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EC number: 202-739-6 | CAS number: 99-20-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 14. January 1998 - 9. July 1998
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 998
- Report date:
- 1998
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Trehalose
- EC Number:
- 202-739-6
- EC Name:
- Trehalose
- Cas Number:
- 99-20-7
- Molecular formula:
- C12H22O11
- IUPAC Name:
- trehalose
- Test material form:
- solid: crystalline
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 7L111
- Expiration date of the lot/batch: 10 December 1999
- Purity test date: not stated
RADIOLABELLING INFORMATION (if applicable)
not applicable
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at ambient temperature
- Stability under test conditions: assumed stable
- Solubility and stability of the test substance in the solvent/vehicle: assumed stable
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: not applicable
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
none
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Wiga, Germany
- Age at study initiation: 11 weeks (male) / 12 weeks (female)
- Weight at study initiation: ca. 210 g
- Fasting period before study: no
- Housing:
During the quarantine and acclimatization period, the males and females were housed
in groups of 4 per sex
For mating one male and two females were housed
together
Mated females were housed individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 9 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 3 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/ 12
IN-LIFE DATES: From: 14. January 1998 To: 24. February 1998
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
During the quarantine and acclimatization period, the rats were fed a closed formula
diet obtained from SDS.
From day 0 of gestation, the female rats were fed a somewhat modified diet (batch no.
4070) supplemented with different concentrations of the test substance. The
modification consisted of the omission of 20% barley from the diet. The barley was replaced by the test substance and/or pregelatinized potato starch.
Diets were prepared by mixing the various ingredients in a mechanical blender and
stored in a refrigerator.
VEHICLE
none - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analyses to determine the content, homogeneity and stability of the test substance in
the carrier were conducted in all diets using HPLC method.
Before analysis of samples from the study, the method was validated to conform with
the following criteria:
- linearity: the correlation coefficient of the calibration curves should be greater than
or equal to 0.996;
- selectivity: no peak should be found in the blank carrier with a retention time of 95-
105% of that of the test substance;
- repeatability: the relative standard deviation in the percentage recovery and the
retention time when the recovery test is performed 3 times at each concentration
used in the study should be less than 10 and 2% respectively;
- recovery: the recovery of the test substance from the carrier should be between 80
and 110% at all concentrations used in the study.
The stability of the test substance under (simulated) experimental conditions was
demonstrated by analyzing samples with (low-, mid- and high dose) and without
(control) the test substance on the day of diet preparation, after storage at room
temperature in an open container (for 7 days) and after storage in a refrigerator in a
closed container (for about 5 weeks).
To determine the homogeneity of the test substance in the diet, 5 samples per dose
level (low-, mid- and high-dose) taken once at different locations in the feed container
and 1 control sample were analyzed.
Diet samples will be taken immediately after preparation of the diets and stored at
< -18 °C pending analysis. - Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/2
- Length of cohabitation: until pregnancy occurs
- not applicable: After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: not applicable
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: - Duration of treatment / exposure:
- The test substance was administered in the diet from fertilization (gestation day 0) up to
Cesarian section (gestation day 21). - Frequency of treatment:
- once dayly
- Duration of test:
- from fertilization (gestation day 0) up to
Cesarian section (gestation day 21)
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg diet
- Remarks:
- control group
- Dose / conc.:
- 25 000 mg/kg diet
- Dose / conc.:
- 50 000 mg/kg diet
- Dose / conc.:
- 100 000 mg/kg diet
- No. of animals per sex per dose:
- 28
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: not stated
- Rationale for animal assignment (if not random):
After mating the mated females were distributed over the 4 experimental groups in
such a way that the animals from the same day of pregnancy were equally distributed
over all groups.
In the mid-dose group 2 females (C151 and C167) were mated by the same male (48);
all other females mated by the same male were placed in different groups
- Other:
Examinations
- Maternal examinations:
- Each female was observed daily from the start of the study and, if necessary, handled
to appraise its physical condition. Signs of ill health and reaction to treatment as well
as mortality were recorded. On working days, all cages were checked again late in the
afternoon for dead or moribund animals to minimize loss of animals from the study.
During weekends and holidays only one check per day was carried out.
Body weights of the rats were recorded on days 0, 7, 14 and 21 of gestation.
The quantity of food consumed by each animal was measured over the periods days 0-
7, 7-14 and 14-21 of gestation by weighing the feeders.
The females were killed by decapitation after ether anaesthesia on gestation day 21 and
examined for gross abnormalities. Maternal tissue showing severe macroscopic
abnormalities was removed and fixed in a neutral, aqueous phosphate buffered 4%
solution of formaldehyde. - Ovaries and uterine content:
- The uteri (including the fetuses), ovaries and placentas of all females killed on day 21
were examined for the following parameters:
- number of corpora lutea
- number of implantation sites
- number of early and late resorptions
- number of live and dead fetuses
- sex of the fetuses
- number of grossly visible malformed fetuses and fetuses with external
abnormalities
- weight of ovaries
- weight of uterus, containing placentas and fetuses
- weight of uterus, empty
- weight of fetuses
- weight of the placentas
- gross evaluation of the placentas - Fetal examinations:
- First all fetuses of each litter were examined carefully for anomalies. The sex of the
fetuses was determined. Half of the number of fetuses in each litter was fixed in
Bouin's fixative and subsequently examined for soft tissue anomalies according to a
method modified after Barrow and Taylor (1969) and then discarded.
The other half of the foetuses were fixed in 70% ethanol, subsequently partly
eviscerated and then cleared in potassium hydroxide and stained with Alizarin Red S
modified after Dawson (1926). These foetuses were examined for skeletal
abnormalities and then retained.
The fetopathological examinations were initially restricted to all foetuses of the animals
of the control group and the high dose group. Only when alterations were observed in
the high-dose group, the examinations were, after consultation with the sponsor,
extended to the intermediate-dose groups. - Statistics:
- The resulting data were analyzed using the methods mentioned below. P < 0.05 was
considered as a level of significance.
Clinical findings were evaluated by Fisher's exact probability test.
Body weight, body weight gain, organ weights and food consumption data were
subjected to one-way analysis of variance (ANOVA) followed by Dunnett's multiple
comparison tests.
Fisher's exact probability test was used to evaluate the number of pregnant females
and females with live fetuses. Number of corpora lutea, implantations, live and dead
fetuses and early and late resorptions were evaluated by Kruskal-Wallis nonparametric
analysis of variance followed by the Mann-Whitney U-test . - Indices:
- For each group the following data were recorded:
- female fecundity index = (number of pregnant females/number of females
mated) x 100
- pre-implantation loss = [(number of corpora lutea - number of implantation
sites)/ number of corpora lutea] x 100
- post-implantation loss = [(number of implantation sites- number of live
fetuses)/number of implantation sites] x 100
- gestation index = (number of females with live fetuses/number of females
pregnant) x 100
- sex ratio = (number of live male fetuses/number of live fetuses) x 100 - Historical control data:
- not stated
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- Animal A53 and D 219 of the control and high-dose group showed haemorrhagic
discharge on gestation day 21 and 14, respectively.
Further, daily clinical observations during the gestation period did not reveal any
remarkable findings in the animals' appearance, general condition or behaviour
amongst the dosing and control groups. - Mortality:
- no mortality observed
- Description (incidence):
- No mortalities were observed.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No statistically significant differences in mean body weights and body weight changes
were observed amongst the control and the groups fed trehalose in the diet. - Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No statistically significant difference in food consumption was observed amongst the
control and the groups fed trehalose in the diet. - Food efficiency:
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- No remarkable differences in gravid and empty uterus
weight, ovary weight, carcass weight and net weight change (body weight gain from
day 0 to day 21 of gestation minus gravid uterine weight) were observed between the
control group and the groups fed trehalose in the diet. - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Gross examination did not reveal any significant differences of the maternal organs
and tissues amongst the groups. The few macroscopic findings observed are common
in rats. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not specified
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- For all dose groups 28 females were mated; early delivery was observed in 1 female
(A51) of the control group and 2 females (B93 and B111) of the low-dose group.
At Cesarian section, 21, 23, 24 and 24 females in the control group, low-dose, middose
and high-dose group were pregnant.
There were no statistically significant differences between the control group and the
groups fed trehalose in the diet in the number of corpora lutea, implantations, live and
dead fetuses and early and late resorptions nor in the pre- and post implantation loss
or in the sex ratio of the fetuses. - Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- For all dose groups 28 females were mated; early delivery was observed in 1 female
(A51) of the control group and 2 females (B93 and B111) of the low-dose group.
At Cesarian section, 21, 23, 24 and 24 females in the control group, low-dose, middose
and high-dose group were pregnant.
There were no statistically significant differences between the control group and the
groups fed trehalose in the diet in the number of corpora lutea, implantations, live and
dead fetuses and early and late resorptions nor in the pre- and post implantation loss
or in the sex ratio of the fetuses. - Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- For all dose groups 28 females were mated; early delivery was observed in 1 female
(A51) of the control group and 2 females (B93 and B111) of the low-dose group.
At Cesarian section, 21, 23, 24 and 24 females in the control group, low-dose, middose
and high-dose group were pregnant.
There were no statistically significant differences between the control group and the
groups fed trehalose in the diet in the number of corpora lutea, implantations, live and
dead fetuses and early and late resorptions nor in the pre- and post implantation loss
or in the sex ratio of the fetuses. - Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- For all dose groups 28 females were mated; early delivery was observed in 1 female
(A51) of the control group and 2 females (B93 and B111) of the low-dose group.
At Cesarian section, 21, 23, 24 and 24 females in the control group, low-dose, middose
and high-dose group were pregnant.
There were no statistically significant differences between the control group and the
groups fed trehalose in the diet in the number of corpora lutea, implantations, live and
dead fetuses and early and late resorptions nor in the pre- and post implantation loss
or in the sex ratio of the fetuses. - Dead fetuses:
- no effects observed
- Description (incidence and severity):
- For all dose groups 28 females were mated; early delivery was observed in 1 female
(A51) of the control group and 2 females (B93 and B111) of the low-dose group.
At Cesarian section, 21, 23, 24 and 24 females in the control group, low-dose, middose
and high-dose group were pregnant.
There were no statistically significant differences between the control group and the
groups fed trehalose in the diet in the number of corpora lutea, implantations, live and
dead fetuses and early and late resorptions nor in the pre- and post implantation loss
or in the sex ratio of the fetuses. - Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- For all dose groups 28 females were mated; early delivery was observed in 1 female
(A51) of the control group and 2 females (B93 and B111) of the low-dose group.
At Cesarian section, 21, 23, 24 and 24 females in the control group, low-dose, middose
and high-dose group were pregnant.
There were no statistically significant differences between the control group and the
groups fed trehalose in the diet in the number of corpora lutea, implantations, live and
dead fetuses and early and late resorptions nor in the pre- and post implantation loss
or in the sex ratio of the fetuses. - Changes in number of pregnant:
- not specified
- Description (incidence and severity):
- For all dose groups 28 females were mated; early delivery was observed in 1 female
(A51) of the control group and 2 females (B93 and B111) of the low-dose group.
At Cesarian section, 21, 23, 24 and 24 females in the control group, low-dose, middose
and high-dose group were pregnant.
There were no statistically significant differences between the control group and the
groups fed trehalose in the diet in the number of corpora lutea, implantations, live and
dead fetuses and early and late resorptions nor in the pre- and post implantation loss
or in the sex ratio of the fetuses. - Other effects:
- no effects observed
- Details on maternal toxic effects:
- no maternal toxic effects observed
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 100 000 mg/kg diet
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- changes in number of pregnant
- changes in pregnancy duration
- clinical signs
- dead fetuses
- early or late resorptions
- effects on pregnancy duration
- food consumption and compound intake
- food efficiency
- gross pathology
- maternal abnormalities
- mortality
- necropsy findings
- number of abortions
- organ weights and organ / body weight ratios
- pre and post implantation loss
- total litter losses by resorption
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- No significant differences in the mean fetal body weight and placenta weights were observed
between the control group and the groups fed trehalose in the diet. - Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- There were no statistically significant differences between the control group and the
groups fed trehalose in the diet in the number of corpora lutea, implantations, live and
dead fetuses and early and late resorptions nor in the pre- and post implantation loss
or in the sex ratio of the fetuses. - Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- There were no statistically significant differences between the control group and the
groups fed trehalose in the diet in the number of corpora lutea, implantations, live and
dead fetuses and early and late resorptions nor in the pre- and post implantation loss
or in the sex ratio of the fetuses. - Changes in litter size and weights:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In the low- and high-dose group a statistically significantly decreased number of large
fetuses (i.e. fetus weight > 125% of the mean fetal body weight) were observed.
Furthermore, in the low-dose group a statistically significantly decreased number of
small fetuses (i.e. fetus weight < 75% of the mean fetal body weight) was observed.
The differences in the number of large and small fetuses were not considered to be an
effect of the test substance for reason of their incidental nature and lack of dose
response. - Changes in postnatal survival:
- not examined
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In the low-dose group a fetus with a flexed hindlimb and in the control and high-dose
groups a fetus with a filiformed tail were observed. No other external findings were
observed. - Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
No skeletal malformations were observed in the fetuses of the control and high-dose
group- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- No visceral malformations were observed in the fetuses of the control and high-dose
group - Other effects:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- no embryotoxic / teratogenic effects observed.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- > 100 000 mg/kg diet
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reduction in number of live offspring
- changes in sex ratio
- fetal/pup body weight changes
- changes in litter size and weights
- external malformations
- skeletal malformations
- visceral malformations
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- On the basis of the results obtained in this study it was concluded that:
trehalose, when administered in the diet did not induce maternal nor developmental
toxicity at concentration of 2.5, 5 and 10% (1.4-2.0, 2.8-3.9 and 5.5-7.8 g trehalose/kg
body weight/day) for the low-, mid and high-dose group, respectively. - Executive summary:
1. Trehalose was fed in the diet to mated female Wistar rats (28 animals per dose
group) from days 0-21 of gestation. The concentrations in the diet were 0, 2.5, 5
and 10%. On gestation day 21 the dams were killed and macroscopically
examined. Reproductive organs were weighed and fetuses were examined after
Cesarian section. The viscera and skeletons of the fetuses of the control and highdose
group were examined.
2. The test substance was homogeneously distributed in the diets. The diets were
stable at room temperature and for 42 days in the refrigerator (2-10°C). The
content of the test substance measured in the batch diets prepared for this study
was close to intended at all dose levels.
3. No mortalities were observed.
One animal of the control and high-dose group showed haemorrhagic discharge
on gestation day 14 and 21, respectively.
Further, daily clinical observations during the gestation period did not reveal any
remarkable findings in the animals' appearance, general condition or behaviour
amongst the dosing and control groups.
4. No statistically significant differences in mean body weights, body weight changes
and food consumption were observed amongst the control and the groups fed
trehalose in the diet. The test substance intake during the gestation period ranged
from 1.4-2.0, 2.8-3.9 and 5.5-7.8 g trehalose/kg body weight/day for the low-,
mid and high-dose group, respectively.
5. For all dose groups 28 females were mated; early delivery was observed in 1
female (A51) of the control group and 2 females (B93 and B111) of the low-dose
group. At Cesarian section, 21, 23, 24 and 24 females in the control group, lowdose,
mid-dose and high-dose group were pregnant.
There were no statistically significant differences between the control group and
the groups fed trehalose in the diet in the number of corpora lutea, implantations,
live and dead fetuses and early and late resorptions nor in the pre- and post
implantation loss or in the sex ratio of the fetuses.
No remarkable differences in gravid and empty uterus weight, ovary weight,
carcass weight and net weight change (body weight gain from day 0 to day 21 of
gestation minus gravid uterine weight) were observed between the control group
and the groups fed trehalose in the diet.
6. Fetal external observations of the fetuses and placentas at Cesarian section did not
reveal any remarkable findings which could be related to treatment.
Furthermore, no significant differences in the mean fetal body weight and
placenta weights were observed between the control group and the groups fed
trehalose in the diet.
7. Upon fetal examination there were no treatment-related changes in fetal soft
tissues or fetal skeletal examination.
8. On the basis of the results obtained in this study it was concluded that:
trehalose, when administered in the diet did not induce maternal nor
developmental toxicity at concentration of 2.5, 5 and 10% (1.4-2.0, 2.8-3.9 and
5.5-7.8 g trehalose/kg body weight/day) for the low-, mid and high-dose group,
respectively.
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