Cycloheptapentylose

Endpoint summary

Description of key information

.Beta.-Cyclodextrin is relatively harmless in case of oral, dermal and inhalative administration. 

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Results reported with some details lacking

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

other procedure

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: CFY

Sex:

male/female

Details on test animals or test system and environmental conditions:

animals had a weight of 150 - 200 g

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

dosed as a suspension

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

10

Control animals:

no

Details on study design:

dosed animals were observed for 24 hours

Statistics:

LD50 according to Litchfiled Wilcoxson

Preliminary study:

not applicable

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Remarks on result:

other: no mortality observed

Mortality:

no mortality was observed

Clinical signs:

other: lower tonicity and hyperpnoea were observed within the first hour. The animals recovered after 24 h.

Gross pathology:

no signs observed

Other findings:

none

Interpretation of results:

GHS criteria not met

Conclusions:

Beta-cyclodextrin is practically nontoxic if administered orally to rats.

Executive summary:

Beta-Cyclodextrin was administered to groups of 10 male and female rats at a limit concentration of 5000 mg/kg bw. No mortality was observed within these groups. In the first hour lower tonicity and hyperpnoea were observed. All animals recovered after 24 h. No other signs of toxcicity were observed. The LD50 of beta-cyclodextrin was determined to be > 5000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study report with minor details (characterisation of test item) lacking

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

yes

Remarks:

see principles

Principles of method if other than guideline:

Five young. adult, male and female albino rats (approximately 8 weeks of age) of the Sprague-Dawley derived strain were used in this study. The rats were chosen by ran-dom selection from the acclimated animals. Animals selected for the study weighed be-tween 206 and 217 grams. The animals were exposed to the test article for 4 hours. Six minutes were added to the 240 minute exposure period in order to allow the test system to reach 99 percent of the desired concentration (point of equilibration). Food and water were not made available during the exposure period. During the exposure period, the animals were individually housed in wire-mesh cages. Following exposure, the animals remained in the chamber for a minimum. of six minutes. The chamber was maintained during these six minutes at the designated airflow rate of 100 L/minute using clean am-bient air only.. After the exposure, animals were again individually housed. Animals were observed twice daily and body weights were recorded periodically throughout the 14-day study period. All animals were subjected to a gross necropsy and examined for lesions and/or abnormalities.

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

1. Species/Strain: Sprague-Dawley Rats
2. Source: Charles River Breeding Laboratories. Inc.
3. Age at Initiation: Young adult
4. Number/Sex: 5/sex.
5. Identification: Color coded cage tag.
6. Housing: Individually housed in stainless steel wire
mesh bottom cages.
8. Water: Tap water, ad libitum. except during the exposure period. Water is monitored for contaminants at periodic intervals according to the FDRL Standard Operating Pro-cedures
9: Environment: All animals will be housed in environment controlled rooms with tem-perature and relative humidity regulated as per “Guide for the Care and Use of Labora-tory Animals”. A 12-hour light-dark cycle will be maintained.
10. Quarantine: Minimum of 5 days. During this conditioning period, the rats will be ob-served for any clinical signs of disease. All rats with any evidence of disease or physical abnormalities will be discarded.
Animals selected for the study weighed between 206 and 217 grams.

Route of administration:

inhalation: dust

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

The exposure was performed in a 128 L acrylic (plexiglass), portable chamber designed by the FDRL scientific staff. Total airflow through the chamber was maintained at a rate of 100 L/minute using a transvector jet and monitored using a pre-standardized pressure gauge attached to the transvector jet. The test atmosphere was vented via an air treatment system constructed of a glass fiber pre-filter, Micretain HEPA filter and an activated charcoal bank. The test article was delivered into the exposure chamber by means of a NBS-II dust generator using an air inlet port, which allows the test article and incoming air to mix evenly within the chamber at the top before being drawn down over the animals.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gravimetry

Duration of exposure:

4 h

Remarks on duration:

6 additional minutes were chosen in order to allow the test system to reach 99 percent of the desired concentration (point of equilibration)

Concentrations:

Nominal Concentration: The nominal concentration of Beta Cyclodextrin was 15.4 mg/L, Which was calculated by dividing the total amount of test article utilized in milli-grams by the total volume of air in liter that passed through the chamber.
Actual Concentration: The actual chamber concentration of Beta Cyclodextrin was 4.9 mg/L of air which was determined by gravimetric analysis.
Chamber air was drawn through a pre-weighed glass fiber filter (Gelman Type A/E, 99.7% efficient at 0.3 µm) held in an open-faced holder. The change in weight of the filter was then determined (mg) and divided by the volume of chamber air sampled through the filter (L). Four samples per hour were taken and the average actual concen-tration calculated.

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

Five young. adult, male and female albino rats (approximately 8 weeks of age) of the Sprague-Dawley derived strain were used in this study. The rats were chosen by ran-dom selection from the acclimated animals. Animals selected for the study weighed be-tween 206 and 217 grams. The animals were exposed to the test article for 4 hours. Six minutes were added to the 240 minute exposure period in order to allow the test system to reach 99 percent of the desired concentration (point of equilibration). Food and water were not made available during the exposure period. During the exposure period, the animals were individually housed in wire-mesh cages. Following exposure, the animals remained in the chamber for a minimum. of six minutes. The chamber was maintained during these six minutes at the designated airflow rate of 100 L/minute using clean am-bient air only. After the exposure, animals were again individually housed. Animals were observed twice daily and body weights were recorded periodically throughout the 14-day study period. All animals were subjected to a gross necropsy and examined for le-sions and/or abnormalities.

Statistics:

not reported

Preliminary study:

not applicable

Sex:

male/female

Dose descriptor:

LC0

Effect level:

> 4.9 mg/L air

Exp. duration:

4 h

Remarks on result:

other: no mortality observed at limit concentration

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 4.9 mg/L air

Exp. duration:

4 h

Remarks on result:

other: none

Mortality:

none obserbed

Clinical signs:

other: No mortality occurred. Nasal discharge was noted in all animals immediately following exposure. This effect generally cleared by day 2 of the study. .

Body weight:

Body weight data were just slightly affected. The test article exposure did not exhibit an adverse effect upon body weight gain in males. Weight loss was recorded in one female at days 8 and 15.

Gross pathology:

No lesions or abnormalities were noted during gross necropsy examination.

Other findings:

none observed

Particle SizeAnalysis: Particle size analyseswereperformed once perhourusing a multijet cascade impactor (Model 02-200, In-ToxProductsAlbuquerque, NM). Stages one to seven of the impactorwerefittedwith preweighedstainless steel impaction substrates. Stage eight (final filter stage)wasfitted with a preweighed cellulose filter membrane (Gelman TypeA/Et47mm,Triacetate,99.7%efficient at 0.3µm).Chamber airwas drawn throughthe impactor at a rate of 20 L/minute and the change in weight of each collection substrate (including the filter) was subsequently determined. The mean cumulative percent of aerosol collected at each stage was determined and a lognormal distribution curve plotted. Themeanparticle size of the aerosolgenerated ,geometric standard deviation and percent of the sample (by weight) comprised of particles < 12µmin size were determined. 

 

Chamber Specifications

Chamber volume (L): 128 L

Airflow exchange rate: 100 L/minute

Equilibrium time (99%): 6 minutes

Exposure duration at equilibrium: 240 minutes

Total exposure duration: 246 minutes '

Equilibrium/total exposure duration: 2%

Total volume of air: 24600 L

Test article utilized: 379.6 g

 

Mass median aerodynamic diameter (MMAD): 3.8 µm

Geometric standard deviation (ag): 2.2

Estimated percent of collected particles < 12 µm: 92%

 

Test Atmosphere Temperature and Relative Humidity:

Initial temperature (OC): 22

Final temperature (OC): 23

Average temperature (OC): 23

Range (QC): 22-23

Initial relative humidity (%): 41

Final relative humidity (%): 44

Average relative humidity (%): 43

Range (%): 40-46

Interpretation of results:

relatively harmless

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Substanec reveals a low degree of toxicity.

Executive summary:

Five young. adult, male and female albino rats (approximately 8 weeks of age) of the Sprague-Dawley derived strain were used to evaluate the inahaltion toxicity of .beta.-cyclodextrin. The study was a limit whole body inhalation study at a nominal concentration of 15.4 mg/l and a gravimetrically measured concentration of 4.9 mg/l. It was performed to a guideline equivalent to OECD 403. The average actual concentration of Beta Cyclodextrin was 32% of the nominal concentration. Adsorption of the test article to chamber surfaces, dermal exposure to the animals and the generation of particle aggregates which do not remain suspended in the test atmosphere, contributed to this difference.. The animals were exposed to the test article for 4 hours. Six minutes were added to the 240 minute exposure period in order to allow the test system to reach 99 percent of the desired concentration (point of equilibration). Food and water were not made available during the exposure period. During the exposure period, the animals were individually housed in wire-mesh cages. Animals were observed twice daily and body weights were recorded periodically throughout the 14-day study period. All animals were subjected to a gross necropsy and examined for lesions and/or abnormalities. No mortality occurred. Nasal discharge was noted in all animals immediately following exposure. Body weight data were just slightly affected. The test article exposure did not exhibit an adverse effect upon body weight gain in males. Weight loss was recorded in one female at days 8 and 15. No lesions or abnormalities were noted during gross necropsy examination. Four-hour whole-body exposure to a dust generated from Beta Cyclodextrin at an average actual concentration of 4.9 mg/L failed to produce mortality in five male and five female Sprague-Dawley rats. The LC0 is >= 4.9 mg/l and it can be assumed that the LC50 is also > 5.0 mg/l due to lack of mortality and only slight signs of toxicity in this test.

 

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

5 000 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: OECD Guideline study report but substance identity (Copper compound used) could not be determined

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

The animals used for this study were Sprague-Dawley rats lCO: OFA-SD (lOPS Caw) supplied by lffa Credo. 69210 L'Arbresle. France. Upon their arrival at the testing facility the animals were acclimatized to the experimental environment for at least 5 days dur-ing which they were observed daily.
On the first day of treatment, the adult animals were approximately 8 weeks old, and had a mean weight of 273 ± 7 g for the males and 228 ± 5 g for the females. They were individually identified by earmarks or earnotches.

Temperature: 22 ± 3°C
Hygrometry: 50 ± 20% relative humidity
Light/dark cycle: 12 hours of light/12 hours of dark
The air was non-recycled and filtered by absolute filters.
The animals were housed in groups of 4 to 7 animals of the same sex per cage during the acclimatization period and individually during the study. They were housed in steri1izable polycarbonate cages (48 x 27 x 20 cm) during the acclimatization period, and (35.5 x 23.5 x 19.3 cm) throughout the study. They were covered with a stainless steel lid containing food and a water bottle. Sifted and dusted sawdust was provided as litter (SICSA, 94142 Alfortville France). An analysis of the potential residues and major contaminants was performed periodically (Laboratoire Wolff, 92110 Clichy, France).

During the study, the animals were fed ad libitum with a certified pellet diet "Rats - Mice sustenance ref. A04 C" (U .A.R., 91360 Villemoisson-sur Orge, France). An analysis of the quality of the food and the major contaminants (pesticides, heavy metals, mycotox-ins, etc.) was performed by the supplier and given for each batch. During the study, the animals had free access to tap water filtered by a 0.22 micron filter membrane (Societe Millipore, 78140 Velizy, France) and contained in water bottles. Bacteriological and chemical analyses of the water and detection of the major contaminants (pesticides, heavy metals and nitrosamines) were made periodically (Laboratoire Municipal et Re-gional de Rouen, 76000 Rouen, France - Centre de Nutrition Humaine, 54000 Nancy, France - Laboratoire Departemental d 'Analyses , 27000 Evreux, France) .

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

The day before treatment. the dorsal area of each animal was clipped with an electric clipper on an area of 6 x 8 cm. Only animals with healthy
intact skin were used for the study. The skin was pre-moistened with 2 ml of water for injections and then applied to an area of skin representing approximately 10% (5 x 6 cm for the females and 5 x 7 cm for the males) of the body surface of the animal.
The test substance and the gauze patch were held in contact with the skin for 24 hours by means of an adhesive hypoallergic aerated semi-occlusive dressing (Laboratoires de Pansements et d'Hygiene. 21300 Chenove. France) attached to a restraining bandage (Laboratoires 3M Sante. 92245 Malakoff. France). This dressing prevented the ingestion of the test substance by the animal

Duration of exposure:

24 hours

Doses:

2000 mg/kg

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed frequently after application of the test substance and at least once
a day for 14 days in order to determine the reversibility or irreversibility of any clinical signs.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, pathology.

Statistics:

not reported

Preliminary study:

not applicable

Sex:

male/female

Dose descriptor:

LD0

Effect level:

>= 2 000 mg/kg bw

Remarks on result:

other: none

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 2 000 mg/kg bw

Remarks on result:

other: none

Mortality:

No deaths occurred during the observation period.

Clinical signs:

other: No clinical signs were observed during the study.

Gross pathology:

The macroscopic examination of the main organs of the animals sacrificed
at the end of the study revealed no apparent abnormality.
Due to the absence of macroscopic lesions. no samples were taken for
histological examinations.

Other findings:

none

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The LD0 of beta-Cyclodextrin administered to Sprague-Dawley rats was >= 2000 mg/kg bw under the conditions of the study.

Executive summary:

Beta-Cyclodextrin (95% pure; 4.5% Copper) was evaluated in rats according to OECD Guideline No. 402. The test substance was prepared in its original form on a moistened compress at a dose of 2000 mg/kg and then applied to the skin of 10 Sprague-Dawley rats (5 males and 5 females). After 24 hours under a semi-occlusive dressing, residual test substance was removed using a compress saturated with water.

The mortality. general behaviour and body weight gain of the animals were observed for a period of 14 days after the single application of the test substance. A necropsy was performed on each animal sacrificed at the end of the study.

The general behaviour and body weight gain of the animals were not influenced by the treatment. No deaths occurred at the dose level of 2000 mg/kg. The macroscopic examination revealed no abnormalities in the animals sacrificed at the end of the study.

Under our experimental conditions, the LD 50 of the test substance beta-Cyclodextrin administered by dermal route in rats was higher than or equal to 2000 mg/kg.No signs of toxicity were observed at this dose level.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

Beta-Cyclodextrin was administered to groups of 10 male and female rats at a limit concentration of 5000 mg/kg bw. No mortality was observed within these groups. In the first hour lower tonicity and hyperpnoea were observed. All animals recovered after 24 h. No other signs of toxcicity were observed. The LD50 of beta-cyclodextrin for rats of both sex was determined to be > 5000 mg/kg bw.

Beta-Cyclodextrin was administered to groups of 10 male and female mice at a limit concentration of 3000 mg/kg bw. No mortality was observed within these groups. In the first hour lower tonicity, somnolentia and hyperpnoea were observed. All animals recovered after 24 h. No other signs of toxcicity were observed. The LD50 of beta-cyclodextrin for mice of both sex was determined to be > 3000 mg/kg bw.

Beta cyclodextzrin (98% pure) was assessed for its dermal toxicity in 5 rats of each sex according to OECD Guideline 402. The test item was held in contact with the skin by a dressing throughout a 24-hour period. The dressing consisted of a gauze-dressing and non-irritating tape and was fixed with an additional dressing in a suitable manner. Under the conditions of the study, single dermal application of the test item to rats at a limit dose of 2000 mg/kg body weight was associated with mild signs of toxicity, but no mortality. Chromodacryorrhea was observed in 2 of 5 female animals and in 1 of 5 male animals. 1 of 5 female animals and 1 of 5 male animals showed a dark discolouration of the right lung. The body weight development of all male and female animals was within the expected range, except for a slight weight loss in 1 out of 5 female animals. Scratches were observed in 2 of 5 female. All signs of irritation were reversible within the observation period, except for 1 of 5 female animals. For acute percutaneous toxicity neither mortalities nor significant clinical signs of toxicity were observed at a dose of 2000mg/kg body weight.

Beta-Cyclodextrin was also evaluated in rats in another study according to OECD Guideline No. 402. The test substance was prepared in its original form on a moistened compress at a dose of 2000 mg/kg and then applied to the skin of 10 Sprague-Dawley rats (5 males and 5 females). After 24 hours under a semi-occlusive dressing, residual test substance was removed using a compress saturated with water.

The mortality. general behaviour and body weight gain of the animals were observed for a period of 14 days after the single application of the test substance. A necropsy was performed on each animal sacrificed at the end of the study.

The general behaviour and body weight gain of the animals were not influenced by the treatment. No deaths occurred at the dose level of 2000 mg/kg. The macroscopic examination revealed no abnormalities in the animals sacrificed at the end of the study.

Under our experimental conditions, the LD 50 of the test substance beta-Cyclodextrin administered by dermal route in rats was higher than or equal to2000 mg/kg.No signs of toxicity were observed at this dose level.

Five young. adult, male and female albino rats (approximately 8 weeks of age) of the Sprague-Dawley derived strain were used to evaluate the inahaltion toxicity of .beta.-cyclodextrin. The study was a limit whole body inhalation study at a nominal concentration of 15.4 mg/l and a gravimetrically measured concentration of 4.9 mg/l. It was performed to a guideline equivalent to OECD 403. The average actual concentration of Beta Cyclodextrin was 32% of the nominal concentration. Adsorption of the test article to chamber surfaces, dermal exposure to the animals and the generation of particle aggregates which do not remain suspended in the test atmosphere, contributed to this difference.. The animals were exposed to the test article for 4 hours. Six minutes were added to the 240 minute exposure period in order to allow the test system to reach 99 percent of the desired concentration (point of equilibration). Food and water were not made available during the exposure period. During the exposure period, the animals were individually housed in wire-mesh cages. Animals were observed twice daily and body weights were recorded periodically throughout the 14-day study period. All animals were subjected to a gross necropsy and examined for lesions and/or abnormalities. No mortality occurred. Nasal discharge was noted in all animals immediately following exposure. Body weight data were just slightly affected. The test article exposure did not exhibit an adverse effect upon body weight gain in males. Weight loss was recorded in one female at days 8 and 15. No lesions or abnormalities were noted during gross necropsy examination. Four-hour whole-body exposure to a dust generated from Beta Cyclodextrin at an average actual concentration of 4.9 mg/L failed to produce mortality in five male and five female Sprague-Dawley rats.

Justification for classification or non-classification

The LC50 under inhalative administration is > 4.9 mg/l and it can be assumed that the LD50 is also > 5.0 mg/l due to lack of mortality in this test. The LD50 of beta-cyclodextrin after oral administration for mice and rats was determined to be > 3000 mg/kg bw and > 5000 mg/kg bw respectively. The LD50 of beta-cyclodextrin after dermal administration for rats was determined to be > 2000 mg/kg bw.