4-O-α-D-glucopyranosyl-D-glucitol

Endpoint summary

Description of key information

Acute oral toxicity:

Read-across from Syrups, corn, hydrogenated (CAS 68425-17-2/ EC 270-337-8): LD50 rat and mouse > 24.37 g/kg bw (Reliability 2 key studies; Non GLP; OECD 423 test guideline) (Research Laboratories of Roquette Freres, 1982).

Based on the analogy approach applied together with the supporting peer reviewed data on Maltitol (LD50 mouse > 25.3 mL/kg bw; CIR, 2008), the target substance Maltitol is not considered to be hazardous for acute oral toxicity according to CLP.

Acute dermal toxicity: no data required according to REACh (Regulation (EC) No 1907/2006), Annex VII

Acute inhalation toxicity: no data required according to REACh (Regulation (EC) No 1907/2006), Annex VII

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: read-across data with original study of reliability 2

Justification for type of information:

See attached document for read across analogy rationale and justification.

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LD50

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

No mortalities were reported during the study period.

Clinical signs:

There were no significant clinical signs observed during the 14 days of the study.

Body weight:

The mean body weight of mice administered Lycasin® 80/55 at a dose level of 14.62, 19.50, or 24.37 g/kg body weight was reported to be 25.4, 26.6, and 27.2 g for males, and 22.2, 23.6 and 22.8 for females, respectively. The weight gain in the animals treated by oral route is comparable between the treated groups and the control group with one exception; females receiving the dose of 19.5 g/kg body weight had weights significantly greater than those females of the control group. The authors reported that since these observations are not found in groups which received the greater doses, it is unlikely that the variations in weight gain are directly related to the test substance

Gross pathology:

Not examined.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the experimental conditions of the source study, the analogue substance, Syrups, corn, hydrogenated, did not show mortality or adverse effects after single oral administration in mice up to the highest dose tested (LD50 > 24.37 g/kg bw). Hence, based on the read across analogy, the target substance, Maltitol, is not considered to be hasardous for acute oral toxicity.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: read-across data with original study of reliability 2

Justification for type of information:

See attached document for read across analogy rationale and justification.

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LD50

Remarks:

Main study

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

Preliminary study: Two deaths (1/sex) were reported 24 hours following the forced feeding.
Main study: No mortalities were reported during the study period.

Clinical signs:

Preliminary study: No data.
Main study: None.

Body weight:

Preliminary study: No data.
Main study: The weight gain of the animals fed by oral route is comparable between the two groups.

Gross pathology:

Not examined.

The authors noted that in the case of a death, the experiment would be redone on 20 other animals. During the first trial, 2 deaths were observed, in which the authors attributed the deaths to a feeding error. The authors noted that the animals were nervous and a slightly bleedy nose was observed. No further details were available. Thus, the trial was repeated using the same methodology on a population of 10 animals per sex. The results discussed in this entry are based on the second (main) trial.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the experimental conditions of the source study, the analogue substance, Syrups, corn, hydrogenated, did not show mortality or adverse effects after single oral administration in rats at the tested dose of 24.37 g/kg bw (LD50 > 24.37 g/kg bw). Hence, based on the read across analogy, the target substance, Maltitol, is not considered to be hasardous for acute oral toxicity.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study without detailed documentation.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

-reliability scoring based on 2001 guideline

Deviations:

yes

Remarks:

-source/origin of test article, age of the animals, acclimatization period, individual observations of clinical signs, and specific time-points for observation period were not provided; dose volume administered was higher than recommended amount by OECD

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

mouse

Strain:

other: OF1 (Swiss)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: IFFA CREDO (FRANCE)
- Age at study initiation: Not reported
- Weight at study initiation: Mean body weight range: 25.4 to 27.2 g (males); 22.2 to 23.6 g (females)
- Fasting period before study: No food was available on the night before the experiment. Water was given as needed.
- Housing: Makrolon cages (5 animals/cage)
- Diet (e.g. ad libitum): U.A.R. Réf. A03 15 mm pellets (daily ration, according to age and weight: 16 to 22 g); ad libitum
- Water (e.g. ad libitum): Water was acidified with hydrochloric acid (pH 2 -3) and autoclaved for 15 minutes at 115°C; ad libitum
- Acclimation period: Not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 21
- Humidity (%): 55 to 60
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 0.25 mL/10 g body weight
Controls received the same amount of distilled water.

Doses:

14.62 g/kg body weight for both males and females [based on Lycasin® 80/55 dry weight]
19.50 g/kg body weight for both males and females [based on Lycasin® 80/55 dry weight]
24.37 g/kg body weight for both males and females [based on Lycasin® 80/55 dry weight]

No. of animals per sex per dose:

5/sex/dose

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed frequently on the day of the experiment. During the following 13 days, mortality and the general aspect of the survivors were recorded. Each animal was weighed the day of the experiment and on Days 3, 7, 10, and 14.
- Necropsy of survivors performed: no

The authors noted that in the case of a death, the experiment would be redone on 20 (10/sex) other animals; however, no deaths were reported during the study period.

Statistics:

Statistical analysis was conducted on body weight gain data.

Key result

Sex:

male/female

Dose descriptor:

other: LD50 could not be determined.

Remarks on result:

other: No mortalities were reported during the study period.

Mortality:

No mortalities were reported during the study period.

Clinical signs:

There were no significant clinical signs observed during the 14 days of the study.

Body weight:

The mean body weight of mice administered Lycasin® 80/55 at a dose level of 14.62, 19.50, or 24.37 g/kg body weight was reported to be 25.4, 26.6, and 27.2 g for males, and 22.2, 23.6 and 22.8 for females, respectively. The weight gain in the animals treated by oral route is comparable between the treated groups and the control group with one exception; females receiving the dose of 19.5 g/kg body weight had weights significantly greater than those females of the control group. The authors reported that since these observations are not found in groups which received the greater doses, it is unlikely that the variations in weight gain are directly related to the test substance.

Gross pathology:

Not examined.

Interpretation of results:

not classified

Remarks:

Criteria used for interpretation of results: CLP EC 1272/2008

Reference 4

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study without detailed documentation.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

-reliability scoring based on 2001 guideline

Deviations:

yes

Remarks:

-source/origin of test article, age of the animals, acclimatization period, individual observations of clinical signs, and specific time-points for observation period were not provided; dose volume administered was higher than recommended amount by OECD

GLP compliance:

no

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:

TEST ANIMALS
- Source: IFFA CREDO (FRANCE)
- Age at study initiation: Not reported
- Weight at study initiation: Mean body weight range: 181 to 188 g (males); 140.8 to 142.5 g (females).
- Fasting period before study: No food was available on the night before the experiment. Water was given as needed.
- Housing: Makrolon cages (5 animals/cage)
- Diet (e.g. ad libitum): U.A.R. Réf. A03 15 mm pellets (daily ration, according to age and weight: 16 to 22 g); ad libitum
- Water (e.g. ad libitum): Water was acidified with hydrochloric acid (pH 2 - 3) and autoclaved for 15 minutes at 115°C; ad libitum
- Acclimation period: Not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 21
- Humidity (%): 55 to 60
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 25 mL/kg

Doses:

24.37 g/kg body weight [based on the dry weight of Lycasin® 80/55]

No. of animals per sex per dose:

Preliminary study: 5/sex/group
Main study: 10/sex/group

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed frequently on the day of the experiment. During the following 13 days, mortality and the general aspect of the survivors were recorded. Each animal was weighed the day of the experiment and on Days 3, 7, 10, and 14.
- Necropsy of survivors performed: no

The authors noted that in the case of a death, the experiment would be redone on 20 other animals.

Statistics:

Statistical analysis was performed on body weight gain data.

Key result

Sex:

male/female

Dose descriptor:

other: LD50 could not be determined.

Remarks on result:

other: Main study: No mortalities were reported during the study period.

Mortality:

Preliminary study: Two deaths (1/sex) were reported 24 hours following the forced feeding.
Main study: No mortalities were reported during the study period.

Clinical signs:

Preliminary study: No data.
Main study: None.

Body weight:

Preliminary study: No data.
Main study: The weight gain of the animals fed by oral route is comparable between the two groups.

Gross pathology:

Not examined.

The authors noted that in the case of a death, the experiment would be redone on 20 other animals. During the first trial, 2 deaths were observed, in which the authors attributed the deaths to a feeding error. The authors noted that the animals were nervous and a slightly bleedy nose was observed. No further details were available. Thus, the trial was repeated using the same methodology on a population of 10 animals per sex. The results discussed in this entry are based on the second (main) trial.

Interpretation of results:

not classified

Remarks:

Criteria used for interpretation of results: other: CLP EC 1272/2008

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

24 370 mg/kg bw

Quality of whole database:

Reliable acute oral read across toxicity studies (Reliability 2) were used as key studies to fulfill the tonnage driven data requirement of REACH. The selected key studies are further supported by a reliability 4 peer reviewed data on the target substance.

Additional information

Only a peer reviewed (Reliability 4) acute oral toxicity data is available on the target substance (CIR, 2008; unpublished report unavailable for review). The acute oral toxicity of Maltitol (at a dose of 25.3mL/kg bodyweight) was evaluated in 5 male mice (22.5 g - 28.0 g). The animals were weighed and examined for 8 days and necropsy was performed at the end of the study. There were no observed clinical signs or necropsy findings related to the test material. Under the experimental conditions of the test, the acute oral LD50 in mice was determined to be >25.3 mL/kg body weight (> ca. 39 898.1 mg/kg bw based on density of 1.577 g/cm2). No other reliable acute oral toxicity study was available for Maltitol. Thus, a read across approach was used to fulfill data requirement for this endpoint.

The read across approach is based on the available metabolic data which demonstrate that the target substance Maltitol (CAS585-88-6 / EC 209-567-0), the read-across substances Syrups, corn, hydrogenated (CAS 68425-17-2/ EC 270-337-8) and Syrups, wheat, hydrolyzed starch (No CAS / EC 931-687-3), as well as the substances Maltose, Sorbitol and Dextrins share a common metabolic pathway as they are all converted to D-glucose and/or sorbitol via hydrolysis of their glycosidic linkages by the intestinal brush border carbohydrases. On the basis of their common mono- and disaccharide metabolites, the properties of the target substance are expected to be similar to the read-across substances. Considering this, it is anticipated that exposure to any of the aforementioned saccharides would ultimately result in the formation of D-glucose and/or sorbitol. As such, Maltitol, Syrups, corn, hydrogenated and Syrups, wheat, hydrolyzed starch may be used as appropriate surrogates for each other for the toxicological information endpoints.

Reliable acute oral toxicity data (Reliability 2; Similar to OECD 423; 1982) are available on the read-across substance Syrups, corn, hydrogenated (Lycasin® 80/55). Groups of male and female mice and rats were orally administered Lycasin® 80/55 by gavage. Groups of mice received a single dose of 14.62, 19.50, or 24.37 g/kg body weight of the analogue substance and groups of rats received a single dose of 24.37 g/kg body weight of the substance. All mice and rats were observed for 14 days. No significant clinical signs were observed in mice during the study period and no details on clinical signs were provided in rats. No treatment related changes in body weight were reported in mice or rats neither in the treated groups nor in their respective control groups. No mortalities were observed in mice or rats. Thus, the LD50 was determined to be higher than the highest doses tested (i.e., > 24.37 g/kg body weight) for both mice and rats.

Based on the data available on both the target (Reliability 4 peer reviewed supporting study) and the read-across substance, the registered substance Maltitol is not considered to be hazardous for acute oral toxicity.

Justification for classification or non-classification

Acute Toxicity, oral: The read-across substance has an acute oral LD50 value in rat and mouse > 24.37 g/kg bw (i.e. > 5000 mg/kg bw). Based on the read-across rationale and the supporting data on the target substance, the substance Maltitol does not meet the criteria for classification according to Regulation (EC) No 1272/2008.

Specific Target Organ Toxicity– Single Exposure: Based on the supporting data on the target substance and the key data available on the read-across substance, the target substance is not likely to exhibit significant toxic effects arising from a single exposure. As a result, the substance does not meet the criteria for classification according to Regulation (EC) No 1272/2008.