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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000
Report Date:
2000

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 415 (One-Generation Reproduction Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
water
Remarks:
distilled water
Details on exposure:
Method of administration or exposure: Gavage

Mass median aerodynamic diameter:
Not applicable
Frequency of treatment:
Dosing regime (males): 7 days/week
Dosing regime (females): 7 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
60 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 200 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Male: 28 animals at 0 mg/kg or mg/l
Male: 28 animals at 60 mg/kg or mg/l
Male: 28 animals at 300 mg/kg or mg/l
Male: 28 animals at 1200 mg/kg or mg/l
Female: 28 animals at 0 mg/kg or mg/l
Female: 28 animals at 60 mg/kg or mg/l
Female: 28 animals at 300 mg/kg or mg/l
Female: 28 animals at 1200 mg/kg or mg/l

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
There were no treatment-related clinical signs observed during the course of the study.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
At 1200 mg/kg 3 animals (2 males, 1 female) died as a result of dosing trauma.

At 300 mg/kg two females were found dead and one female was killed in extremis during the maturation phase of the study.
The deaths were consistent with dosing trauma.

At 30 mg/kg one male was killed in extremis during the mating phase of the study. Diuresis was observed on the day of termination. Post mortem observations included distension with haemorrhagic walls of the urinary bladder. In addition the prostrate was oedematous.

One female was killed in extremis during the lactation phase of the study. The deaths was consistent with dosing trauma.

At 0 mg/kg one male was killed in extremis during the post maturation phase of the study. On the day of termination there was clinical evidence of respiratory distress. Post mortem examination showed a jellified mass within the thorax.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There were no significant treatment-related intergroup differences in male or female bodyweight gain.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no significant treatment-related intergroup differences in male or female food consumption or food conversion.
Ophthalmological findings:
no effects observed
Description (incidence and severity):
There were no findings observed for selected males or females, either pretest or during week 10 of the study.
Haematological findings:
no effects observed
Description (incidence and severity):
There were no toxicologically significant intergroup differences in male or female blood haematological values.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There were no toxicologically significant intergroup differences in male or female blood chemistry values.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no significant treatment-related intergroup differences for organ weights.
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
At 1200 mg/kg there was a treatment-related effect on the stomachs of both males and females. Within the forestomach, subepithelial cell infiltrates, occasionally with associated acanthosis of the limiting ridge was observed. With the glandular stomach there was an increased incidence and severity of agglomeration of secretion and goblet cell hyperplasia.
At 300 and 60 mg/kg there were no treatment-related effects on the stomach.

All the remaining morphological changes were those commonly observed in laboratory maintained rats of this age and strain.
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive performance:
no effects observed
Description (incidence and severity):
There were no significant treatment-related effects upon male or female mating or conception rates. The majority of pre-coital intervals were within the normal four to five day period. The distribution of pre-coital intervals were comparable for all groups.

Details on results (P0)

Gestation and Parturition:

There were no significant treatment-related effects on the gestation or parturition indices. The distribution of gestation lengths were comparable for all groups, with the majority of gestation lengths being between twenty-two and twenty-three days.


Necroscopy Findings:

There were no significant treatment-related intergroup differences in the type of incidence of macroscopic anomalies observed for both males and females. The types of anomaly observed were those typically observed for this type of study.

Effect levels (P0)

open allclose all
Dose descriptor:
NOEL
Effect level:
ca. 300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
Dose descriptor:
NOEL
Effect level:
> 1 200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Description (incidence and severity):
There were no significant treatment-related intergroup differences in the type and incidence of clinical signs observed for offspring throughout lactation. The clinical signs were those commonly observed in this type of study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There were no significant treatment-related intergroup differences in both the mean total litter weight or mean individual offspring bodyweight throughout lactation. There were no significant treatment-related intergroup differences in offspring maturation, as denoted by the onset and completion of landmarks of development, throughout lactation.

Details on results (F1)

Litter Size, Sex and Offspring Viability:

There were no siginificant treatment-related intergroup differences in the mean total number of offspring born.
Subsequent offspring viability throughout lactation was comparable for all groups including controls. There were no significant intergroup differences in the offspring sex ratios at either days 1 or 21 of lactation.

Offspring Reflexological Assessment:

There were no significant treatment-related intergroup differences in offspring reflexological responses.


Offspring Necroscopy Findings:

There were no significant treatment-related intergroup differences in the incidence and type of observations seen at post mortem examination of offspring from either the imterim and terminal necroscopy. The type of findings are those commonly observed for this study type.

Effect levels (F1)

Dose descriptor:
NOEL
Generation:
F1
Based on:
test mat.
Sex:
male/female
Remarks on result:
not measured/tested

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
At a dose level of 1200 mg TILCOM AT35/kg bodyweight there was a minor histopathological effect upon the stomachs of both males and females. There was no effect on either sex during the in-life phase of the study and no effect on either reproductive performance or offspring growth and survival. The no effect level for adult toxicity was therefore 300 mg TILCOM AT35/kg bodyweight. The no effect level for reproductive performances was in excess of 1200 mg TILCOM AT35/kg bodyweight.