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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:
data from handbook or collection of data
Justification for type of information:
Data is from a peer reviewed journal

Data source

Reference
Reference Type:
publication
Title:
Maternal reproductive effects of the given test chemical in Sprague-Dawley rats
Author:
Davis et al.
Year:
1996
Bibliographic source:
Toxicology Letters

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Pregnant rats were exposed to the test chemical during gestation to investiagte potential toxicological effects on reproduction and development.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Details on test material:
- Name of test material (as cited in study report):sodium salicylate
- Molecular formula :C7H6O3.Na
- Molecular weight : 160.1035 g/mol
- Substance type: organic
- Physical state: solid
- Smilies notation: c1(c(cccc1)O)C(=O)[O-].[Na+]
- InChI: 1S/C7H6O3.Na/c8-6-4-2-1-3-5(6)7(9)10;/h1-4,8H,(H,9,10);/q;+1/p-1

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
Details on test animals and env. conditions
TEST ANIMALS
- Source: Charles River Laboratories
(Portage, MI).
- Age at study initiation: 63 days
- Weight at study initiation: 182-263g
- Fasting period before study: No data available

- Housing: The animals were housed individually
- Use of restrainers for preventing ingestion (if dermal): yes/no
- Diet (e.g. ad libitum): Food (Certified Rodent
Chow 5002, Purina Mills, Inc., St. Louis, MO) ad libitum
.
- Water (e.g. ad libitum): water were provided ad libitum
- Acclimation period: No data available


ENVIRONMENTAL CONDITIONS
- Temperature (°C):21.11±1.2 °C
- Humidity (%):57±3.8%
- Air changes (per hr): No data available

- Photoperiod (hrs dark / hrs light): No data available


IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5% aqueous methyl cellulose
Details on exposure:
Details on exposure
PREPARATION OF DOSING SOLUTIONS:
Test chemical was mixed with 0.5% aqueous methyl cellulose to form dosing solution
DIET PREPARATION
- Rate of preparation of diet (frequency):No data available
- Mixing appropriate amounts with (Type of food )
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): Test chemical was mixed with 0.5% aqueous methyl cellulose
- Concentration in vehicle: 0, 20, 80 or 200 mg/kg bw/day
- Amount of vehicle (if gavage): 10ml/kg

- Lot/batch no. (if required): No data available
- Purity: No data available
Other :
One-half of the dose was given to the animals in the morning and the second half 6-8 h later
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No Data Available
Details on mating procedure:
- Impregnation procedure: [artificial insemination / purchased timed pregnant / cohoused]
- If cohoused: No Data Available
- M/F ratio per cage: 1:1
- Length of cohabitation: No Data Available
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: [no / yes (explain)]
- Verification of same strain and source of both sexes: [yes / no (explain)]
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy:The occurrence of copulation was determined by daily inspection for a copulatory plug. The day at which evidence of mating was detected was designated gestation day 0,
- Any other deviations from standard protocol: No Data Available
Duration of treatment / exposure:
Gestation day 15 to 21.
Frequency of treatment:
Twice daily. One half of the dose was given in the morning and the second half 6-8 hours later.
Doses / concentrations
Remarks:
0, 20, 80 or 200 mg/kg bw/day
No. of animals per sex per dose:
Total: 86 animals

0 mg/kg bw/day: 25 animals
20 mg/kg bw/day: 25 animals
80 mg/kg bw/day:25 animals
200 mg/kg bw/day: 16 animals
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose were determined in pilot study using an identical protocol which yielded an effect level of 200 mg/ kg/day and a NOEL of less than 100 mg/kg/day for oral exposure to the test chemical.

- Rationale for animal assignment (if not random):

- Other:

Examinations

Maternal examinations:
Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes
Time schedule: The animals were observed twice daily throughout the study for mortality and signs of overt toxicity.

BODY WEIGHT: Yes
Time schedule for examinations: Individual body weights were recorded on gestation days 0, 6, 15, 16, 17, 18, 19, 20 and 21.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No
Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
Time schedule for examinations:

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: No data
- Number of implantations: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data
- Other: No Data
Fetal examinations:
Litters were examined for numbers of live and stillborn pups and gross abnormalities. The pups were sexed and weighed individually on lactation day 0.
Statistics:
All measured parameters were subjected to Bartlett’s test for hlomogeneity of variance. Then all treatment groups and the vehicle-treated control
group were compared by one-way analysis of variance (ANOVA). Pairwise comparisons were made using the appropriate t-test (for equal and unequal variance) as described by Steel and Torrie using Dunnett’s multiple comparison tables, or pairwise comparisons were made with a Bonferroni correction to determine the significance.
Indices:
No data available
Historical control data:
No data available

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Clinical signs of maternal physical distress during parturition included labored breathing, decreased activity, and blood staining in the abdominal, nasal, and oral areas. No evidence of increased maternal distress was noted in animals from either the mid-dose (80 mg/kg/day) or low-dose (20 mg/kg/day).
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
The incidence of maternal perinatal death was significantly increased at 200 mg/kg compared to the control group. That is, 4 of 10 animals at 200 mg/kg died or had to be sacrificed due to extreme distress whilst only 1 of 21 animals treated at 0 mg/kg died perinatally. At 20 or 80 mg/kg/day, no evidence of increased peripatum mortality was noted.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No effects on gestational body weight gain .
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
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):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Treatment at 200 mg/kg resulted in a significant increase in labor duration compared to control data (mean, ≈3.5 hours at 200 mg/kg vs. mean, ≈1.2 hours at 0 mg/kg). Gestation length was unaffected by treatment.

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
not examined
Total litter losses by resorption:
not examined
Early or late resorptions:
not examined
Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
A non-statistical increase in fetal peripartum deaths was reported at 200 mg/kg compared to the control group (9.7% fetuses affected at 200 mg/kg vs 3.1% of fetuses affected at 0 mg/kg).
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Gestation length was unaffected by treatment.
Changes in number of pregnant:
no effects observed

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
>= 80 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
clinical signs
mortality
body weight and weight gain
effects on pregnancy duration
dead fetuses
other: labor duration
Remarks on result:
other: No toxic effects observed
Key result
Dose descriptor:
LOAEL
Effect level:
<= 200 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
mortality
other: labor duration
Remarks on result:
other: effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
effects observed, non-treatment-related
Description (incidence and severity):
A non-statistical increase in fetal peripartum deaths was reported at 200 mg/kg compared to the control group (9.7% fetuses affected at 200 mg/kg vs 3.1% of fetuses affected at 0 mg/kg).
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Sex ratio was unaffected by treatment.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
No significant effects were observed on mean pups per litter or mean pup weight.
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
No external visible abnormalities were observed in any of the pups that survived delivery. Gross examination was not performed on fetuses that died peripartum.
Skeletal malformations:
not examined
Visceral malformations:
not examined

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
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
Remarks on result:
other: No toxic effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no
Treatment related:
no

Applicant's summary and conclusion

Conclusions:
NOAEL for developmental toxicity was considered at 200 mg/kg bw/day in pregnant female rats follwoing exposure to the test chemical from gestation day 15 to 21.
Executive summary:

Pregnant female rats were treated with the test chemical by oral gavageat 0, 20, 80 and 200 mg/kg bw/day from day 15 to 21 of gestation. Twenty-five rats were used per dose level up to 80 mg/kg whereas sixteen rats were used at 200 mg/kg. No significant effects were observed on gestational body weight gain and no signs of toxicity were observed until onset of delivery. Treatment at 200 mg/kg resulted in a significant increase in labor duration compared to control data (mean, ≈3.5 hours at 200 mg/kg vs. mean, ≈1.2 hours at 0 mg/kg). Gestation length was unaffected by treatment. A non-statistical increase in fetal peripartum deaths was reported at 200 mg/kg compared to the control group (9.7% fetuses affected at 200 mg/kg vs 3.1% of fetuses affected at 0 mg/kg). No significant effects were observed on mean pups per litter, live pups per litter, mean pup weight, or sex ratio. No external visible abnormalities were observed in any of the pups that survived delivery. Gross examination was not performed on fetuses that died peripartum. The incidence of maternal perinatal death was significantly increased at 200 mg/kg compared to the control group. That is, 4 of 10 animals at 200 mg/kg died or had to be sacrificed due to extreme distress whilst only 1 of 21 animals treated at 0 mg/kg died perinatally. NOAEL for developmental toxicity was considered at 200 mg/kg bw/day in pregnant female rats follwoing exposure to the test chemical from gestation day 15 to 21.