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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Data waiving (study scientifically not necessary / other information available): According to column 2 of REACH Annex VIII, the study does not need to be conducted if a pre-natal developmental toxicity study is available.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because a pre-natal developmental toxicity study is available
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
According to colum 2 of REACH Annex VIII, the study does not need to be conducted if a pre-natal developmental toxicity study is available.
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

Weight of evidence: Based on two studies from analogue substances, and following a worst-case scenario approach, the NOAEL of the substance is considered to be 3127 mg/kg bw/d in rats, both for maternal and developmental toxicity.

- Read-across from supporting substance (structural analogue or surrogate). Source: Key study. Method according to OECD 414, GLP study. The analogue substance neohesperidin dihydrochalcone did not exhibit any maternal toxicity, fetotoxicity, embryotoxicity, or teratogenicity in Wistar Crl:(WI)WU BR rats at doses up to 5% in diet. Therefore, the NOAEL of the analogue substance in rats was set at 3300 mg/kg bw/d. Based on the read-across approach, the target substance is not toxic to reproduction and has a NOAEL of 3127mg/kg bw/d for both maternal and developmental toxicity.

- Read-across from supporting substance (structural analogue or surrogate). Source: Key study. Method similar to OECD 414. Daily oral administration of the analogue substance methyl hesperidin to 19 -20 Wistar rats per group at doses of 2, 4 and 8 g/kg, from the 7th day of pregnancy to the 17th of pregnancy did not induce any maternal toxicity, fetotoxicity, embryotoxicity, or teratogenicity. Therefore, the NOAEL for maternal and developmental toxicity in rats was set at 8000 mg/kg bw. Based on the read-across approach, the target substance is not toxic to reproduction and has a NOAEL of 7435mg/kg bw/d for both maternal and developmental toxicity.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
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')

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The analogue substance shares the same functional groups with the target and has a similar molecular weight, and comparable values for the relevant molecular properties.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
- Source: neohesperidin dihydrochalcone, CAS No. 20702-77-6, EC No. 243-978-6, purity 96.9%, water content 9.3%.
- Target: see 'test item'.

3. ANALOGUE APPROACH JUSTIFICATION
Please find Reporting Format in 'Attached justification'.

4. DATA MATRIX
Please find Data Matrix included in 'Attached justification'.
Reason / purpose:
read-across source
Related information:
Composition 1
Test material information:
Composition 1
Specific details on test material used for the study:
TEST MATERIAL
- Name of test material: naringin
- IUPAC name: 5-hydroxy-2-(4-hydroxyphenyl)-4-oxo-3,4-dihydro-2H-chromen-7-yl 2-O-(6-deoxy-α-L-mannopyranosyl)-β-D-glucopyranoside
- Molecular formula: C27H32O14
- Molecular weight: 580,5346
- Smiles notation: CC1C(O)C(O)C(O)C(OC2C(O)C(O)C(CO)OC2Oc2cc3c(c(O)c2)C(=O)CC(c2ccc(O)cc2)O3)O1
- Structural formula attached as image file (if other than submission substance): see 'Attached justification'
Species:
rat
Strain:
Wistar
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
>= 3 127 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: no significant effects observed
Remarks on result:
other: Read-across from analogue substance
Remarks:
For the analogue substance, NOAEL = 5% (ca. 3300 mg/kg bw/day)
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Fetal/pup body weight changes:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
3 127 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no significant effects observed.
Remarks on result:
other: Read-across from analogue substance.
Remarks:
For the analogue substance, NOAEL = 5% (ca. 3300 mg/kg bw/day)
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
Based on the read-across approach, the NOAEL of naringin for teratogenicity and maternal toxicity in Crl:(WI)WU BR rats has been set at 3217mg/kg bw/d.
Executive summary:

Read-across from supporting substance (structural analogue or surrogate): A study was conducted to assess the embryotoxic, fetotoxic, and teratogenic potential of the oral administration of the analogue substance neohesperidin dihydrochalcone in rats by a method according to OECD 414 (GLP study). Starting from day 0 of gestation, 28 mated female Wistar Crl:(WI)WU BR rats per group received experimental diets containing the analogue substance at levels of 0 (control), 1.25, 2.5, and 5%. Based on the test results, the test item, at a dietary level of up to 5% (corresponding to an intake of about 3.3 g/kg bw/day) did not exhibit any maternal toxicity, fetotoxicity, embryotoxicity, or teratogenicity in Wistar Crl:(WI)WU BR rats. Therefore, the NOAEL of the analogue substance neohesperidin dihydrochalcone in rats was set at 3300 mg/kg bw/d. Based on the read-across approach, the NOAEL of the target substance for teratogenicity and maternal toxicity in rats has been set at 3127 mg/kg bw/d.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1986
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH (see 'Attached justification')

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The analogue substance shares the same functional groups with the target and has a similar molecular weight, and comparable values for the relevant molecular properties.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
- Source: methyl hesperidin, CAS No. 11013-97-1.
- Target: see 'test item'.

3. ANALOGUE APPROACH JUSTIFICATION
Please find Reporting Format in 'Attached justification'.

4. DATA MATRIX
Please find Data Matrix included in 'Attached justification'.
Reason / purpose:
read-across source
Related information:
Composition 1
GLP compliance:
not specified
Limit test:
no
Test material information:
Composition 1
Specific details on test material used for the study:
TEST MATERIAL
- Name of test material: naringin
- IUPAC name: 5-hydroxy-2-(4-hydroxyphenyl)-4-oxo-3,4-dihydro-2H-chromen-7-yl 2-O-(6-deoxy-α-L-mannopyranosyl)-β-D-glucopyranoside
- Molecular formula: C27H32O14
- Molecular weight: 580,5346
- Smiles notation: CC1C(O)C(O)C(O)C(OC2C(O)C(O)C(CO)OC2Oc2cc3c(c(O)c2)C(=O)CC(c2ccc(O)cc2)O3)O1
- Structural formula attached as image file (if other than submission substance): see 'Attached justification'
Species:
rat
Strain:
Wistar
Route of administration:
oral: gavage
Vehicle:
water
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
not specified
Effects on pregnancy duration:
no effects observed
Early or late resorptions:
not specified
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
7 435 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: no significant effects were observed.
Remarks on result:
other: read-across from supporting substance (structural analogue or surrogate)
Remarks:
For the analogue substance, NOAEL = 8000 mg/kg bw/day.
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Fetal/pup body weight changes:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
7 435 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no significant effects were observed.
Remarks on result:
other: read-across from supporting substance (structural analogue or surrogate)
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
Based on the read-across approach, the NOAEL of the target substance can be set at 7435 mg/kg bw/d for both maternal and developmental toxicity.
Executive summary:

A prenatal developmental toxicity test was conducted by a method similar to OECD 414. Daily oral administration of the analogue substance methyl hesperidin to 19 -20 Wistar rats per group at doses of 2, 4 and 8 g/kg, from the 7th day of pregnancy to the 17th of pregnancy was performed. A control group receiving 16 ml/kg distilled water was run in parallel. No changes in death rate, food consumption or body weight gain were observed for any of the treated groups. There was no significant change in mean fetal number, sex ratio and fetal mortality in any of the treated fetuses, no abnormalities related to the test item were observed. Based on the results, the NOAEL for maternal and developmental toxicity in rats was set at 8000 mg/kg bw. The test item was not teratogenic under test conditions. Based on the read-across approach, the NOAEL of the target substance can be set at 7435 mg/kg bw/d for both maternal and developmental toxicity.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
3 127 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Both studies have a Klimisch score of 2.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Weight of evidence: Based on two studies from analogue substances, and following a worst-case scenario approach, the NOAEL of the substance is considered to be 3127 mg/kg bw/d in rats, both for maternal and developmental toxicity.

- Read-across from supporting substance (structural analogue or surrogate). Source: Key study. A study was conducted to assess the embryotoxic, fetotoxic, and teratogenic potential of the oral administration of the analogue substance neohesperidin dihydrochalcone in rats by a method according to OECD 414 (GLP study). Starting from day 0 of gestation, 28 mated female Wistar Crl:(WI) WU BR rats per group received experimental diets containing the analogue substance at levels of 0 (control), 1.25, 2.5, and 5%. Based on the test results, the test item, at a dietary level of up to 5% (corresponding to an intake of about 3.3 g/kg bw/day) did not exhibit any maternal toxicity, fetotoxicity, embryotoxicity, or teratogenicity in Wistar Crl:(WI)WU BR rats. Therefore, the NOAEL of the analogue substance neohesperidin dihydrochalcone in rats was set at 3300 mg/kg bw/d. Based on the read-across approach, the NOAEL of the target substance for teratogenicity and maternal toxicity in rats has been set at 3127 mg/kg bw/d.

- Read-across from supporting substance (structural analogue or surrogate). Source: Key study. A prenatal developmental toxicity test was conducted by a method similar to OECD 414. Daily oral administration of the analogue substance methyl hesperidin to 19 -20 Wistar rats per group at doses of 2, 4 and 8 g/kg, from the 7th day of pregnancy to the 17th of pregnancy was performed. A control group receiving 16 ml/kg distilled water was run in parallel. The analogue substance neohesperidin dihydrochalcone did not exhibit any maternal toxicity, fetotoxicity, embryotoxicity, or teratogenicity, so the NOAEL for maternal and developmental toxicity in rats was set at 8000 mg/kg bw. Based on the read-across approach, the NOAEL of the target substance can be set at 7435mg/kg bw/d for both maternal and developmental toxicity.

Justification for classification or non-classification

Based on the available information, the substance is not classified for toxicity to reproduction in accordance with CLP Regulation (EC) No. 1272/2008.