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Diss Factsheets

Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
13.02.-05.11.2008
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
other: Body responsible for the test
Title:
Unnamed
Year:
2008
Report date:
2008

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EU Method B.34 (One-Generation Reproduction Toxicity Test)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
463-070-5
EC Name:
-
Cas Number:
106966-25-0
Molecular formula:
C7H17N2O2Br
IUPAC Name:
2-(3-methoxy-3-oxopropyl)-1,1,1-trimethylhydrazinium bromide

Test animals

Species:
other: Albino laboratory rat
Strain:
other: Wistar Han
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: SPF (Specified Pathogen Free) breeding, VELAZ s.r.o., CZ
- Age at study initiation: males 5-6 weeks, females - 9 weeks
- Diet: complete peleted diet for rats and mice in SPF breeding (ST 1 BERGMAN) was used. Diet was sterilised before used.
- Housing: animals were housed in SPF animal room in plastic cages containing sterilised clean shavings of soft wood. During mating period, one
male with two females were housed together in one cage. Mated females were individually housed in labelled cages. Offspring was kept with mother
until weaning.
- Water (e.g. ad libitum): free access to drinking water (water ad libitum). Water was sterilised before using.
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3 degree of Celsius
- Humidity (%): 30-70 %
- Air changes (per hr): 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hour light/ 12 hour dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: water for injection
Details on mating procedure:
- M/F ratio per cage: one male with two females
- Proof of pregnancy: by prescence of spermatozoa in vaginal smear was examinated daily during mating period
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): mated females were individualy housed in labelled cages.
Duration of treatment / exposure:
Dosing regime: males 7 days/ week, females 7 days/ week
No. of animals per sex per dose:
No of animals (males) Dose/ conc (mg/kg)
10 0
10 30
10 60
10 120

No of animals (females) Dose/ conc (mg/kg)
22 0
22 30
22 60
22 120


Control animals:
yes

Examinations

Parental animals: Observations and examinations:
The administration of the test substance negatively influenced mortality of parental females, clinical status after application of parental males and
females, microscopical structure and biomery of reproductive organs in parental females and reproductive performance males and females.
This negative influence expressed especially at the highest dose level: previous euthanasia of one moribund pregnant female, impairment of clinical status after application in males and females (watery excrements and chromodacryorhea), increased number of microscopical findings in ovaries of females (proliferetion of stroma and degenerate follicles), slight decrease of absolute and reletive weights of reproductive organs in females,
decreased ability of males to impregnate females, decreased ability of females to achieve pregnancy and decreased total number of pups.
Postmortem examinations (parental animals):
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Tables 12-13 were prepared for microscopic examination and weighed, respectively.
Postmortem examinations (offspring):
Yes
Reproductive indices:
Effects on F1 generation: Decreased number of pups in females at the highestdose could relate with negative influence of the test substance on
early prenatal dvelopment of organism in uterus.
Offspring viability indices:
At dose level 0 mg/kg from 164 born pups, live born are 161 pups. At dose level 30 mg/kg from 200 born pups, live born are 197 pups, a dose level 60 mg/kg from 188 born pups, live born are 188 pups. At dose level 120 mg/kg from 139 born pups, live born are 137 pups.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
effects observed, treatment-related

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
effects observed, treatment-related
Reproductive function: sperm measures:
effects observed, treatment-related
Reproductive performance:
effects observed, treatment-related

Details on results (P0)

The administration of the test substance negatively influenced mortality of parental females, clinical status after application of parental males and
females, microscopical structure and biomery of reproductive organs in parental females and reproductive performance males and females.
This negative influence expressed especially at the highest dose level: previous euthanasia of one moribund pregnant female, impairment of clinical status after application in males and females (watery excrements and chromodacryorhea), increased number of microscopical findings in ovaries of females (proliferetion of stroma and degenerate follicles), slight decrease of absolute and reletive weights of reproductive organs in females,
decreased ability of males to impregnate females, decreased ability of females to achieve pregnancy and decreased total number of pups.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day
Sex:
female
Basis for effect level:
other: see 'Remark'

Results: F1 generation

General toxicity (F1)

Clinical signs:
effects observed, treatment-related
Mortality / viability:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Details on results (F1)

VIABILITY (OFFSPRING):At dose level 0 mg/kg from 164 born pups, live born are 161 pups. At dose level 30 mg/kg from 200 born pups, live born
are 197 pups, a dose level 60 mg/kg from 188 born pups, live born are 188 pups. At dose level 120 mg/kg from 139 born pups, live born are 137
pups.

During observation of pups (the average number of live an dead pups in litter, sex, average weight of litter and pups, postnatal development and
occurrence of pathological macroscopic findings) negative influence of the test substance treatment was not detected.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
60 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The test substance administration negatively influenced mortality of parental females, clinical status after application of parental males and females, microscopical structure and biometry of reproduction organs in parental females and reproduction performance in parental males and females.
The test substance administration did not affect offspring development after parturition. But it is not possible to exclude negative influence of the test substance on early prenatal development of organism in uterus at the highest dose level (significant decrease of total number of pups at a dose level 120 mg/kg/day.