Registration Dossier

Administrative data

Endpoint:
toxicity to reproduction: other studies
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Non-guideline study not performed under GLP. Non-standard study design. 3 –generations Studied in mice. Only a low level of experimental detail reported. Route of administration was in the diet at 0.1%, 0.5% or 1.0%. No data provided to show achieved concentration, homogeneity or stability in the diet preparations. Purity/composition/origin of test substance not given. Food consumption not shown but achieved doses reported as 143, 688 or 1345 mg/kg/day respectively representing 10%, 70% and 95% of the acute oral LD50. Results do not give detail of the clinical condition of the animals other than a condition percentage that was assessed on a 5 weekly basis. No record of the animal breeding procedures. Reproductive parameters are not measured in detail (44%-45% of all females across all dose groups and generations did not litter. However no dose response and no further data given) – number of females to litter (%) and pups born that were raised to weaning age (%) were reduced in all treated groups with no dose response. Parental survival time was significantly reduced compared with controls for all dose groups. As was percentage of pups raised to weaning age. A NOAEL was not derived.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Chronic toxicity studies of analgesic and antipyretic drugs and congeners
Author:
Wright HN
Year:
1967
Bibliographic source:
Toxicol. Appl. Pharmacol., 1967, 11, 280-292

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Male and female mice in mated groups of five (2 males, 3 females) were powder-fed with 0.1, 0.5, and 1.0% of the test substance in the diet, starting at weaning in each generation. The condition of the mice was recorded at 5-week intervals. Numbers of litters born and numbers of young raised to weaning age, as well as gross abnormalities, were recorded. Number of mated females, % having no litters, litters not raised, and numbers of pups per female (born, raised to weaning) are reported per dose.
GLP compliance:
no
Type of method:
in vivo

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): salicylamide (SAM)
- Substance type: pure active ingredient
- Physical state: solid
- Analytical purity: U.S.P. quality, without further purification
- Impurities (identity and concentrations): no data

Test animals

Species:
mouse
Strain:
other: ABC-A, albino, inbred for 25 generations
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: developed in author's laboratory, derived from ABC mice (Dr. J.J. Bittner)
- Age at study initiation: weanling
- Weight at study initiation: no data
- Fasting period before study: no
- Housing: cages of 5, mated groups: 2 males and 3 females
- Diet (ad libitum): Purina Labeena, Ralston-Purina Co., St. Louis, USA
- Water (ad libitum): tap water
- Acclimation period: none

ENVIRONMENTAL CONDITIONS
- Temperature (°C), humidity (%), air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 14 hours dark, 10 hours light

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Remarks:
powder feeding
Details on exposure:
ROUTE:
- oral: powder feeding

DIET PREPARATION
- Rate of preparation of diet (frequency): twice weekly
- Mixing appropriate amounts with (Type of food): commercial food (Purina Labeena), finely ground
- Storage temperature of food: room temperature

VEHICLE
- none
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:

lifetime (averages 45.6 to 50.0 weeks in first generation) , start at weaning

Frequency of treatment:
continuous, daily
Duration of test:
45.6 to 50.0 weeks in first generation, 32.4 to 43.0 weeks in second, 38.5 to 52.7 weeks in third generation
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0.1, 0.5, and 1.0% in feed
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
143, 688, and 1345 mg/kg bw/day
Basis:
actual ingested
mean calculated for whole dose groups, from food intake
No. of animals per sex per dose:
49, 45, and 55 mated females (doses 0.1%, 0.5%, and 1.0%, total in all generations), no data on males

Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: 2, 10, and 20 times the expected maximal human therapeutic dosage
- Rationale for animal assignment (if not random): no data
- Rationale for selecting satellite groups: mated and unmated groups, not further specified
- Post-exposure recovery period in satellite groups: none
- Section schedule rationale (if not random): animals maintained until spontaneous death
Statistics:
Number of mated females (over all generations)
% of mated females having no litters, per dose (over all generations)
% of litters not raised to weaning, per dose (over all generations)
Mean number of pups born per female, per dose (over all generations)
Mean number of pups weaned per female, per dose (over all generations)

Results and discussion

Effect levels

Dose descriptor:
NOAEC
Effect level:
< 1 000 mg/kg diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Clearly reduced reproductive capacity at all dose levels: Half the females had no litter, only 26% of the pups born were raised to weaning age.
Remarks on result:
not determinable
Remarks:
no NOAEC identified

Any other information on results incl. tables

Clearly reduced reproductive capacity at all dose levels:

Concentration in diet (%) No. of mated females % females w. no litters % litters not raised to weaning mean no. of pups born / female mean no. of pups weaned / female
0.1 49 44.9 52.9 4.0 1.9
0.5 45 55.6 79.3 3.9 0.8
1.0 55 45.5 60.0 4.5 1.9

Most of the litters not raised were cannibalized.

Only very occasional evidences of gross malformations were found in any dose.

After the third generation, the study had to be terminated due to insufficient numbers of young.

Applicant's summary and conclusion

Conclusions:
The study is considered to be relevant, but not reliable or suitable for risk assessment or classification and labeling purposes with regard to developmental or reproductive toxicology.