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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1986
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: fulfill the basical principle, detailed information, performed scientifically

Data source

Reference
Reference Type:
publication
Title:
Effect of Methyl Hesperidin on Prenatal Development of Rats
Author:
Kunio Kawashima, Shinsuke Nakaura, Makoto Usami, Megumi Yamaguchi, Satoru Tanaka, Akira Takanaka and Yoshihito Omori
Year:
1986
Bibliographic source:
Bulletin of the National Institute of Hygienic Sciences Tok [BULL. NATL. INST. HYG. SCI., TOKYO.]. no. 104, pp. 64-68. 1986.
Report date:
1986

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
not specified
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
Methyl hesperidin
IUPAC Name:
Methyl hesperidin
Constituent 2
Reference substance name:
11013-97-1
Cas Number:
11013-97-1
IUPAC Name:
11013-97-1
Test material form:
not specified
Details on test material:
As for methyl hesperidin, the standardized product according to Japan’s Specification and Standards for Food Addictives (Hamari Chemicals, Lot. No. TO8PG-177) was used.

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
All the pregnant rats were accommodated one by one in aluminum cages (Made by Natsume Seisakusho Co., Ltd), where solid feed (Oriental Yeast, MF) and tap-water could be freely taken.
Regarding to the animal feeding and breeding room, the temperature was set as 25 ±2 ℃, the relative humidity was set as 55 ±5%, the air exchange rate was set as 15/hr, and the dark-and-light switch rate was set as 12 hours (light period: 6:00-18:00).

Administration / exposure

Route of administration:
other: oral administration by stomach tube
Vehicle:
water
Details on exposure:
Methyl hesperidin was dissolved in distilled water and then given to rats. Since the toxicity of methyl hesperidin is extremely low, by considering its solubility and the dosage of its solution against rats, the dosage was set by 3 stages with the highest level as 8 g/16 ml/kg, following which, divided by common ratio 2, another 2 stages as 4 g/8 ml/kg and 2 g/4 ml/kg were respectively set. During the period from the 7th day to the 17th day of pregnancy including the period of organogenesis of fetuses, oral administration was performed to 19-20 pregnant rats of each group by stomach tube once a day. In addition, 16 ml/kg distilled water was orally given to the rats of the control group as the same.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
In order to get pregnant rats, males were arranged to live together with the nulliparous females all night, the female rats with sperm recognized in vaginal smear next morning were provided for test and this day was taken as the day 0 of pregnancy.
Duration of treatment / exposure:
10 days
Frequency of treatment:
once a day
Duration of test:
no data
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Remarks:
control
Dose / conc.:
2 000 mg/kg bw/day
Dose / conc.:
4 000 mg/kg bw/day
Dose / conc.:
8 000 mg/kg bw/day
No. of animals per sex per dose:
19-20 pregnant rats of each group
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
The general conditions of the pregnant rats were observed, and the body weight and food consumption were measured on a daily base.
Ovaries and uterine content:
On the 20th day of pregnancy, uterus was taken out by cesarean section under ether anesthesia, and corpora lutea count, implantation count and fetal death were checked.
Fetal examinations:
Regarding to the living fetuses, the exterior abnormalities were searched by hand-touch and visual contact, and the body weights were measured. Regarding to each matrix, around 1/3 of the living fetuses were fixed for about 2 weeks by Bouin solution, during which, internal organs were checked by Wilson method. After about 2/3 of the rest fetuses were fixed by 90% ethanol, alizarin red stain skeleton specimen were made to check the abnormalities of skeletal system under magnifying glass.
Statistics:
The result of test was compared with that of the control group by the levels of P<0.05 and P<0.01 by X2 test (the death rate of maternal rats), t test (body weight, food consumption, corpora lutea count, implantation count, number of fetuses and weight of fetuses) and rank sum test (death rate of fetuses, occurrence rate of morphological abnormality, number of ossification). In addition, as for t test, in case of equal variances, the student’s method was used, in case of unequal variances, the method of Aspin-Welch was used.
Indices:
the death rate of maternal rats, death rate of fetuses, occurrence rate of morphological abnormality,
body weight, food consumption, corpora lutea count, implantation count, number of fetuses and weight of fetuses, number of ossification
Historical control data:
no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: One death animal in the mid-dose group, not considered treatment related

Details on maternal toxic effects:
No change in particular was found in food consumption in all the groups with the dose of methyl hesperidin through the entire dosing period, and the body weight gain was also smooth. No abnormality was recognized in general condition either.
As for the maternal rat with all the litter dead, 1 case was recognized in the group of 4 g/kg, however, no significant difference was recognized in occurrence rate. Regarding to the average corpora lutea count, average implantation count and implantation rate, no significant change was recognized in between the control group and the groups with the dose of methyl hesperidin.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
8 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
8 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No significant change was recognized in between the control group and the groups with the dose of methyl hesperidin in average number of fetuses, sex ratio, and average body weight of fetuses.
No abnormal case was observed including the control group in results of visual test.
The cases of dilatation of renal pelvis were observed in each group including the control group by 1.7-4.9%, however, no significant difference was recognized in occurrence rate.
Ossification status was judged by checking the number of metatarsal bones, sacral vertebrae and caudal vertebra, however, no significant difference was recognized from the control group regarding to all of these.
As skeleton deformity, 1 case (0.7%) of the front vertebra of sacral vertebra was observed out of 27 fetuses in the group of 4g/kg, however, no significant difference was recognized in occurrence rate.
Regarding to the fetuses which have skeletal mutation, 113 cases (79.0%) were observed in the control group, 112 cases (76.0%) were observed in the group of 2g/kg, 132 cases (78.8%) were observed in the group of 4g/kg and 139 cases (79.8%) were observed in the group of 8g/kg. Comparing with the control group, no significant difference was recognized in the occurrence rate of each group with the dose of methyl hesperidin. The types of skeletal mutation observed and their occurrence rates were shown as follows. Cervical rib was observed in each group including the control group by 1.7-3.4%.The deformity of cervical lordosis was observed in the group of 8g/kg by 0.6%, the abnormality of thoracic body (deformity, separation) was observed in each group including the control group by 14.2%-18.6%, however, no significant difference was observed in their occurrence rate. In addition, the abnormality of sternebra (deformity, separation and damage) was observed by 43.2%-61.2% in each group including the control group. Lumbar rib (including rudimentary rib) was observed in each group including the control group by 31.0%-42.0%. However, no significant difference was recognized in its occurrence rate.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
There was no evidence of an increase in fetal death or of malformation attributable to the treatment with methyl hesperidin in any of dose levels examined. It is concluded that test substance has no teratogenic effect in rats under the present experimental conditions.
Executive summary:

The prenatal developmental toxicity test was conducted by orally with Wistar rats. 2, 4 and 8 g/kg of methyl hesperidin were given to the pregnant rats from the 7th day to 17th day of pregnancy including the period of organogenesis of infuses once a day, the effect on the maintenance of pregnancy and the occurrence of fetuses was observed. There was no change recognized in death rate, food consumption and body weight gain for pregnant matrix in all the groups with the dose of test item. Regarding to the fetuses of the 20thday of pregnancy, no significant change was recognized in average number of fetuses, sex ratio and the death rate of fetuses in all the group with the dose of methyl hesperidin. Regarding to the inspection on the outside appearance, skeleton and internal organs, no abnormal case supposed to be derived from the dose of test substance was observed.

Based on the description above, it is concluded that methyl hesperidin is not a teratogen. According to CLP (Regulation EC No.1272/2008), test substance shall not be classified.