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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
4 dose levels, administered on GD 6-15 by oral gavage, examination for skeletal and external malformations on GD 20
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
Virgin adult female albino rats (Wistar derived stock) were individually housed in mesh bottom cages in temperature and humidity controlled quarters with free access to food and fresh tap water.
Route of administration:
oral: gavage
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Females rats were mated with young adult males, and observation of the vaginal sperm plug was considered Day 0 of gestation.
Duration of treatment / exposure:
GD 6-15
Frequency of treatment:
daily
Duration of test:
until GD 20
Dose / conc.:
13.5 mg/kg bw/day (actual dose received)
Dose / conc.:
62.7 mg/kg bw/day (actual dose received)
Dose / conc.:
292 mg/kg bw/day (actual dose received)
Dose / conc.:
1 350 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
20 - 25 pregnat rats
Control animals:
yes, sham-exposed
other: positve control: dosed with Aspirin (250 mg/kg bw/d)
Maternal examinations:
Body weights were recorded on Days 0, 6, 11, 15, and 20 of gestation. All animals were observed daily for appearance and behavior with particular attention to food consumption and weight, in order to rule-out any abnormalities which may have occurred as a result of anorexic effects in the pregnant female animal.
Fetal examinations:
All fetuses were examined grossly for the presence of external congenital abnormalities, One-third of the fetuses of each litter underwent detailed visceral examinations employing 10X magnification. The remaining two-thirds were cleared in potassium hydroxide (KOH), stained with alizarin red S dye and examined for skeletal defects.
Clinical signs:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Maternal body weight after 20 days was 334 g in average in highest dose group, against a mean body weight of 356 in sham controls.
Early or late resorptions:
effects observed, non-treatment-related
Description (incidence and severity):
no significant difference between treated and sham control animals
Dead fetuses:
no effects observed
Changes in number of pregnant:
no effects observed
Key result
Dose descriptor:
LOAEL
Effect level:
>= 1 350 mg/kg bw/day (nominal)
Basis for effect level:
body weight and weight gain
Key result
Abnormalities:
no effects observed
Reduction in number of live offspring:
no effects observed
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
no significant difference between treated and sham control animals
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
no significant difference between treated and sham control animals
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 350 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
external malformations
skeletal malformations
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Abnormalities:
effects observed, non-treatment-related
Localisation:
skeletal: skull
skeletal: sternum
skeletal: rib
skeletal: vertebra
other: external: extremities (unspecified)
Developmental effects observed:
yes
Lowest effective dose / conc.:
13.5 mg/kg bw/day (actual dose received)
Treatment related:
no
Relation to maternal toxicity:
developmental effects occurring together with maternal toxicity effects, but not as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
no
Relevant for humans:
no
Conclusions:
The administration of up to 1350 mg/kg (body weight) of the test material to pregnant rats for 10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.
Executive summary:

The developmental toxicity of Syloid 244 was assessed in rats treated on GD 6 -15.

Reason / purpose:
reference to same study
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
4 dose levels, administered on GD 6-10 by oral gavage, examination for skeletal and external malformations on GD 14
GLP compliance:
not specified
Limit test:
no
Species:
hamster
Strain:
other: golden hamsters
Details on test animals and environmental conditions:
Virgin adult female golden hamsters from an outbred strain were individually housed in mesh bottom cages in temperature and humidity controlled quarters with free access to food and fresh tap water at all times.
Route of administration:
oral: gavage
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Females hamsters were mated with young adult males and the appearance of motile sperm in the vaginal smear was considered Day 0 of gestation.
Duration of treatment / exposure:
GD 6-10
Frequency of treatment:
daily
Duration of test:
until GD 14
Dose / conc.:
16 mg/kg bw/day (actual dose received)
Dose / conc.:
74.3 mg/kg bw/day (actual dose received)
Dose / conc.:
345 mg/kg bw/day (actual dose received)
Dose / conc.:
1 600 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
20 - 22 pregnat hamsters
Control animals:
yes, sham-exposed
other: positve control: dosed with Aspirin (250 mg/kg bw/d)
Maternal examinations:
Body weights were recorded on. Days 0 , 8, 10, and 14 of the gestation period. All animals were observed daily for appearance and behavior with particular attention to food consumption in order to better recognize any abnonnmlities resulting from anorexic effects in the pregnant animal.
Fetal examinations:
All fetuses were examined grossly for the presence of external congenital abnormalities, One third of the fetuses of each litter underwent detailed visceral examinations employing 10X magnification. The remaining two-thirds were cleared in potassium hydroxide (KOH), stained with alizarin red S dye and examined for skeletal abnormalities.
Clinical signs:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Maternal body weight after 14 days was 147.6 g in average in highest dose group, against a mean body weight of 157.4 in sham controls.
Early or late resorptions:
effects observed, non-treatment-related
Description (incidence and severity):
no significant difference between treated and sham control animals
Dead fetuses:
no effects observed
Changes in number of pregnant:
no effects observed
Key result
Dose descriptor:
LOAEL
Effect level:
>= 1 600 mg/kg bw/day (nominal)
Basis for effect level:
body weight and weight gain
Key result
Abnormalities:
no effects observed
Reduction in number of live offspring:
no effects observed
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
no significant difference between treated and sham control animals
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
no significant difference between treated and sham control animals
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 600 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
external malformations
skeletal malformations
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Abnormalities:
effects observed, non-treatment-related
Localisation:
skeletal: skull
skeletal: sternum
skeletal: rib
skeletal: vertebra
other: external: extremities (unspecified)
Developmental effects observed:
yes
Lowest effective dose / conc.:
16 mg/kg bw/day (actual dose received)
Treatment related:
no
Relation to maternal toxicity:
developmental effects occurring together with maternal toxicity effects, but not as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
no
Relevant for humans:
no
Conclusions:
The administration of up to 1600 mg/kg (body weight) of the test material to pregnant hamsters for 5 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.
Executive summary:

The developmental toxicity of Syloid 244 was assessed in hamsters treated on GD 6 -10.

Reason / purpose:
reference to same study
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
4 dose levels, administered on GD 6-18 by oral gavage, examination for skeletal and external malformations on GD 29
GLP compliance:
not specified
Limit test:
no
Species:
rabbit
Strain:
Dutch
Details on test animals and environmental conditions:
Virgin, adult Dutch belted female rabbits were individually housed in mesh bottom cages in temperature and humidity-controlled quarters with free access to food and fresh tap water.
Route of administration:
oral: gavage
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Each doe was inseminated artificially with 0.3 ml of diluted semen from, a proven donor buck using approximately 20 x 10^6 motile sperm.
Duration of treatment / exposure:
GD 6-18
Frequency of treatment:
daily
Duration of test:
until GD 29
Dose / conc.:
16 mg/kg bw/day (actual dose received)
Dose / conc.:
74.3 mg/kg bw/day (actual dose received)
Dose / conc.:
345 mg/kg bw/day (actual dose received)
Dose / conc.:
1 600 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10 - 15 pregnat rabbits
Control animals:
yes, sham-exposed
other: positve control: dosed with 6-AN (2.5 mg/kg) on GD 9
Details on study design:
On Day 0, each doe was given an injection of 0.4 ml of human chorionic gonadotropin (400 IU) via the margins 1 ear vein. Three hours later, each
doe was inseminated artificially with 0.3 ml of diluted semen from, a proven donor buck using approximately 20 x 10^6 motile sperm. Beginning on Day 6 and continuing daily through Day 18 the females were dosed with the indicated dosages by oral intubation. The controls were sham treated with the vehicle at a level equivalent to the group receiving the highest test dose.
Maternal examinations:
Body weights were recorded on Days 0, 6, 12, 18, and 29 of gestation. All animals were observed daily for appearance and behavior, with particular attention to food consumption and body weight in order to rule out any abnormalities which may have occurred as a result of anorexic effects in the pregnant female animal.
Fetal examinations:
All fetuses underwent a detailed gross examination for the presence of external congenital abnommlities. The live fetuses of each litter were then placed in an incubator for 24 hours for the evaluation of neonatal survival. All surviving pups were sacrificed, and all pups examined for visceral abnormalities (by dissection) . All fetuses were then cleared in potassum hydroxide (KOH), stained with alizarin red S dye and examined for skeletal defects.
Clinical signs:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Maternal body weight after 29 days was 3.34 kg in average in highest dose group, against a mean body weight of 3.84 kg in sham controls.
Early or late resorptions:
effects observed, non-treatment-related
Description (incidence and severity):
no significant difference between treated and sham control animals
Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
no significant difference between treated and sham control animals; the highest mortality was in the lowest dose group, but not in shame control animals.
Changes in number of pregnant:
no effects observed
Key result
Dose descriptor:
LOAEL
Effect level:
>= 1 350 mg/kg bw/day (nominal)
Basis for effect level:
body weight and weight gain
Key result
Abnormalities:
no effects observed
Reduction in number of live offspring:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
no significant difference between treated and sham control animals
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 600 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
external malformations
skeletal malformations
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Abnormalities:
effects observed, non-treatment-related
Localisation:
skeletal: skull
skeletal: sternum
skeletal: rib
skeletal: vertebra
Developmental effects observed:
yes
Lowest effective dose / conc.:
16 mg/kg bw/day (actual dose received)
Treatment related:
no
Relation to maternal toxicity:
developmental effects occurring together with maternal toxicity effects, but not as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
no
Relevant for humans:
no
Conclusions:
The administration of up to 1600 mg/kg (body weight) of the test material to pregnant rabbits for 13 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.
Executive summary:

The developmental toxicity of Syloid 244 was assessed in rabbits treated on GD 6 -18.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1973
Report Date:
1973

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
4 dose levels, administered on GD 6-15 by oral gavage, examination for skeletal and external malformations on GD 17
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: nanoform, no surface treatment
Details on test material:
CAS.-Nr.: 7631-86-9, Gel, Surface Area/BET [m2/g]: 349, purity > 99%

Test animals

Species:
mouse
Strain:
CD-1
Details on test animals and environmental conditions:
Virgin adult female albino CD-1 outbred mice were ganghoused in disposable plastic cages in temperature and humidity-controlled quarters with free access to food and fresh tap water.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Females mice were mated with young adult males, and observation of the vaginal sperm plug was considered Day 0 of gestation.
Duration of treatment / exposure:
GD 6-15
Frequency of treatment:
daily
Duration of test:
until GD 17
Doses / concentrationsopen allclose all
Dose / conc.:
13.4 mg/kg bw/day (actual dose received)
Dose / conc.:
62.3 mg/kg bw/day (actual dose received)
Dose / conc.:
289 mg/kg bw/day (actual dose received)
Dose / conc.:
1 340 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
21 - 26 pregnant dams
Control animals:
yes, sham-exposed
other: positive control: dosed with Aspirin (150 mg/kg bw/d)

Examinations

Maternal examinations:
Body weights were recorded on Days 0, 6, 11, 15, and 17 of gestation. All animals were observed daily for appearance and behavior with particular attention to food consumption and weight, in order to rule out any abnormalities which may have occurred as a result of anorexic effects in the pregnant female animal.
On Day 17 all dams were subjected to Caesarean section under surgical anesthesia, and the numbers of implantation sites, resorption
sites, and live and dead fetuses were recorded. The body weights of the live pups were also recorded. The urogenital tract of each dam
was examined in detail for anatomical normality.
Fetal examinations:
All fetuses were examined grossly for the presence of external congenital abnormalities. One-third of the fetuses of each litter underwent detailed visceral examinations employing 10X magnification. The remaining two-thirds were cleared in potassium hydroxide (KOH), stained with alizarin red S dye and examined for skeletal defects.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Maternal body weight after 17 days was 43.6 g in average in highest dose group, against a mean body weight of 50.1 in sham controls.

Maternal developmental toxicity

Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
no significant difference between treated and sham control animals
Changes in number of pregnant:
no effects observed

Effect levels (maternal animals)

Key result
Dose descriptor:
LOAEL
Effect level:
>= 1 340 mg/kg bw/day (actual dose received)
Basis for effect level:
body weight and weight gain

Maternal abnormalities

Abnormalities:
not examined

Results (fetuses)

Reduction in number of live offspring:
no effects observed
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
no significant difference between treated and sham control animals
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
no significant difference between treated and sham control animals

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 340 mg/kg bw/day (actual dose received)
Sex:
not specified
Basis for effect level:
reduction in number of live offspring
external malformations
skeletal malformations
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Key result
Abnormalities:
effects observed, non-treatment-related
Localisation:
skeletal: skull
skeletal: sternum
skeletal: rib
skeletal: vertebra
other: external: extremities (unspecified)

Overall developmental toxicity

Developmental effects observed:
yes
Lowest effective dose / conc.:
13.4 mg/kg bw/day (actual dose received)
Treatment related:
no
Relation to maternal toxicity:
developmental effects occurring together with maternal toxicity effects, but not as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
no
Relevant for humans:
no

Applicant's summary and conclusion

Conclusions:
The administration of up to 1340 mg/kg (body weight) of the test material to pregnant mice for 10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnoimmaities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.
Executive summary:

The developmental toxicity of Syloid 244 was evaluated in mice treated on GD 6 -15.