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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP and appropriate guidelines
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report Date:
2002

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
A preliminary study was performed to assess the effect of FR-370, when administered continuously via the diet, on the reproductive performance of rats. The study was not performed according to OECD 415 (one-generation reproduction toxicity study) but the study design was similar to OECD 421 (reproduction/developmental toxicity screening test), with the important exception that the F0 females were followed a considerable longer period than 4 days after delivery.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
FR-370
Batch No.: 141476
Purity: 99.8%
White to off-white powder
Storage: Dry, cool, well vintilated area (ambient 21 deg C)

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Age ordered: 8-9 weeks
Age on start of treatment: 9-10 weeks
Weight range ordered: 280-300g (males), 180-200g (females)
Supplier: Charles River (UK) Limited
Air supplied: Filtered, not circulated
Temperature: 19-23 Deg C
RH: 40-70%
Light: 12 hour light: 12 hour dark
Rodent facility: Full barrier

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
see attached document on materials and methods
Details on mating procedure:
see attached document on materials and methods
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
see attached document on formulation chemistry
Control (0 ppm)
Treatment 2000, 10000, 20000 ppm
Duration of treatment / exposure:
Duration of treatment:
F0 animals: For 28 days before pairing until termination either after all litters have been born for the males or after weaning of F1 generation for the females.
F1 animals: From weaning until approx. 6 weeks of age.
Details on study schedule:
see attached document on study schedule and design
No. of animals per sex per dose:
Male: 8 animals at 0 mg/kg or mg/l
Male: 8 animals at CA 160 mg/kg or mg/l
Male: 8 animals at CA 760 mg/kg or mg/l
Male: 8 animals at CA 1590 mg/kg or mg/l
Female: 8 animals at 0 mg/kg or mg/l
Female: 8 animals at CA 400 mg/kg or mg/l
Female: 8 animals at CA 1780 mg/kg or mg/l
Female: 8 animals at CA 4110 mg/kg or mg/l
Details on study design:
see attached document on study schedule and design

Examinations

Parental animals: Observations and examinations:
mortality, bodyweight, food consumption, food conversion efficiency, mating performance fertility, gestation length and gestation index were examined
Oestrous cyclicity (parental animals):
not examined
Sperm parameters (parental animals):
not examined
Litter observations:
Implantations, litter size, offspring survival, sex ratio, body weight, balano preputial separation, vaginal opening and macroscopic examination were conducted.
Postmortem examinations (parental animals):
yes
Postmortem examinations (offspring):
yes
Statistics:
not done
Reproductive indices:
litter size
Offspring viability indices:
Litter size and offspring survival indices examined.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
see details on results
Body weight and weight changes:
no effects observed
Description (incidence and severity):
see details on results
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
see details on results
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
not examined
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Test substance intake: see details on results

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
see details on results

Details on results (P0)

Dietary inclusion levels of 2000, 10000 and 20000 ppm
generated average achieved intakes of approximately 160, 760
and 1590 mg/kg/day respectively for F0 males and 170, 905
and 1775 mg/kg/day respectively for F0 females before
pairing. Intakes by females were slightly higher through
gestation and reached peaks of 400, 1780 and 4110 mg/kg/day
at 2000, 10000 and 20000 ppm respectively during the second
week of lactation when food consumption was at its highest.


F0 generation animals showed no signs of adverse reaction to
treament and there were no deaths following administration
of FR-370 at dietary inclusion levels up to 20000 ppm.


Control bodyweight and cumulative bodyweight change were
higher than expected, compared with background data and were
above values in the treated groups throughout the entire
treatment period. There was no evidence of a dosage
relationship and intergroup differences were considered to
be unrelated to treatment. Group mean body weight and
bodyweight gain values for females before pairing and during
gestation and lactation were unaffected by treatment.


Food consumption for males and females in the four week
period before pairing and for females during gestation and
lactation were similar to respective Control values. Food
conversion efficiency was slightly lower for treated males
compared to the concurrent Control values, these were
considered to be of no biological importance.


There was no adverse effect of treatment upon pre-coital
interval, mating performance and fertility, gestation length
and gestation index.


Numbers of implantations, litter size, offspring survival
and sex ratio were unaffected by dietary administration of
FR-370. Offspring bodyweights to weaning were unaffected by
levels of FR-370 of up to 20000 ppm in the diet.


There were no consistent observations at necropsy of the F0
animals, offspring killed prior to scheduled termination,
and surplus of offspring killed after selection of the F1
generation, that were considered to be an adverse effect of
treatment with FR-370 in the diet.

Effect levels (P0)

Key result
Dose descriptor:
NOEC
Effect level:
>= 20 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects indicated up to the highest doe tested.

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Mortality / viability:
no mortality observed
Description (incidence and severity):
see details on results
Body weight and weight changes:
no effects observed
Description (incidence and severity):
see details on results
Sexual maturation:
no effects observed
Description (incidence and severity):
see details on results
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
see details on results
Histopathological findings:
not specified

Details on results (F1)

Effects on F1 generation:
Dietary inclusion levels of 2000, 10000 and 20000 ppm
generated average achieved intakes of approximately 285,
1500, and 3040 mg/kg/day respectively, for selected males
during the first two weeks of the male F1 treatment period.
Average inatke for the two weeks of treatment for selected
F1 females receiving 2000, 10000 and 20000 ppm were 290,
1580 and 3095 respectively.


The general condition of the selected F1 animals in the
treated groups was similar to that of Controls and there
were no premature deaths in groups receiving FR-370.


At the start of the F1 generation (approximately 4 weeks of
age) group mean values of bodyweight for selected F1 animals
at 10000 and 20000 ppm were slightly lower than Control
values and remained lower than Controls throughout the F1
generation for the two week treatment period for females,
and the three week treatment period for males.


Group mean values of food consumption and food conversion
efficiency for selected F1 animals were similar to Controls
throughout the F1 generation treatment period and were
unaffected by treatment.


The timing of balano preputial separation for selected F1
males and of vaginal opening in F1 selected females were
considered to have been unaffected by treatment.


Macroscopic examination of selected F1 animals revealed no
consistent abnormalities which were considered to be related
to treatment with FR-370 at 2000, 10000 and 20000 ppm in
the diet.


Conclusion:


It was concluded that a dietary level of 20000 ppm would be
suitable as the highest dietary concentration for a main
multigeneration study in the CD rat. This equates to the
maximum dietary cocentration required by the EPA regulations
for a material where high human exposure is not predicted.

Effect levels (F1)

Key result
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
>= 20 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects noted at the highest dose tested

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
It was concluded that a dietary level of 20000 ppm would be
suitable as the highest dietary concentration for a main
multigeneration study in the CD rat. This equates to the
maximum dietary cocentration required by the EPA regulations
for a material where high human exposure is not predicted.
Executive summary:

See attached document on summary