animal. - Analytical verification of doses or concentrations:
- no
- Remarks:
- not required.
- Duration of treatment / exposure:
- 24 years: test item administration was initiated within 24 hours after birth and was continued until the animals died or were euthanized at the end of the study.
- Frequency of treatment:
- 5 days a week
- Dose / conc.:
- 25 mg/kg bw/day (nominal)
- Control animals:
- yes, concurrent no treatment
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Use of 10 times the allowable daily intake was the standard choice of dose for the National Cancer Institute’s nonhuman primate carcinogenicity testing program at the time of inception of this study.
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: The individual monkeys underwent complete physical examinations by a veterinarian every 6 months.
BODY WEIGHT: Yes / No / No data
- Time schedule for examinations:
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data
OPHTHALMOSCOPIC EXAMINATION: No / No data
HAEMATOLOGY / CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: the following routine blood examinations were performed at intervals of 3–6 months: hematocrit, hemoglobin, white blood cell count, platelet count, and other clinical parameters (i.e., alkaline phosphatase, total bilirubin, serum glutamic pyruvic transaminase, and serum glutamic oxalacetic transaminase).
- Anaesthetic used for blood collection: Yes (identity) / No / No data
- Animals fasted: Yes / No / No data
- How many animals: 20
URINALYSIS: Yes
- Time schedule for collection of urine: One to 2 years before the animals were euthanized, urine samples were collected from two male and two female monkeys that had been treated with sodium saccharin and from two male and two female controls of the cynomolgus and the rhesus species. Collection was from 8 AM to 10 AM.
- Animals fasted: Yes
- Parameters: Urinary pH was determined by use of the Beckman combination electrode (Beckman Instruments, Inc., Fullerton, CA), and urine chemistries were determined on an Ektachem 700 Chemistry Analyzer (Eastman Kodak Co., Rochester, NY), except for chloride determinations, which were measured on an Astra 4 Automated Analyzer (Beckman Instruments, Inc.), and protein determinations, which were measured by use of
the Bradford protein assay (BioRad Laboratories, Richmond, CA). The urine samples were examined for solid material by means of scanning electron microscopy. A sample of fresh-voided control urine was also collected and examined by for the potential of sodium saccharin to associate (coelute) with urinary macromolecules. Urinary filters were examined by means of scanning electron microscopy (Phillips 515 Scanning Electron Microscope; Phillips, Inc., Eindhoven, The Netherlands) with attached energy dispersive spectroscopy (Kevex Micro-X 7000 Analytical Spectrometer with Quant-X Program; Kevex, Inc., Hayward, CA).
NEUROBEHAVIOURAL EXAMINATION: No / No data - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
- Monkeys that died or were euthanized were carefully necropsied. Animals remaining for the terminal euthanasia were put under deep anesthesia.
HISTOPATHOLOGY: Yes
- The following tissues and organs were fixed in buffered formalin: brain, pituitary, salivary gland, thyroid, tongue, cheek pouches, trachea, esophagus, lungs, heart, aorta, liver, gallbladder, spleen, kidneys, adrenals, stomach, pancreas, duodenum, jejunum, ileum, large intestine, lymph nodes, urinary bladder, testis, prostate, seminal vesicles (or ovaries and uterus), breast, skin, and bone marrow, as well as any grossly apparent tumor tissue. Tissue sections were routinely processed for paraffin embedding and stained with hematoxylin–eosin. - Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No serum, hematologic, or chemical abnormalities were detected in these animals during their lifetime.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No serum, hematologic, or chemical abnormalities were detected in these animals during their lifetime.
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- Measurement of urine chemistries showed no differences between treated monkeys and controls.
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - Group 1: The most frequent histopathologic findings at necropsy of these monkeys involved the respiratory system. Five of these monkeys were found at necropsy to have lung infection, edema, congestion, or atelectasis. In one monkey, acute bronchial aspiration and pneumonia were present. In two monkeys, there was myocardial fibrosis associated with myocardial fatty degeneration. One monkey had chronic ulcers of the stomach and esophagus, and another monkey had histologically observed chronic ileitis. None of these monkeys had abnormalities of the urothelium, including the renal pelvis, ureters, urinary bladder, or urethra.
- Group 2: three of the 12 monkeys had myocardial fibrosis and three had myocardial fatty degeneration. In seven of these 12 monkeys, fatty degeneration of the liver was noted, and one animal had a liver cyst. Light microscopy showed no evidence in any of these monkeys of urothelial changes, i.e., in the renal pelvis, the ureters, the urinary bladder, or the urethra. No abnormalities were seen in the urinary bladders of the 12 treated monkeys and the six control monkeys examined by scanning electron microscopy following glutaraldehyde fixation. - Histopathological findings: neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - Group 2: Histologic examination revealed a thyroid lymphoma in the first monkey, leiomyoma of the uterus in the second monkey, and a papillary
cystadenoma of the ovary and leiomyoma of the stomach in the third monkey. The lesions observed in age-matched control monkeys showed myocardial
and hepatocellular changes similar to those observed in the treated animals, but no definite tumors were seen. It should be noted that the three types of tumors found in the saccharin-treated monkeys have also been observed in breeders and normal controls in this monkey colony - Other effects:
- no effects observed
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Critical effects observed:
- no
- Conclusions:
- The results from this long-term study clearly show that there is no adverse effect of sodium saccharin administered in the diet of three species of monkeys beginning at birth and continuing for nearly the entire lifetime of the animals. Therefore, the test item is deemed non-carcinogenic.
- Executive summary:
A carcinogenicity study of the test item in monkeys was performed following the National Cancer Institute’s nonhuman primate carcinogenicity testing program guides. Twenty monkeys underwent long-term treatment with sodium saccharin from 24h after birth and until the animals died or were euthanized at the end of the study (24 years). For group 1, total doses of test item consumed by these monkeys averaged 403.0 g and ranged from 229.9 to 721.0 g; for group 2, the total dose consumed averaged 718.9 g and ranged from 455.4 to 1136.2 g. The results from this long-term study clearly show that there is no adverse effect of sodium saccharin administered in the diet of three species of monkeys beginning at birth and continuing for nearly the entire lifetime of the animals. Therefore, the test item is deemed non-carcinogenic.
Reference
Table 1. Tumors and other lesions in monkeys treated with sodium saccharin
Animal No. |
Species* |
Age at Month Sex† first dose dosed Total dose, g Major autopsy findings |
|||||
|
|
Group 1: monkeys that died during the course of the experiment from non-neoplastic diseases |
|||||
827K |
Rh |
M |
2 days |
103 |
267.8 |
Bronchial aspiration |
|
1206S |
Cy |
F |
2 days |
128 |
229.9 |
Bronchopneumonia; ulcer of the esophagus and stomach |
|
1204S |
Rh |
M |
1 week |
157 |
457.5 |
Congestion of the lung, spleen, and kidney; edema of the lung |
|
826K |
Gr |
F |
2 days |
168 |
299.7 |
Septic hepatitis |
|
821J |
Gr |
F |
Birth |
170 |
307.7 |
Septic hepatitis |
|
1214S‡ |
Gr |
M |
Birth |
192 |
467.1 |
Myocardial degeneration; atelectasis of the lung; congestion of the liver, lung, spleen, and kidney; hypoplastic bone marrow; atrophy of the thyroid; cholelithiasis |
|
1207S |
Rh |
M |
Birth |
214 |
721.0 |
Myocardial fibrosis; congestion of the liver and lung; renal tubular necrosis; kyphosis |
|
828K‡ |
Gr |
F |
1 day Group 2: monke |
282 ys euthanized a |
473.6 fter >207 mont |
Chronic ileitis hs in the experiment |
|
1213S |
Cy |
F |
Birth |
207 |
318.7 |
Fatty infiltration of the liver; colloid cyst of the thyroid; endometriosis; chronic ulcer of the rectum; hydronephrosis of the kidney |
|
1215S‡ |
Cy |
M |
1 day |
213 |
803.0 |
Myocardial fatty infiltration; fatty infiltration of the liver; atrophy of the testis |
|
1205S‡ |
Hybrid |
F |
3 days |
214 |
598.9 |
Fatty degeneration of the liver; myocardial fibrosis and fatty degeneration |
|
1209S‡ |
Rh |
F |
1 day |
214 |
633.1 |
Ductal hyperplasia of the pancreas |
|
1211S‡ |
Cy |
M |
1 day |
214 |
658.3 |
Myocardial fibrosis and fatty degeneration; fatty infiltration of the liver; hyalinization of the pancreatic islet cells; atrophy of the testis |
|
1212S‡ |
Cy |
F |
1 day |
214 |
461.2 |
Myocardial fatty degeneration; fatty infiltration of the liver; hyalinization of the pancreatic islet cells |
|
829K‡ |
Gr |
F |
Birth |
281 |
515.6 |
Leiomyoma of the uterus; diverticulosis of the colon |
|
820J‡ |
Rh |
F |
Birth |
282 |
1021.5 |
Congestion and fatty degeneration of the liver; ovarian cyst |
|
823J‡ |
Rh |
M |
Birth |
282 |
1136.2 |
Fatty degeneration of the liver; colloid cyst of the thyroid |
|
824K‡ |
Rh |
M |
Birth |
282 |
1054.3 |
Lymphoma of thyroid; cyst of the pituitary gland |
|
825K‡ |
Gr |
F |
10 days |
282 |
455.4 |
Papillary cystadenoma of the ovary; leiomyoma of the stomach |
|
818J |
Cy |
M |
1 day |
283 |
970.1 |
Myocardial fibrosis; liver cyst |
|
*Rh 4 rhesus (Macaca mulatta); Cy 4 cynomolgus (Macaca fascicularis); Gr 4 African green (Cercopithecus aethiops).
†M 4 male; F 4 female.
‡Bladder observed by scanning electron microscopy.
Table 2. Major autopsy findings in control monkeys
Animal No. |
Species* |
Sex† |
Euthanized or died‡ |
Observation, mo |
Major histologic findings |
1234T§ |
Cy |
F |
E |
206 |
Myocardial degeneration; hyalinization of the pancreatic islet cells |
1188S§ |
Cy |
M |
E |
217 |
Atrophy, testis |
1156R§ |
Rh |
F |
E |
224 |
|
947M |
Rh |
M |
E |
234 |
|
944M |
Rh |
M |
E |
237 |
Fatty infiltration of the liver; hemorrhage and edema of the lung; inguinal hernia |
987M |
Cy |
F |
E |
240 |
Hypertrophy of the left kidney; absence of the right kidney; endometriosis; oil injury of the right eye |
1017N |
Cy |
M |
E |
244 |
Fibrosis, papillary muscle, left ventricle |
1041N§ |
Cy |
M |
E |
248 |
Atrophy of the testis; fatty infiltration of the liver; hyalinization of the pancreatic islet cells; cystic dilation of the prostate glands |
989M§ |
Rh |
M |
E |
257 |
Nodular cortical hyperplasia of the left adrenal |
6971 |
Rh |
M |
E |
261 |
Diverticulitis; emphysema and interstitial fibrosis of the lung |
899L |
Cy |
M |
E |
268 |
Chronic bronchitis |
901L§ |
Cy |
F |
E |
277 |
Proliferation, follicular epithelial cell of the thyroid |
778J |
Rh |
M |
D |
284 |
|
780J |
Cy |
M |
D |
285 |
Myocardial fibrosis; hyalinization of the pancreatic islet cells |
779J |
Rh |
F |
E |
299 |
Fatty infiltration, clear cell foci of the liver; chronic gastritis; cholecystitis; adenomyosis of the uterus |
678H |
Cy |
F |
E |
301 |
Fatty infiltration of the liver; hyalinization of the pancreatic islet cells; endometriosis; splenomegaly; hydronephrosis of the right kidney |
*Rh 4 rhesus (Macaca mulatta); Cy 4 cynomolgus (Macaca fascicularis); Gr 4 African green (Cercopithecus aethiops).
†M 4 male; F 4 female.
‡E 4 euthanized; D 4 died.
§Urinary bladder examined by scanning electron microscopy.
Table 3. Urinary chemistries from monkeys ø2 years before being euthanized*
|
*Values are listed for individual monkeys (value from one monkey; value from second monkey).
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
Carcinogenicity: via inhalation route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Carcinogenicity: via dermal route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
Based on the available information, the test item is not classified for carcinogenic properties.
The carcinogenicity of sodium saccharin was evaluated by International Agency for Research on Cancer (IARC) - Summaries & Evaluations, vol: 73 (1999). It is concluded :
In making its evaluation, the Working Group concluded that sodium saccharin produces urothelial bladder tumours in rats by a non-DNA-reactive mechanism that involves the formation of a urinary calcium phosphate-containing precipitate, cytotoxicity and enhanced cell proliferation. This mechanism is not relevant to humans because of critical interspecies differences in urine composition.
Saccharin and its salts are not classifiable as to their carcinogenicity to humans (Group 3).
Additional information
A carcinogenicity study of the test item in monkeys was performed following the National Cancer Institute’s nonhuman primate carcinogenicity testing program guides. Twenty monkeys underwent long-term treatment with sodium saccharin from 24h after birth and until the animals died or were euthanized at the end of the study (24 years). For group 1, total doses of test item consumed by these monkeys averaged 403.0 g and ranged from 229.9 to 721.0 g; for group 2, the total dose consumed averaged 718.9 g and ranged from 455.4 to 1136.2 g. The results from this long-term study clearly show that there is no adverse effect of sodium saccharin administered in the diet of three species of monkeys beginning at birth and continuing for nearly the entire lifetime of the animals. Therefore, the test item is deemed non-carcinogenic.
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