Registration Dossier

Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1960
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Limited, reported, non-GLP, the data are sufficient for evaluation of the reproduction end point

Data source

Reference
Reference Type:
publication
Title:
Die Vertraglichkeit der Benzoesaure im chronischen Futterungsversuch
Author:
Kieckebusch, W. and Lang, K.
Year:
1960
Bibliographic source:
Arzeneimittel-Forschung volume 10, 1001-1003

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
A feeding study was performed, in which 4 generations of rats received the test substance (0.5% or 1%). The first generation was exposed for 8 weeks an then allowed to mate (1/1 for a period of 14 days). Mating was repeated in week 48 to raise a second litter. Survival of the first and second generation was measured. The third generation was terminated after 16 weeks and examined histopathologically. In this generation weights of brain, heart, liver, spleen, kidneys and testes were determined. The fourth generation was terminated after weaning of the pups. Body weights were determined in week 4, 8 and 12 weeks of each generation (week 12 males only). Feeding efficiency was measured in all generations after 2,4, 6 and 8 weeks. Some reproduction parameters were assessed: percentage of infertility, delayed sexual maturation, litter size, total pups, surviving pups. These parameters were assessed for all generations (summed) and forthe first two generations separately
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
not specified

Test animals

Species:
rat
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
generation I and II mean 785-827 days
generation III 16 weeks
generation IV until weaning of first litter
Frequency of treatment:
continuously in feed
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.5 and 1%
Basis:
nominal in diet
No. of animals per sex per dose:
20 animals
Control animals:
yes, plain diet
Positive control:
None stated

Examinations

Parental animals: Observations and examinations:
Body weights were determined in week 4, 8 and 12 weeks of each generation (week 12 males only).
Reproductive parameters: percentage of infertility, delayed sexual maturation, litter size, total pups
Oestrous cyclicity (parental animals):
None stated
Sperm parameters (parental animals):
None stated
Litter observations:
number of pups, survival of pups, litter size
Postmortem examinations (parental animals):
Histopathology of generation III animals on week 16
Weights of brain, heart, liver, spleen, kidneys and testes in generation III animals
Postmortem examinations (offspring):
none stated
Statistics:
None stated
Reproductive indices:
None stated
Offspring viability indices:
None stated

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
not specified
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

1% the test substance was tolerated without unfavourable side-effects on growth, food utilization, duration of life, procreation, weight of organs, histological pattern of organs and fertility.
Addition of 0.5% the test substance to the food resulted in significant prolongation of life.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female

Results: F2 generation

Effect levels (F2)

Dose descriptor:
NOAEL
Generation:
F2
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

The authors include a calculation of the 1% dose related to the saturation of the metabolic system at that concentration. They conclude that no bioaccumulation will occur. In addition, theoretically the conclusion was derived that the no effect level in this study is closed to the maximum tolorated level for the test substance.

Applicant's summary and conclusion

Conclusions:
No effects were noted after chronic dietary exposure of rats to 1% the test substance in diet. Furthermore, no effects were observed on fertility in four generations after chronic dietary exposure of rats to 1% the test substance in diet. No effects on reproduction were seen.
Executive summary:

A feeding study was performed, in which 4 generations of rats received the test substance (0.5% or 1%). The first generation was exposed for 8 weeks an then allowed to mate (1/1 for a period of 14 days). Mating was repeated in week 48 to raise a second litter. Survival of the first and second generation was measured. The third generation was terminated after 16 weeks and examined histopathologically. In this generation weights of brain, heart, liver, spleen, kidneys and testes were determined. The fourth generation was terminated after weaning of the pups. Body weights were determined in week 4, 8 and 12 weeks of each generation (week 12 males only). Feeding efficiency was measured in all generations after 2,4, 6 and 8 weeks. Some reproduction parameters were assessed: percentage of infertility, delayed sexual maturation, litter size, total pups, surviving pups. These parameters were assessed for all generations (summed) and forthe first two generations separately No effects were noted after chronic dietary exposure of rats to 1% the test substance in diet. Furthermore, no effects were observed on fertility in four generations after chronic dietary exposure of rats to 1% the test substance in diet. No effects on reproduction were seen.