Cyclohexapentylose

Carcinogenicity

Description of key information

The read-across substances .gamma.- and .beta.-cyclodextrin did not show any evidence of carcinogenic effects to rats when administered orally at concentrations of up to 3.7 g/kg bw (males) and 4.5 g/kg bw (females) for .gamma.-cyclodextrin and 675 mg/kg bw for .beta.-cyclodextrin. As the water solubility of .gamma.-cyclodextrin is comparable with .alpha.-cyclodextrin - whereas .beta.-cyclodextrin shows a significantly lower water solubility – the feeding study using .gamma.-cyclodextrin as test material has been selected as key study.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

GLP compliance:

yes (incl. QA statement)

Species:

rat

Strain:

other: Wistar (Crl:(WI)WU BR)

Sex:

male/female

Details on test animals or test system and environmental conditions:

Characterization:
The study was conducted with albino rats. The rat was used because this species is considered the most suitable for this type of study, and is usually required by regulatory agencies. Young, male and female Wistar rats (Crl:(WI)WU BR) were obtained from a colony maintained under SPF-conditions at Charles River Deutschland, Sulzfeld, Germany. The animals arrived on 22 January 1997 when they were about 3-4 weeks old. Upon arrival, the rats were checked for overt signs of ill health and anomalies, and kept in quarantine. During the quarantine period, the microbiological status of the rats was checked by serological investigation in random samples. On 28 January 1997, after the results of serology turned out to be satisfactory, the quarantine room was cleared for use as experimental room and the rats were further acclimatized to the conditions in this room until initiation of treatment on 6 February 1997. The body weights on the experimental start date were within ± 20% of the mean weight and ranged from 142 to 206 g (mean 174 g) for males and from 110 to 153 g (mean 130 g) for females.

Allocation:
On the day of arrival (22 January 1997) the rats were checked for overt signs of ill health and anomalies. Healthy animals were allocated to the various groups by computer randomization. Seven days (on 30 January 1997) before the start of the treatment the rats were weighed. On the starting day of the treatment (nominal day 0; 6 February 1997), the rats were weighed again and checked for adequate growth. One rat was replaced because its weight exceeded the variation indicated in the protocol (> +20% of the mean weight). Subsequently the treatment was started. No rats were replaced by reserve animals after the start of the treatment. The remaining rats were kept as sentinel animals but not used in the study.

Identification:
The study was identified as computer study no. 1883 and the different groups were coded by a letter and a colour. On the day of arrival, the rats were identified with a temporary mark on their tail. During the quarantine period each rat was uniquely identified by an animal identification number (even numbers for males and odd for females) which was tattooed in the ears. Each cage was provided with a card showing the study number, colour code, group letter, cage number and animal identification numbers.

Animal maintenance:
From their arrival in the animal room until the end of the study, the rats were group-housed (three rats per cage, separated by sex) in macrolon cages with sterilized wood shavings (Woody Clean; Type 3/4) as bedding material. The cages and bedding were changed weekly. Per sex, control group and test groups were always housed in the same room. The cages were stratified over the cage racks in such a way that each cage rack contained equal numbers of cages of each group. Housing conditions were conventional. The temperature in the animal room was targeted at 22 ±3°C, and the relative humidity at 50 ±20%. These conditions were monitored continuously by means of a thermohygrograph. The actual temperature was generally kept between 19-25°C, but occasionally exceeded the target ranges during a few hours or a few days, reaching minima of 18°C (in one case 17°C during 2 hours) and maxima up to 26°C. The actual relative humidity was generally kept between 40-70%. Due to wet cleaning of the room, the relative humidity sometimes exceeded the upper value during periods of one or a few hours, reaching maxima up to c. 100%. On various other occasions, the relative humidity exceeded the upper value of 70% during periods lasting a few hours to a few days. During these periods, the relative humidity was generally between 70-80%, but occasionally reached maxima up to 90 or 95%. The number of air changes was about 10 per hour. Lighting was artificial by fluorescent tubes, time switch controlled at a sequence of 12 hours light, 12 hours dark.

Feed and drinking water:
From the arrival of the rats until the end of the study, feed and drinking water were provided ad libitum. The feed was provided as a powder in stainless steel cans, covered by a perforated stainless steel plate which prevented spillage. During the quarantine period, the rats were fed a closed formula diet (Rat & Mouse No. 3 Breeding Diet, RM3). During the two-year treatment period, this diet was slightly modified. The modification consisted of the omission of 20% barley from the diet. The barley was replaced by the test substance and/or pregelatinized potato starch. Each batch of the modified diet was analysed by the supplier for nutrients and contaminants. The drinking water was given in polypropylene bottles, which were cleaned weekly and filled as needed. Tap water suitable for human consumption (quality guidelines according to Dutch legislation based on the EEC Council Directive 80/778IEEC) was supplied. Results of the routine physical, chemical and microbial examination of the drinking water as conducted are made available. In addition, periodically (twice per year) analyses water samples were taken for a limited number of variables.

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

0, 2.5, 5, 10 % (0.9, 1.9, 3.7 g/kg bw/day (males))
0, 2.5, 5, 10 % (1.1, 2.2, 4.5 g/kg bw/day (females))

Duration of treatment / exposure:

24 months

Frequency of treatment:

7 days/week

Remarks:

Doses / Concentrations:
0, 2.5, 5, 10 %
Basis:
nominal in diet

No. of animals per sex per dose:

50 rats/sex/group (4 groups: 3 treatment groups, one control group)

Control animals:

yes, plain diet

Details on study design:

Administration of the test substance:
The test substance was administered orally, because this is an anticipated route of human exposure. The test substance was administered in the feed for 24 months (7 days/week) at constant dietary levels of 0%, 2.5%, 5% or 10%.
The test substance was incorporated in the feed at the expense of 20% barley. The control, low-dose, mid-dose and high-dose diet were compensated by adding respectively 20%, 17.5% 15% and 10% pregelatinized potato starch.
Fresh batches of each test diet and the control diet were prepared approximately once every 2-3 weeks. Homogeneity was obtained by mixing in a mechanical blender (Lodige) for two minutes. After preparation the diets were stored in a refrigerator until use. The feed in the animal feeders was replaced by fresh portions once per week and topped up as needed.

Study design and dose levels:
The study comprised four groups of 50 rats/sex each, viz. one control group (A) and three treatment groups (B, C and D) receiving different levels of .gamma.-cyclodextrin.
The feeding of the experimental diets was started on 6 February 1997 (nominal day 0). The study was terminated with the autopsy of the male rats on 8-12 February 1999 (nominal days 732-736) and of the female rats on 15-19 February 1999 (nominal days 739-743).

Positive control:

not available

Observations and examinations performed and frequency:

Analyses of the test substance in the carrier:
Immediately after preparation of each batch of diets, samples were taken of each diet (0, 2.5, 5 and 10% .gamma.-cyclodextrin) and stored in a freezer. The homogeneity of the test substance in the diet was assessed in the first batch of diets prepared (on 3 February 1997) and again in a batch prepared approximately one year later (on 2 March 1998), by analysing five samples per concentration, taken at different places in the feed container.
For each dietary level of .gamma.-cyclodextrin, the content of the test substance was determined approximately once every three months (viz. in the diets prepared on 3 February 1997, 14 May 1997, 27 August 1997, 18 November 1997, 2 March 1998, 18 May 1998, 19 August 1998, 11 November 1998 and 27 January 1999).
The stability of .gamma.-cyclodextrin in the diet after storage for more than one week in the animal room, for more than one month in a freezer and for 6 weeks in a refrigerator was examined by analysing diets of the present carcinogenicity study (study 1883; 2.5%, 5% and 10% level, prepared on 3 February 1997 or 29 December 1998) or the concurrent toxicity study (study 1882; 5% and 20% level, prepared on 19 February or 23 October 1997).

Clinical signs:
Each animal was checked daily in the morning hours by careful observations. Monday through Friday, all cages were checked again in the afternoon for death or moribund animals. On Saturdays, Sundays and public holidays, only one check per day was carried out. All abnormalities, signs of ill health or reactions to treatment were recorded. Any animal showing signs of severe debility or intoxication, particularly if death appeared imminent, were killed to prevent loss of tissues by cannibalism or autolysis.
From six months after the start of the study (from 7 August 1997) until the end of the study, the animals were palpated weekly to detect palpable masses. Time of appearance, location and dimensions of all grossly visible or palpable masses were recorded (palpable mass = cutaneous or subcutaneous nodule; the size was recorded if larger than 5 mm diameter).

Body weights:
The body weight of each animal was recorded before starting the administration of the test substance (day 0), then weekly for the first 13 weeks and subsequently once every month. In addition, the animals were weighed on the scheduled sacrifice date in order to calculate their organ to body weight ratios.
Body weights were also recorded in the pretreatment period to monitor adequate growth during the quarantine/ acclimatization period. The latter data are not presented, but have been kept as raw data.

Food consumption and food conversion efficiency:
The quantity of food consumed by the animals of each cage was assessed on a cage basis, by weighing the feeders, over each 1-week period during the first 13 weeks of the study and subsequently over 1-week periods once every month. The results were expressed in grams per rat per day.
The efficiency of food utilization over periods of 7 days was calculated during the period of rapid growth (the first 13 weeks of the study) and expressed in gram weight gain per gram of food consumed.

Intake of the test substance:
The intake of .gamma.-cyclodextrin per kg body weight per day was calculated from the nominal dietary concentration of the test substance, the mean food consumption and the mean body weight at the end of the pertaining week.
The overall test substance intake (g/kg body weight/day) was calculated as a time weighted average. To calculate this time-weighted average, a value was assigned to each week (either the calculated drug intake or, for weeks in which no value was obtained, the subsequent calculated value). The total of all values was divided by 104.

Haematology:
Blood samples were taken from the tip of the tail of all rats after 12 months (day 347 and 349 for males, and day 350 and 351 for females), after 18 months (day 537 and 538 for males, and day 538 and 539 for females) and after 24 months (day 718 and 719 for males, and day 720 and 721 for females). K2-EDTA was used as anticoagulant. The following variables were determined:
Haemoglobin; packed cell volume; red blood cell count; total white blood cell count; differential white blood cell count; thrombocyte count; mean corpuscular volume (MCV); mean corpuscular haemoglobin (MCH); mean corpuscular haemoglobin concentration (MCRC).
From all animals killed in extremis, blood was collected from the tip of the tailor from the abdominal aorta. A blood smear was prepared and differential white blood cell counts were conducted.

Histopathological examination:
The tissues for light microscopic examination were embedded in paraffin wax, cut in 5 µm sections and tained with haematoxylin and eosin. Histopathological examination was performed on all tissues and organs listed above of all animals of the control group and the high-dose group, and of the animals of the intermediate-dose groups killed in extremis or found dead (if not precluded by cannibalism or autolysis).
The kidneys, liver, lungs and gross lesions/ tissues showing abnormality and lesions suspected to be tumours were examined in all animals of all groups.

Sacrifice and pathology:

The study was terminated with the autopsy of the rats on a number of successive working days (male rats on 8-12 February 1999 (nominal days 732-736) and female rats on 15-19 February 1999 (nominal days 739-743)). On each day, rats from each group were killed in a sequence such that the necropsies of animals from each group were spread throughout the day.
The animals were killed by exsanguination from the abdominal aorta under ether anaesthesia. They were subsequently examined macroscopically for pathological changes. A thorough autopsy was also performed on animals which died or were killed intercurrently.
At scheduled autopsy, the following organs were weighed (paired organs together) as soon as possible after dissection to avoid drying, and the relative weights (organ to body weight ratio's) were calculated from the organ weights and the terminal body weights:
Adrenals; caecum (filled and empty); kidneys; liver.
Samples of the following tissues and organs of all animals were preserved in a neutral aqueous phosphate-buffered 4% solution of formaldehyde (10% dilution of formalin):
Adrenals; aorta; axillary lymph nodes; brain (brain stem, cerebrum and cerebellum); caecum; coagulating glands; colon; epididymides; exorbitallachrymal glands; eyes; femur with joint (knee); Harderian glands; heart; kidneys; liver; lungs; mammary glands (female+male); mandibular (cervical) lymph nodes; mesenteric lymph nodes; nasal cavity (turbinates); nerve-peripheral (sciatic nerve); oesophagus; ovaries; oviduct (fallopian tubes); pancreas; parathyroids; parotid salivary glands; pituitary; prostate; rectum; seminal vesicles; skeletal muscle (thigh); skin/subcutis; small intestines; spinal cord (at three levels); spleen; sternum with bone marrow; stomach; sublingual salivary glands; submaxillary salivary glands; testes; thymus (or thymic region); thyroid; tongue; tracheal bronchi; urinary bladder; uterus (with cervix); vagina; Zymbal's glands.
All gross lesions/ tissues showing abnormality and suspect tumours.

Statistics:

The statistical procedures used to evaluate the results were as follows:
- Body weights: one-way analysis of covariance using pre-exposure (day 0) weights as the covariate. When group means were significantly different (p<0.05), individual pairwise comparisons were made using Dunnett's multiple comparison method;
- Food consumption, food conversion efficiency, red blood cell and coagulation variables, total- and absolute differential white blood cell counts and organ weights: analysis of variance (Anova) followed by Dunnett's multiple comparison tests;
- Total- and relative differential (percentages) white blood cell counts: Kruskal-Wallis nonparametric one-way analysis of variance. When this analysis yielded a significant difference, pairwise comparisons between the control- and treatment groups were made by means of Mann-Whitney V-tests;
- Mortality data and histopathological changes: Fisher's exact probability test. Statistical analysis of histopathological findings was only performed on 'protocol organs' to be examined in all animals of a group. ('Protocol organs' = the organs listed in “Sacrifice and Pathology”, except gross lesions/ suspect tumours).
All analyses were two-sided. Group mean differences with an associated probability of less than 0.05 were considered to be statistically significant.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

sparsely haired skin and blepharitis with discharge and/or encrustation around the eyes; overall mortality rate was low

Mortality:

mortality observed, treatment-related

Description (incidence):

sparsely haired skin and blepharitis with discharge and/or encrustation around the eyes; overall mortality rate was low

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

slightly decreased (males)

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

significantly decreased

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

incidental decrease in thrombocyte count (males)

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

relative weight of the filled caecum was slightly/statistically significantly increased (males); relative weight of the kidneys was increased (females)

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Kidneys: proteinaceous cast(s), nephrosis, mononuclear cell infiltrate (males), brown pigment accumulation (females). Liver: bile ducti ductular cell hyperplasia, aggregates of res cells, necrotic hepatocytes, focal mononuclear cell infiltrate (males) etc

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Fibroadenomas of the mamma (females); incidence of pituitary adenomas (males+females); incidence of endometrial stromal polyps (a benign tumour) in the uterus

Details on results:

Clinical signs and survival:
There were no dose-related differences in appearance, general condition or behaviour among the groups, and the rats were generally in good condition. Clinical signs frequently observed included sparsely haired skin and blepharitis with discharge and/or encrustation around the eyes. Since all clinical signs occurred only incidentally or at comparable incidences in test groups and controls, they did not represent any adverse effect of the test substance.
The time of onset and incidence of the grossly visible or palpable masses did not suggest any treatment-related effect. Mortality rate was not affected by the test substance. Moreover, the overall mortality rate was low. About 75% of the rats survived the 2-year treatment period.

Body weights:
Mean body weights were slightly (overall 5-6%) decreased in males of all treatment groups. The differences with the controls were often statistically significant, especially in the mid- and high-dose group. There was, however, no dose-response relationship. In females there were no statistically significant differences in body weights among the groups, apart from a decrease in the high-dose group on day 560.

Food intake and food conversion efficiency:
In the first few weeks of the study, food intake was occasionally statistically significantly decreased in males of all treatment groups and in females of the mid and high-dose group, but there were no noticeable differences in overall food intake. Food conversion efficiency was similar among the groups.

Haematology:
There were no statistically significant changes in red blood cell variables or thrombocyte counts, apart from an incidental decrease in thrombocyte count in males of the low- and mid-dose group after 12 months which was neither confirmed at the high-dose level, nor at subsequent stages.
There were no statistically significant changes in total white blood cell counts in surviving rats. Differential white blood cell counts showed some incidental differences with the controls. Since these changes were not consistent or dose-related they were not ascribed to the treatment with .gamma.-cyclodextrin.

Organ weights:
In males, the relative weight of the filled caecum was slightly, though statistically significantly increased in the mid- and high-dose group. The absolute weight of the filled caecum was statistically significantly increased in males of the high-dose group only. There were no significant changes in empty caecal weights.
The relative weight of the kidneys was increased in females of the low- and high-dose group, but there was no dose-response relationship and the absolute values were not affected.

Pathology:
Cause of death:
The test substance did not affect the cause of death. Most decedents died or were killed because of a fatal tumour. The most frequently occurring fatal tumour was adenoma of the pituitary.

Macroscopic examination:
Gross examination at autopsy did not reveal any treatment-related abnormalities. The macroscopic changes observed are common in rats of this strain and age, and occurred in one or a few animals only or at comparable incidences in test groups and controls.

Microscopic examination:
Non-neoplastic lesions: Microscopic examination did not reveal any treatment-related histopathological changes. The changes observed are common in rats of this strain and age.
Most changes were about equally distributed among the groups, or they occurred in one or a few animals only. The incidence of some other histopathological changes observed in treated animals differed statistically significantly from that of controls.
However, in all these cases the incidence of such a lesion was either lower than in controls and/or a dose-response relationship was absent. Examples are:
Kidneys: proteinaceous cast(s), nephrosis and mononuclear cell infiltrate in males, brown pigment accumulation in females. Liver: bile ducti ductular cell hyperplasia, aggregates of res cells and necrotic hepatocytes, focal mononuclear cell infiltrate and (focal) cholangiofibrosis in males, (multiple) focus of cellular alteration; acidophilic/ clear cell type in males and females. Lungs: haemorrhage(s) in females. These findings were considered normal background pathology and of no toxicological significance.

Neoplastic lesions: The occurrence of neoplastic lesions was not affected by the treatment. Statistical analysis of the tumour incidences in the various organs did not reveal significant differences between the high-dose group and the controls.
Most tumours occurred in one or a few animals only, and there were no unusual tumour types. A number of neoplastic lesions which occurred at a relatively high overall incidence is mentioned below:
- Fibroadenomas of the mamma were frequently seen in females of all groups, controls included. They occurred at a similar incidence in the high-dose group and controls. Moreover, fibroadenoma, of the mamma is a benign tumour which normally occurs in a rather high incidence in females of this strain. Therefore, their occurrence in the present study was considered quite normal and not treatmentrelated.
- The incidence of pituitary adenomas in the control- and high-dose group was 6/47 and 10/46 in males, and 16/50 and 14/50 in females, respectively. The incidence of pituitary adenomas in males of the high-dose group was relatively high (22%) as compared to the concurrent controls (13%). In females the incidence in the highdose group (28%) was slightly lower than in the controls (32%). The incidence of pituitary adenomas in control animals of 18 long-term rat studies performed in our Institute was 185/848 (22%) in males and 272/844 (32%) in females. Therefore, compared with background data, the occurrence of pituitary adenomas in the present study was quite normal and not considered to be associated with treatment.
- The incidence of endometrial stromal polyps (a benign tumour) in the uterus was relatively high in the high-dose group (24%) as compared to the concurrent controls (10%). The incidence of endometrial stromal polyps in control animals of 18 long-term rat studies performed in our Institute was 174/877 (20%). Compared with these background data, the occurrence of endometrial stromal polyps in the high dose group was not unusual, and was not considered to be associated with treatment.
Summarizing, the exposure to .gamma.-cyclodextrin for two years neither induced specific tumours nor affected the incidence of tumours.

Relevance of carcinogenic effects / potential:

Summarizing, the exposure to .gamma.-cyclodextrin for two years neither induced specific tumours nor affected the incidence of tumours.

Dose descriptor:

NOAEL

Effect level:

> 10 other: % in the diet

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Substance intake for 10 % .gamma.-CD, male: 3700 mg/kg bw/d 10 % .gamma.-CD, female: 4500 mg/kg bw/d

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Conclusions:

In conclusion, the present study in which .gamma.-cyclodextrin was administered in the diet up to 10% for the major part of the life-span of rats, did not reveal any tumourigenic properties of the test substance.

Executive summary:

For this endpoint the read-across approach based on grouping of substances (category approach) was used.

The possible carcinogenicity of the read-across substance .gamma.-cyclodextrin was examined in a chronic (24 months) study with groups of 50 male and 50 female Wistar rats. The test substance was incorporated in the feed of the rats at constant levels of 0% (control), 2.5%, 5% and 10%. These dietary levels were equal to an overall intake (time-weighted average) of 0.9, 1.9 and 3.7 g/kg bw/day in males and 1.1, 2.2 and 4.5 g/kg bw/day in females of the low-, mid- and highdose group, respectively.

The rats were generally in good condition. There were no treatment-related differences in general condition, behaviour or time of onset or incidence of palpable masses among the groups. The overall mortality rate was low and not affected by the test substance.

Body weights of males of all treatment groups were lower than in controls throughout the study, but the decrease was only slight (about 5-6%), and not dose-related. Overall food intake was similar in treatment groups and controls.

Haematology conducted in all rats after 12, 18 and 24 months did not reveal any treatment-related changes in red blood cell variables and thrombocyte counts, or in total- and differential white blood cell counts.

Macroscopic examination at autopsy did not reveal any treatment-related changes. The weight of the filled caecum was slightly increased in males of the mid- and high-dose group.

The exposure to .gamma.-cyclodextrin was not associated with treatment-related histopathological changes, and neither induced specific tumours nor affected the incidence of spontaneous tumours.

It was concluded that the present study did not reveal any tumourigenic properties of the test substance.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

3 700 mg/kg bw/day

Species:

rat

Quality of whole database:

Klimisch 1

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

Chronic feeding of .gamma.- and .beta.-cyclodextrin to rats did not cause any treatment related carcinogenic effects.

Additional information

The carcinogenic potential of the read-across substance .gamma.-cyclodextrin was examined in a chronic (24 months) study with groups of 50 male and 50 female Wistar rats according to OECD Guideline 451. The test substance was incorporated in the feed of the rats at constant levels of 0% (control), 2.5%, 5% and 10%. These dietary levels were equal to an overall intake (time-weighted average) of 0.9, 1.9 and 3.7 g/kg bw/day in males and 1.1, 2.2 and 4.5 g/kg bw/day in females of the low-, mid- and highdose group, respectively. Haematology conducted in all rats after 12, 18 and 24 months did not reveal any treatment-related changes in red blood cell variables and thrombocyte counts, or in total- and differential white blood cell counts. Macroscopic examination at autopsy did not reveal any treatment-related changes. The weight of the filled caecum was slightly increased in males of the mid- and high-dose group. The exposure to .gamma.-cyclodextrin was not associated with treatment-related histopathological changes, and neither induced specific tumours nor affected the incidence of spontaneous tumours. It was concluded that the presented study did not reveal any tumourigenic properties of the test substance.

 

The read-across substance .beta.-cyclodextrin was examined in an oncogenicity study in F344 rats according to OECD Guideline 451. 50 animals of each sex were administered with 0, 25, 75, 225 and 675 mg/kg/day for 122 weeks (males) and 130 weeks (females) respectively. In addition, neither toxic clinical signs nor effects on body weight, food and water consumption were detected throughout the study period. The highest dosage tested in this study was 675 mg/kg per day. Regarding the observed increased incidence of several tumors in the study, none of the tumors exceeded the background data. Uterine adenocarcinomas, although occurring at a slightly higher incidence in the highest dosage group, but not statistically significant, are regarded as a spontaneous, incidental finding, and of no biological significance. In fact, the incidence of this neoplasm showed a dramatic increase when the incidence of the testing facility background data accumulated for 24 month studies, was compared to the concurrent controls (range of 3.3-8.3% in 24 month studies, compared to 24% incidence in the current control). Therefore it can be concluded that the slight increase of uterine adenocarcinoma in the current study in the highest dosage group occurred by chance and has no bearing on the treatment with beta-cyclodextrin. Regarding the parathyroid adenoma and subcutaneous fibroma, the incidence in all groups was comparable with the background data. In relation to the significant trend for the Leydig cell tumour, this effect was not considered related to treatment but due to the naturally high incidence of this tumor in this strain, and due to the fact that the incidence of the tumor did not exceed the literature data on this tumor in Fischer 344 rats, which is generally considered to be about 100%. In conclusion, chronic feeding of .beta.-cyclodextrin to Fischer 344 rats did not cause any treatment related carcinogenic effects.

Justification for selection of carcinogenicity via oral route endpoint:
OECD Guideline study