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Diss Factsheets

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report date:
2011

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Reference substance name:
-
EC Number:
440-560-7
EC Name:
-
Cas Number:
346709-25-9
Molecular formula:
Unspecified
IUPAC Name:
2,6,8-triamino-4H,10H-pyrimido[5,4-g]pteridin-4-one; pyrimido[5,4-g]pteridine-2,4,6,8-tetramine
Test material form:
solid: particulate/powder
Details on test material:
Batch: 0004760225
Description Yellow solid (powder)
purity: 100%
Test substance storage: At room temperature in the dark
Stability under storage conditions: Stable
Expiry date: 22 October 2020

Test animals

Species:
rat
Strain:
other: Crl:WI(Han)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: (P) Approximately 11 weeks.
- Weight at study initiation: (P) Males: 297 - 321 g; Females: 195 - 215 g
- Housing: groups of 5 animals/sex/cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: At least 5 days prior to start of treatment.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 3°C (actual range: 16.2 - 22.4°C)
- Humidity (%):40 - 70% (actual range: 22 - 62%)
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 19 January 2011 (allocation) To:11 March 2011

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Formulations (w/w) were prepared daily within 6 hours prior to dosing and were homogenized to a visually acceptable level. No adjustment was
made for specific gravity/density of the test substance, vehicle, and/or formulation.

VEHICLE

- Concentration in vehicle: adjusted for dose and volume
- Amount of vehicle (if gavage): 5 mL/kg body weight

Details on mating procedure:
- M/F ratio per cage: one-to-one
- Proof of pregnancy: Detection of mating was confirmed by evidence of sperm in the vaginal lavage or by the appearance of an intravaginal
copulatory plug. referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): single cages
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses were conducted on a single occasion during the treatment phase (20 January 2011), according to a validated method. Samples of formulations were analyzed for homogeneity (highest and lowest concentration) and accuracy of preparation (all concentrations). Stability in vehicle over 6 hours at room temperature under normal laboratory light conditions was also determined (highest and lowest concentration).
The accuracy of preparation was considered acceptable if the mean measured concentrations were 90-110% of the target concentration. Homogeneity was demonstrated if the coefficient of variation was ≤ 10%. Formulations were considered stable if the relative difference before and after storage was maximally 10%.
Duration of treatment / exposure:
Males were exposed for 29 days, i.e. 2 weeks prior to mating, during mating, and up to the day prior to scheduled necropsy. Females were exposed for 42-50 days, i.e. during 2 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation (up to the day prior to scheduled necropsy).
Frequency of treatment:
Once daily for 7 days per week
Details on study schedule:
not appliecable for screening study
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on results of a 28-day study
Positive control:
not required.

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily

BODY WEIGHT: Yes
- Time schedule for examinations: Males and females were weighed on the first day of exposure and weekly thereafter. Mated females were weighed on Days 0, 4, 7, 11, 14, 17 and 20 post-coitum and during lactation on Days 1 and 4.


Food consumption: Weekly, except for males and females which were housed together for mating. Food consumption of mated females was measured on Days 0, 4, 7, 11, 14, 17 and 20 post-coitum and on Days 1 and 4 of lactation.
Oestrous cyclicity (parental animals):
not investigated
Sperm parameters (parental animals):
spermatogenic staging profile
Litter observations:
STANDARDISATION OF LITTERS
not relevant for screening study

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, presence of milk in stomach

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was determined as far as possible for pups born or found dead.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals, following completion of the mating period (29 days of dose administration).
- Maternal animals: All surviving animals, lactation days 5 -7

GROSS NECROPSY
- Gross necropsy consisted of macroscopic examination of the cranial, thoracic and abdominal tissues
and organs, with special attention being paid to the reproductive organs

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated below were prepared for microscopic examination:


Cervix
Preputial gland
Clitoral gland
Prostate gland
Coagulation gland
Seminal vesicles
Epididymides
Testes
Mammary gland area
Uterus
Ovaries
Vagina
All gross lesions


The following slides were examined by a pathologist:
- The ovaries, testes and epididymides of the animals of Groups 1 and 4.
- The additional slides of the testes of the males of Groups 1 and 4, and all males suspected to be infertile, to examine staging of spermatogenesis.
- All gross lesions of all animals (all dose groups).
- The reproductive organs* of animal nos. 7 and 47 (Group 1, female was not pregnant) and 11 and 51 (Group 2, female had a total litter loss)
* Reproductive organs includes the cervix, clitoral gland, coagulation gland, epididymides, ovaries, preputial gland, prostate
gland, seminal vesicles, testes, uterus, and vagina.

Organ weights were determined for epididymides and testes.

The numbers of former implantation sites and corpora lutea were recorded for all paired females.
Postmortem examinations (offspring):
Clinical signs,
Body weight
Macroscopical investigation

Statistics:
The following statistical methods were used to analyze the data:
- If the variables could be assumed to follow a normal distribution, the Dunnett-test (many to- one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
- The Steel-test (many-to-one rank test) was applied if the data could not be assumed to follow a normal distribution.
- The Fisher Exact-test was applied to frequency data.
Reproductive indices:
Duration of gestation
Gestation index (%)
Conception index (%)
Fertility index (%)
Mating (%)
Offspring viability indices:
Percentage live males at First Litter Check:
Number of live male pups at First Litter Check x 100 / Number of live pups at First Litter Check

Percentage live females at First Litter Check:
Number of live female pups at First Litter Check x 100 / Number of live pups at First Litter Check

Percentage of postnatal loss at Days 0-4 of lactation:
Number of dead pups on Day 4 of lactation x 100 /Number of live pups at First Litter Check:

Viability index:
Number of live pups on Day 4 post-partum x 100 / Number of pups born alive

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
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

Reproductive function / performance (P0)

Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Effect levels (P0)

Dose descriptor:
NOEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects up to limit dose.

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

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

Effect levels (F1)

Dose descriptor:
NOEL
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: absence of any toxic effect at the limit dose
Remarks on result:
other: as far as can be observed up to PND4

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
no

Applicant's summary and conclusion

Executive summary:

In the OECD 421 screening study for reproductive and developmental toxicity, treatment by oral gavage in male and female Wistar Han rats at dose levels of 100, 300 and 1000 mg/kg body weight/day revealed no parental, reproductive or developmental toxicity up 1000 mg/kg body weight/day.