Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented, according to accepted guidelines.

Data source

Reference
Reference Type:
publication
Title:
Safety assessment of hydrogenated starch hydrolysates
Author:
Modderman JP
Year:
1993
Bibliographic source:
Regulatory Toxicology and Pharmacology 18, 80-144 (1993)

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
achieved concentrations not analytically verified, not all physical chemical properties of test substance reported
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): HSH (7:54:39) Lycasin 80/55
- Physical state: Not reported
- Analytical purity: 6.5% sorbitol, 54.5% maltitol, 16.7% maltotriitol, and 22.3% higher-order hydrogenated saccharides
- Lot/batch No.: not reported
- Expiration date of the lot/batch: not reported
- Storage condition of test material: not reported

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Iffa Credo, St. Germain, Arbresle, France
- Age at study initiation: not reported
- Weight at study initiation: 250 ± 20 g
- Fasting period before study: no
- Housing: 37.5X 23.5X 16 cm cages, with corn cob litter
- Diet (e.g. ad libitum): stock diet (A04 diet, U.A.R. Co., Villemoisson, Sur-Orge, France) (frequency not reported)
- Water (e.g. ad libitum):sterilized water ad libitum
- Acclimation period: 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 1°C
- Humidity (%): 60 ± 10%
- Air changes (per hr): 12/hr
- Photoperiod (hrs dark / hrs light):12/12


IN-LIFE DATES: Not reported

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: reported to be in prepared solution, however solution substance (vehicle) not reported
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Test solutions were prepared at concentrations of 30% (group I), 50% (group II), and 70% (group III) (dry weight/volume). Solutions were stored at -4°C before use.


Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
not reported
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1 (reported as monogamous cohabitation)
- Length of cohabitation: not reported
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility: not reported
- Further matings after two unsuccessful attempts: not reported
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: no
Duration of treatment / exposure:
day 6 to day 15 of gestation
Frequency of treatment:
daily
Duration of test:
Until day 20
Doses / concentrations
Remarks:
Doses / Concentrations:
3000, 5000, or 7000 mg/kg bw/d
Basis:
actual ingested
No. of animals per sex per dose:
25-29 pregnant females per dose
Control animals:
other: Yes, 10 ml/kg bw of distilled water
Details on study design:
- Dose selection rationale: not reported
- Rationale for animal assignment (if not random): random

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily



DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: Day 0, every day from day 6 to day 15, and day 20


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: ovaries and uterus

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data
- Other: total placenta weight measured
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data
Statistics:
Data represented by means and standard errors of the mean were evaluated using one-way analysis of variance. Multiple comparisons of these data were made using Student-Newman-Keuls modification of the t test. Nonparametric evaluations were made using the X² test with the Bonaferroni correction for multiple comparisons or the Fisher exact test, when the data was insufficient to use the X².
Indices:
yes
Historical control data:
not reported

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No deaths or clinical signs attributable to treatment were observed in any of the treated groups nor were any behavioral anomalies noted among the animals during the course of the experiment. The weight gain of the treated groups was comparable to that of the control groups.

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
The fetal mortality rate for all groups was extremely low. Fewer corpus lutea was observed in the low-dose group. No difference between number of implantation points, total number of fetuses, mortality rate of fetuses, and number of resorptions. A significant difference in mean fetal weight was observed in the mid-dose group but not differences in the low- and high-dose groups were observed compared to controls. A significant increase in the number of runts was observed in the low-dose group but the number was not different in the mid- and high-dose groups compared to control.. No major malformations of the skeleton, no soft-tissue/visceral malformations were observed

Effect levels (fetuses)

Dose descriptor:
NOEL
Effect level:
7 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion