Cyclohexapentylose

Endpoint summary

Description of key information

.Alpha.-cyclodextrin is practical nontoxic after oral, dermal and inhalative administration. 
Due to the physico-chemical properties (molecular weight, solubility) a significant resorption via dermal or inhalativ route is not expected. 

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: Data from handbook or collection of data

Principles of method if other than guideline:

Method unknown

GLP compliance:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 10 000 mg/kg bw

Based on:

test mat.

Conclusions:

The LD50 for .alpha.-cyclodextrin in rats is > 10,000 mg/kg bw.

Executive summary:

The LD50 for .alpha.-cyclodextrin in rats is > 10,000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

10 000 mg/kg bw

Quality of whole database:

Klimisch 2

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Study period:

1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study with acceptable restrictions

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:

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

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 the read-across substance .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

Quality of whole database:

Klimisch 1

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

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 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Species/strain: Healthy rats, WISTAR Crl: WI(Han) (Full-Barrier)
Source: Charles River, 97633 Sulzfeld, Germany
Sex: male and female The female animals were nulliparous and non-pregnant.
Body weight at the beginning of the study: females: 200 - 220 g, males 240 – 260 g
Age at the beginning of the study: females: 17 weeks, males: 10 weeks old
Number of animals: 5 male and 5 female
Housing and Feeding Conditions:
Full-barrier in an air-conditioned room
Temperature: 22 3 °C
Relative humidity: 55 10%
Artificial light, sequence being 12 hours light, 12 hours dark
Air change: 10 x / hour
Free access to Altromin 1324 maintenance diet for rats and mice (lot no. 1310)
Adequate acclimatisation period: 8 days
Free access to tap water, sulphur acidified to a pH value of approx. 2.8 (drinking water, municipal residue control, microbiological control at regular intervals)
The animals were kept individually in IVC cages, type III H, polysulphone cages on Altromin saw fibre bedding (lot no. 060609)

Type of coverage:

semiocclusive

Vehicle:

water

Details on dermal exposure:

Approximately 24 hours before the test, the fur was removed from the dorsal area of the trunk by using an electric clipper. Care was taken to avoid abrading the skin, and only animals with healthy intact skin were used. No less than 10% of the body surface was cleared for the application. The test item was applied at a single dose, uniformly over an area which was approx. 10% of the total body surface. 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.

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

other: Other side of skin served as a control

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: A careful clinical examination was made several times on the day of dosing (at least once during the first 30 minutes and with special attention given during the first 4 hours post-dose). As soon as symptoms were noticed they were recorded. Thereafter, the animals were observed for clinical signs once daily until the end of the observation period. All abnormalities were recorded.
Cageside observations included changes in the skin and fur, eyes and mucous membranes. Also respiratory, circulatory, autonomic and central nervous systems and somatomotor activity and behaviour pattern were examined. Attention was directed to observations of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma. The animals were weighed on day 1 (prior to the application) and on days 8 and 15
- Necropsy of survivors performed: yes

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 mortality was observed

Clinical signs:

other: Chromodacryorrhea was observed in 2 of 5 female animals and in 1 of 5 male animals.

Gross pathology:

1 of 5 female animals and 1 of 5 male animals showed a dark discolouration of the right lung.

Other findings:

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.

Interpretation of results:

relatively harmless

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of the present study, single dermal application of the test item to rats at a dose of 2000 mg/kg body weight was associated with mild signs of toxicity, but no mortality.

Executive summary:

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

The read-across substance .beta.-cyclodextrin 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 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Klimisch 1

Additional information

For this endpoint the read-across approach based on grouping of substances (category approach) was used. .Alpha.-, .beta.- and .gamma.-cyclodextrin are composed of six, seven and eight identical α-D-glucopyranoside units, respectively. The water solubility is between 18.5 and 232 g/L at 25°C with .beta.-cyclodextrin being the least soluble within this group and .gamma.-cyclodextrin having the highest water solubility.

.Alpha.-, beta-, and .gamma.-cyclodextrin are practical nontoxic after oral, dermal and inhalative administration.

ORAL The LD50 of .alpha.-cyclodextrin for rats is > 10000 mg/kg bw. The read across substance .beta.-cyclodextrin was administered to groups of 10 male and 10 female rats at a limit concentration of 5000 mg/kg bw. No mortality was observed within these groups. No other signs of toxicity were observed. The LD50 of .beta.-cyclodextrin for rats was determined to be > 5000 mg/kg bw.

INHALATION In a study according to OECD 403 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 induce mortality in five male and five female Sprague-Dawley rats. The median particle size was 24.26 µm (OECD 110). Due to the good water solubility of.alpha.-cyclodextrin (145 g/L at 25°C) no adverse effects due to particle size are expected.

DERMAL The read-across substance .beta.-cyclodextrin was evaluated in rats in a dermal study according to OECD 402 (Sprague-Dawley rats, 5 males and 5 females). The general behavior and body weight gain of the animals were not influenced by the treatment. No signs of toxicity were observed and no deaths occurred at the dose level of 2000 mg/kg.

Justification for selection of acute toxicity – oral endpoint
Literature

Justification for selection of acute toxicity – inhalation endpoint
Guideline study

Justification for selection of acute toxicity – dermal endpoint
Guideline study with LD50 > 2000 mg/kg bw.

Justification for classification or non-classification

The LD50 of .alpha.-cyclodextrin after oral administration is > 10000 mg/kg bw in rats.

The LD50 of the read-across substance .beta.-cyclodextrin after oral administration is > 5000 mg/kg bw in rats.

The LC50 of the read-across substance .beta.-cyclodextrin for inhalative administration is > 4.9 mg/L in rats.

The LD50 of the read-across substance .beta.-cyclodextrin after dermal administration is > 2000 mg/kg bw in rats.