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Diss Factsheets

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data from peer reviewed journal

Data source

Reference
Reference Type:
review article or handbook
Title:
Safety Assessment of Salicylic Acid, MEA-Salicylate, Ethylhexyl Salicylate, Potassium Salicylate, Methyl Salicylate, Myristyl Salicylate, Sodium Salicylate, TEA-Salicylate, and Tridecyl Salicylate
Author:
COSMETIC INGREDIENT REVIEW
Year:
2003
Bibliographic source:
International Journal of Toxicology 2003

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Reproductive toxicity study of test material was performed on Sprague Dawley rats.
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available

Test material

Constituent 1
Chemical structure
Reference substance name:
Salicylic acid
EC Number:
200-712-3
EC Name:
Salicylic acid
Cas Number:
69-72-7
Molecular formula:
C7H6O3
IUPAC Name:
salicylic acid
Test material form:
solid
Details on test material:
- Name of test material (as cited in study report):Salicylic acid
- Molecular formula :C7H6O3
- Molecular weight :138.1214 g/mol
- Substance type:organic
- Physical state:solid

Test animals

Species:
rat
Strain:
Wistar
Details on species / strain selection:
No data available
Sex:
female
Details on test animals or test system and environmental conditions:
No data available

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: sodium carboxymethylcellulose
Details on exposure:
Details on exposure
PREPARATION OF DOSING SOLUTIONS:
Test material mixed with 0.5% solution of sodium carboxymethylcellulose

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 material mixed with 0.5% solution of sodium carboxymethylcellulose


- Concentration in vehicle: 0,75, 150, or 300 mg/kg- Amount of vehicle (if gavage): 5ml/kg

- Lot/batch no. (if required): No data available
- Purity: No data available
Details on mating procedure:
Gravid female animals were used
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
6 days ( from day 8 through day 14 of gestation )
Frequency of treatment:
once daily
Details on study schedule:
No data available
Doses / concentrations
Remarks:
0, 75, 150, or 300 mg/kg
No. of animals per sex per dose:
Total:80
0 mg/kg bw/day:20
75 mg/kg bw/day:20
150 mg/kg bw/day:20
300 mg/kg bw/day:20
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
No data available

Examinations

Parental animals: Observations and examinations:
Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes

DETAILED CLINICAL OBSERVATIONS: Yes

Time schedule: daily


BODY WEIGHT: No data available
Time schedule for examinations: No data available
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes Food consumption was determined weekly.

Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data available


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

OTHER:
Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
No data available
Postmortem examinations (parental animals):
Postmortem examinations (Parent Animal)
SACRIFICE : On day 20 of gestation, 15 of the animals of each group were killed; the remaining 5 were allowed to deliver
Postmortem examinations (offspring):
Postmortem examinations (offspring)
SACRIFICE
Offspring were killed and autopsied on the 56th
day
- examinations of visceral and skeletal abnormalities
Statistics:
No data available
Reproductive indices:
No data available
Offspring viability indices:
No data available

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Salivation and/or piloerection were observed in this group
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
The 25.7% and 100% fetal mortality was observed in animals of the 150- and 300-mg/kg dose groups as compared to controls respectively.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Maternal body weight gain was inhibited for animals of the 300-mg/kg group
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Feed consumption decreased during the administation of 300 mg/kg Salicylic Acid
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
water consumption decreased during the administation of 300 mg/kg Salicylic Acid
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
Decreased uterine weight was observed in animals of the 150- and 300-mg/kg dose groups as compared to controls; these groups had 25.7% and 100% fetal mortality, respectively

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
75 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
gross pathology
other: Decreased uterine weight was observed in animals of the 150- and 300-mg/kg dose groups as compared to controls; these groups had 25.7% and 100% fetal mortality, respectively
Remarks on result:
other: No effects on reproductive parameters

Target system / organ toxicity (P0)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
Litter size were significantly decreased in the 150-mg/kg dose group.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
neonatal body weight were significantly decreased in the 150-mg/kg dose group.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
The thyroid weight of male offspring from the 75-mg/kg group was significantly increased and the adrenal gland weight of male offspring from the 150-mg/kg group was significantly decreased compared to controls. The incidences of external organ, internal organ, and skeletal anomalies in offspring were 0%, 5.0%, and 0%, respectively, for the 75-mg/kg group and 13.7%, 17.2%, and 79.2%, respectively, for the 150- mg/kg group
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
The incidences of external, internal, and skeletal anomalies in offspring autopsied at the 56th day were 1.8%, 0%, and 2.5%, respectively, for
the 75-mg/kg group and 27.8%, 12.7%, and 65.7%, respectively, for the 150-mg/kg group.
Histopathological findings:
not specified
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Dose descriptor:
LOAEL
Generation:
F1
Effect level:
75 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
viability
mortality
body weight and weight gain
organ weights and organ / body weight ratios
gross pathology
Remarks on result:
other: overall developmental effects observed

Target system / organ toxicity (F1)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
No Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to be 75 mg/kg/day, and the dose-level of 75 mg/kg/day was considered to be the LOAEL for embryo-foetal toxicity. When female wistar rats were treated with test material orally.
Executive summary:

Reproductive toxicity study of test material was performed on female wistar rats.80 rats were divided as 20 rats /dose group.Test material mixed with0.5% solution of sodium carboxymethyl cellulosewere administered in dose concentration 0,75, 150, or 300 mg/kgfrom day 8 through day 14 by oral gavage route.The control group was given 5 ml/kg of vehicle. On day 20 of gestation, 15 of the animals of each group were killed; the remaining 5 were allowed to deliver. The offspring, which were weaned on day 21, were observed daily and weighed every 3 days. Offspring were killed and autopsied on the 56thday for examinations of visceral and skeletal abnormalities

 Maternal body weight gain was inhibited for animals of the 300-mg/kg group. Salivation and/or piloerection were observed in this group. Feed and water consumption decreased during the administration of 300 mg/kg Salicylic Acid. Three animals of this group died within a few days of the initiation of dosing. Decreased uterine weight was observed in animals of the 150- and 300-mg/kg dose groups as compared to controls; these groups had 25.7% and 100% fetal mortality, respectively. Litter size and neonatal body weight, body length, and tail length were significantly decreased in the 150-mg/kg dose group. The incidences of external, internal, and skeletal anomalies in offspring autopsied at the 56th day were 1.8%, 0%, and 2.5%, respectively, for the 75-mg/kg group and 27.8%, 12.7%, and 65.7%, respectively, for the 150-mg/kg group.The offspring from animals of 150-mg/kg Salicylic Acid group had decreased body length and tail length compared to controls. The thyroid weight of male offspring from the 75-mg/kg group was significantly increased and the adrenal gland weight of male offspring from the 150-mg/kg group was significantly decreased compared to controls. The incidences of external organ, internal organ, and skeletal anomalies in offspring were 0%, 5.0%, and 0%, respectively, for the 75-mg/kg group and 13.7%, 17.2%, and 79.2%, respectively, for the 150- mg/kg group. Hence No Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to be 75 mg/kg/day, and the dose-level of 75 mg/kg/day was considered to be the LOAEL for embryo-foetal toxicity.When femalewistar rats were treated with test material orally.