2'-(β-D-glucopyranosyloxy)-4',6'-dihydroxy-3-(4-hydroxyphenyl)propiophenone

Endpoint summary

Description of key information

Oral route: Weight of evidence: Based on the available information for the read-across approach and the supporting information, the oral LD50 of the test item in rats is ≥ 3562 mg/kg bw.

- Read-across from analogue substance. Source: Method similar to OECD 420. Based on read-across approach, the oral LD50 in rats for the target substance was determined to be ≥ 3562 mg/kg bw.

- Read-across from analogue substance. Source: Method similar to OECD 420. Based on read-across approach, the oral LD50 in rats for the target substance was determined to be ≥ 3562 mg/kg bw.

- Supporting study: Method similar to OECD 420. The oral LD50 in rats of an apple extract containing phloridzin was found to be > 2000 mg/kg bw.

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:

experimental study

Adequacy of study:

key study

Study period:

From April 19th to May 3rd, 1973.

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Principles of method if other than guideline:

- Procedure found in Section 191.1 (f)(1) of the Federal Hazardous Substance Act; NPI Standard Test No.6.

GLP compliance:

no

Test type:

fixed dose procedure

Limit test:

yes

Specific details on test material used for the study:

TEST MATERIAL
- Lot No. 6-RS-7, received April 5, 1973.
- Purity (HPLC): 98.5%
- Impurities: Arsenic < 3ppm, Heavy metals < 15ppm.
- Loss on drying: 10.0%
- Residue on ignition: 1.0%
- Name of test material (as cited in study report): neohesperidin dihydrochalcone (Neo-DHC)
- Molecular formula (if other than submission substance): C28H36O15
- Molecular weight (if other than submission substance): 612.5764
- Smiles notation (if other than submission s.): CC1C(O)C(O)C(O)C(OC2C(O)C(O)C(CO)OC2Oc2cc(O)c(C(=O)CCc3ccc(OC)c(O)c3)c(O)c2)O1
- InChl (if other than submission substance): InChI=1/C28H36O15/c1-11-21(34)23(36)25(38)27(40-11)43-26-24(37)22(35)19(10-29)42-28(26)41-13-8-16(32)20(17(33)9-13)14(30)5-3-12-4-6-18(39-2)15(31)7-12/h4,6-9,11,19,21-29,31-38H,3,5,10H2,1-2H3

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 234g (females) and 290g (males).
- Fasting period before study: overnight
- Diet: commercial laboratory animal feed ad libitum.
- Water: bottled spring water ad libitum.
- Acclimation period: 6d.

IN-LIFE DATES: From: April 19, 1973 To: May 3, 1973.

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: The test material was used in a 12.5% gravimetric suspension in water.
- Amount of vehicle (if gavage):

MAXIMUM DOSE VOLUME APPLIED:

DOSAGE PREPARATION: the powdered neohesperidin dihydrochalcone was mixed with 8cc of distilled water and allowed to stand 15min prior to being administered to animals. Females received 1.2g and males 1.5g test item each.

Doses:

5000 mg/kg bw.

No. of animals per sex per dose:

5 per sex per dose

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for signs of pharmacologic activity and drug toxicity at 1, 3, 6 and 24h post-dosage. Observations were made daily thereafter to a total of 14d.
- Necropsy of survivors performed: yes. Animals sacrificed at the end of the 14-day observation period were subjected to complete gross necropsy.
- Other examinations performed: clinical signs, body weight, histopathology.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

All animals were alive at the completion of the test.

Clinical signs:

other: No effects observed.

Gross pathology:

No gross changes observed.

Interpretation of results:

GHS criteria not met

Remarks:

EU criteria

Conclusions:

Based on read-across approach, the target substance was found to be non toxic, LD50 ≥ 5000mg/kg.

Executive summary:

The acute oral toxicity of neohesperidin dihydrochalcone on rats was studied by a method similar to OECD TG 420. A limit test was performed by administering a single dose of 5g/kg bw test item to 10 (5M/5F) Wistar rats, and observing the effects for 14 days (clinical signs, body weights). No effects were observed in any animal. Therefore, the test item was found to be non toxic, with an LD50 > 5000 mg/kg bw.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From Agust 11th to September 24th, 1978.

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Principles of method if other than guideline:

- Procedure by Hagan, E.C. (1959). Acute Toxicity; Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics, pp. 17-25. (see 'Attached background material').

GLP compliance:

no

Test type:

fixed dose procedure

Limit test:

yes

Specific details on test material used for the study:

TEST MATERIAL
- Lot No. 26-RS-17, received 11/8/1978.
- Purity (HPLC): 98.5%
- Impurities: Arsenic < 3ppm, Heavy metals < 15ppm.
- Loss on drying: 10.0%
- Residue on ignition: 1.0%
- Name of test material (as cited in study report): neohesperidin dihydrochalcone (Neo-DHC)
- Molecular formula (if other than submission substance): C28H36O15
- Molecular weight (if other than submission substance): 612.5764
- Smiles notation (if other than submission s.): CC1C(O)C(O)C(O)C(OC2C(O)C(O)C(CO)OC2Oc2cc(O)c(C(=O)CCc3ccc(OC)c(O)c3)c(O)c2)O1
- InChl (if other than submission substance): InChI=1/C28H36O15/c1-11-21(34)23(36)25(38)27(40-11)43-26-24(37)22(35)19(10-29)42-28(26)41-13-8-16(32)20(17(33)9-13)14(30)5-3-12-4-6-18(39-2)15(31)7-12/h4,6-9,11,19,21-29,31-38H,3,5,10H2,1-2H3

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 176-210 g.
- Fasting period before study: overnight
- Diet: commercial laboratory animal feed ad libitum.
- Water: bottled spring water ad libitum.
- Acclimation period: 6d.

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: The test material was used in a 12.5% gravimetric suspension in water.

Doses:

5000 mg/kg bw.

No. of animals per sex per dose:

5 per sex per dose

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for signs of pharmacologic activity and drug toxicity at 1, 3, 6 and 24h post-dosage. Observations were made daily thereafter to a total of 14d.
- Necropsy of survivors performed: yes. Animals sacrificed at the end of the 14-day observation period were subjected to complete gross necropsy.
- Other examinations performed: clinical signs, body weight.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

1/5 males died at day 9, 0/5 females died.

Clinical signs:

other: No effects observed.

Gross pathology:

No gross changes observed.

Table 1. Acute Oral Toxicity for neohesperidin dihydrochalcone.

Animal Number

Sex

Body weight (g)

Hours

Days

Body weight (final, g)

1

3

6

24

2

3

4

5

6

7

14

1

M

204

N

N

N

N

N

N

N

N

N

N

N

358

2

208

N

N

N

N

N

N

N

N

N

N

N

348

3

210

N

N

N

N

N

N

N

N

N

N

N

382

4

176

N

N

N

N

N

N

N

N

N

N

N

308

5

206

N

N

N

N

N

N

N

N

N

N

+

160

6

F

196

N

N

N

N

N

N

N

N

N

N

N

230

7

202

N

N

N

N

N

N

N

N

N

N

N

254

8

188

N

N

N

N

N

N

N

N

N

N

N

244

9

196

N

N

N

N

N

N

N

N

N

N

N

254

10

188

N

N

N

N

N

N

N

N

N

N

N

228

N: normal, D: depression, SD: slight depression, D: severe depression, +: animal death.

Remarks: Animal #1 - #4, #6 - #10: no gross changes observed. Animal #5: No gross changes observed (died on day 9).

Interpretation of results:

GHS criteria not met

Remarks:

EU criteria.

Conclusions:

The test item was found to be non toxic, LD50 ≥ 5000 mg/kg bw.

Executive summary:

The study of the acute oral toxicity of neohesperidin dihydrochalcone on rats was performed by a method similar to OECD TG 420. A limit test was performed by administering a single dose of 5g/kg bw test item to 10 (5M/5F) Wistar rats, and observing the effects for 14 days (clinical signs, body weights). One male died on day 9, but no gross changes were observed, and no effects were noted on any other animal. Therefore, the test item was found to be non toxic, with an LD50 > 5000 mg/kg bw.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2004.

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

unsuitable test system

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

not applicable

GLP compliance:

no

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Remarks:

(Crj: CD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Japan Inc., Japan.
- Age at study initiation: 5-week old
- Weight at study initiation: Male rats weighed 119–133 g and female rats weighed 100–106 g.
- Fasting period before study: Not specified. The rats were not fed for 3 h following administration.

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

0.5% CMC-Na solution

Details on oral exposure:

VEHICLE
- Source: Iwai Chemicals Co., Ltd., Tokyo, Japan, Lot not specified.

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

Doses:

2000 mg /kg.

No. of animals per sex per dose:

5 per sex per dose

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: General condition and body weight were monitored for 14 days after administration.
- Necropsy of survivors performed: yes. The following organs were examined: heart, spleen, trachea, lungs, stomach, duodenum, ileum, jejunum, cecum, colon, rectum, liver, kidneys, urinary bladder, testis, pituitary, thyroids, parathyroid, adrenals gland, brain, submaxillary glands, thymus, seminal vesicle, prostate, ovary, and uterus.
- Other examinations performed: clinical signs, body weight, organ weights.

Statistics:

One-way parametric ANOVA with Dunnett’s test was used to examine the organ weight, body weight, food consumption, hematological and blood chemistry data produced by the oral-toxicity test.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

act. ingr.

Remarks on result:

other: apple exctract containing phloridzin.

Mortality:

All rats treated with the AP at a dose of 2000 mg/kg survived the 14-day observation period.

Clinical signs:

other: No effects.

Other findings:

No significant changes were observed in any organs at the necropsy on day 14.

Interpretation of results:

GHS criteria not met

Remarks:

EU criteria.

Conclusions:

Under test conditions, the LD50 for the test substance is greater than 2000mg/kg.

Executive summary:

The acute oral toxicity of Applephenon®, apple extract from unripe apples containing phloridzin, was studied by means of a limit test, by a method similar to OECD 420 (non-GLP). 5 male and 5 female Sprague-Dawley (Crj: CD) rats were administered a single dose of 2000 mg/kg test item by gavage and observed for 14 days. All rats treated with the AP at a dose of 2000 mg/kg survived the 14-day observation period, no significant changes were observed in any organs at the necropsy on day 14. Under test conditions, the test item was found to be non-toxic by oral route, with an LD50 > 2000 mg/kg. Thus, phloridzin is considered to be non toxic, although an LD50 for phloridzin cannot be calculated.

Reference 4

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
See "attached justification".

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 3 562 mg/kg bw

Based on:

test mat.

Remarks on result:

other: read-across from analogue substance.

Interpretation of results:

GHS criteria not met

Remarks:

EU criteria

Conclusions:

Based on read-across approach, the target substance was found to be non toxic, LD50 ≥ 3562 mg/kg.

Executive summary:

The study of the acute oral toxicity of the analogue substance neohesperidin dihydrochalcone on rats was studied by a method similar to OECD TG 420. A limit test was performed by administering a single dose of 5g/kg bw test item to 10 (5M/5F) Wistar rats, and observing the effects for 14 days (clinical signs, body weights). No effects were observed in any animal. Therefore, the analogue substance was found to be non toxic, with an LD50 > 5000 mg/kg bw. Based on read-across approach, the target substance was found to be non toxic, LD50 ≥ 3562 mg/kg.

Reference 5

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
See "attached justification".

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

GLP compliance:

no

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

water

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 3 562 mg/kg bw

Based on:

test mat.

Remarks on result:

other: read-across from analogue substance.

Interpretation of results:

GHS criteria not met

Remarks:

EU criteria

Conclusions:

Based on the read-across approach, the target substance was found to be non toxic, LD50 ≥ 3562 mg/kg bw.

Executive summary:

The study of the acute oral toxicity of the analogue substance neohesperidin dihydrochalcone on rats was studied by a method similar to OECD TG 420. A limit test was performed by administering a single dose of 5g/kg bw test item to 10 (5M/5F) Wistar rats, and observing the effects for 14 days (clinical signs, body weights). One male died on day 9, but no gross changes were observed, and no effects were noted on any other animal. Therefore, the analogue substance was found to be non toxic, with an LD50 > 5000 mg/kg bw. Based on the read-across approach, the target substance was found to be non toxic, LD50 ≥ 3562 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 562 mg/kg bw

Quality of whole database:

The two studies used for read-across have a Klimisch score of 2.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral route: Weight of evidence:

- Read-across from analogue substance. The acute oral toxicity of neohesperidin dihydrochalcone on rats was studied by a method similar to OECD TG 420. A limit test was performed by administering a single dose of 5g/kg bw test item to 10 (5M/5F) Wistar rats, and observing the effects for 14 days (clinical signs, body weights). No effects were observed in any animal. Therefore, the analogue substance was found to be non toxic, with an LD50 > 5000 mg/kg bw. Based on read-across approach, the oral LD50 in rats for the target substance was determined to be ≥ 3562 mg/kg bw.

- Read-across from analogue substance. The study of the acute oral toxicity of neohesperidin dihydrochalcone on rats was performed by a method similar to OECD TG 420. A limit test was performed by administering a single dose of 5g/kg bw test item to 10 (5M/5F) Wistar rats, and observing the effects for 14 days (clinical signs, body weights). One male died on day 9, but no gross changes were observed, and no effects were noted on any other animal. Therefore, the analogue substance was found to be non toxic, with an LD50 > 5000 mg/kg bw. Based on read-across approach, the oral LD50 in rats for the target substance was determined to be ≥ 5000 mg/kg bw. Based on the read-across approach, the target substance is non toxic, with an LD50 > 3562 mg/kg bw.

- Supporting study: A limit test to determine the acute oral toxicity of Applephenon®, apple extract from unripe apples containing phloridzin, was coherent with the expected results. The study was performed by a method similar to OECD 420 (non-GLP). 5 male and 5 female Sprague-Dawley (Crj: CD) rats were administered a single dose of 2000 mg/kg test item by gavage and observed for 14 days. Under test conditions, the test item was found to be non-toxic by oral route, with an LD50 ≥ 2000 mg/kg. Thus, phloridzin is considered to be non toxic, although an LD50 for phloridzin cannot be calculated.

Based on the available information for the read-across approach and the supporting information, the oral LD50 of the test item in rats is ≥ 3562 mg/kg bw.

Justification for classification or non-classification

Based on available data (oral LD50 ≥ 3562 mg/kg bw in rats), the substance is not classified for acute toxity according to CLP Regulation (EC) No. 1272/2008.