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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report Date:
1979

Materials and methods

Principles of method if other than guideline:
Similar to OECD test method for 2-generation reproductive toxicity study.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: white powder

Test animals

Species:
rat
Strain:
Long-Evans
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on mating procedure:
Nospecific details were provided in the report regarding the mating of F0. There was a fourteen day rest period between weaning of the first litters and initiation of the second mating period.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Test substance administration to the F0 generation females (20/group) was initiated at the onset of gestation and continued throughout the ensuing gestation and lactation periods. Dietary administration of CP 45347 continued to the F1 generation animals (10 males and 20 females/group) through a growth period and a mating, gestation and lactation period for two successive litters.
Frequency of treatment:
Continuously, beginning Day 0 of gestation for the F0 females and continued for the F1 males and females through the F2a and F2b litters. (For a total of 281 days)
Details on study schedule:
Test substance administration of the F0 females was initiated the day signs of mating were observed (Day 0 of gestation) and continued throughout the ensuing gestation and lactation periods. F1 offspring were separated from siblings seven days after the weaning (Day 21 of lactation) of the last litter and were randomly selected to continue as future parents (F1 ). More offspring than needed were selected (12 males and 24 females) for the growth period to ensure the required number of adults (10 male and 20 females) necessary for mating. Following pup selection, remaining offspring and F0 females were sacrificed and discarded after gross external and internal examinations.

F1 animals were raised to maturity and mated to produce the F2a litters. F2a pups were sacrificed, necropsied and discarded at weaning. All F1 females were re-mated after a rest period of at least 14 days to produce the F2b litters. F2b pups were sacrificed and necropsied at weaning. Following completion of the F2b sacrifice, all F1 parents were sacrificed, necropsied and selected tissues preserved.

Litters produced from the mating of the F0 parents were housed together for approximately one week after the last litters had been weaned. Twelve male and twenty-four female offspring were proportionately selected from litters using a random number procedure. The parentage of each selected offspring was recorded to avoid possible brother-sister mating. The F1 generation were housed individually for a growth period of approximately 80 days before being mated to produce the F2a litters.
Doses / concentrationsopen allclose all
Dose / conc.:
300 ppm
Remarks:
Dose levels based on 100% active ingredient
Dose / conc.:
1 000 ppm
Remarks:
Dose levels based on 100% active ingredient
Dose / conc.:
3 000 ppm
Remarks:
Dose levels based on 100% active ingredient
No. of animals per sex per dose:
F0 generation females (20/group)
Dietary administration o f CP 45347 continued to the F1 generation animals (10 males and 20 femaleslgroup) through a growth
period and a mating, gestation and lactation period for two successive litters.


Control animals:
yes, concurrent no treatment

Results and discussion

Results: P0 (first parental animals)

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
> 3 000 ppm
Based on:
labile/free
Remarks:
acid
Sex:
male/female
Basis for effect level:
other: No adverse effects observed

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: F1 generation

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 3 000 ppm
Based on:
labile/free
Remarks:
acid
Sex:
male/female
Basis for effect level:
other: No adverse effects observed

Target system / organ toxicity (F1)

Critical effects observed:
no

Results: F2 generation

Effect levels (F2)

open allclose all
Key result
Dose descriptor:
NOAEL
Generation:
F2a
Effect level:
> 3 000 ppm
Based on:
labile/free
Remarks:
acid
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Key result
Dose descriptor:
NOAEL
Generation:
F2b
Effect level:
> 3 000 ppm
Based on:
labile/free
Remarks:
acid
Sex:
male/female
Basis for effect level:
other: No adverse effects observed

Target system / organ toxicity (F2)

Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
no

Any other information on results incl. tables

In the F1 generation, no treatment effects were observed in growth, food consumption, fertility-reproduction or litter examination parameters. At terminal sacrifice, a lower mean body weight was observed in the mid-dose males and high-dose female groups. In the female groups, mean thyroid weights (absolute and relative to body weight and brain weight) were lower in the treated groups and spleen/body weight ratios were higher at the mid - and high- dose levels (only at the mid-dose leve1 was spleen/brain weight ratio increased).

 

No treatment effects on organ weight data were observed in the treated male groups. Gross post mortem observations and evaluation of selected tissues from five adult F1 generation males and females of the control (300 and 1000 ppm) and high-dose (3000 ppm) groups indicated no findings considered related to the administration of the test substance.

In the F1 females the only effect seen was a reduction in the mean thyroid weights. However in the absence of histopathological/clinical pathology examination results, it is not clear whether or not the weight change a real effect.

In the absence of adverse clinical /reproductive effects for this substance it is unlikely to be of toxicological significance.

 

Dose level (ppm)

Mean Weight (g) (Thyroid) F1 Female

Mean Ratio (Thyroid) F1 Female

0

0,018

0,0056

300

0,014

0,0046

1000

0,015

0,0047

3000

0,013

0,0043

Applicant's summary and conclusion

Executive summary:

In a reproductive toxicity study the test substance was administered continuously via the diet to Long-Evans F0 generation females (20/group) at the onset of gestation and continued throughout the ensuing gestation and lactation periods. Dietary administration was continued to the F1 generation animals (10 males and 20 females /group) through a growth period and a mating, gestation and lactation period for two successive litters.

In the F0 generation, no treatment effects were evident. In the F1 generation, no treatment effects were observed in growth, food consumption, fertility-reproduction or litter examination parameters. In the F1 females the only effect seen was a reduction in the mean thyroid weights. However in the absence of histopathological/clinical pathology examination results, it is not clear whether or not the weight change a real effect. In the absence of adverse clinical /reproductive effects for this substance it is unlikely to be of toxicological significance.