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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
21st December 2011 to 20th August 2012.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted according to GLP and relevant testing guidelines.
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report date:
2012

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
not specified
Qualifier:
according to guideline
Guideline:
other: EPA OPPTS 870.3650, Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test
Deviations:
not specified
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
not specified
Qualifier:
equivalent or similar to guideline
Guideline:
other: EPA OPPTS 870.3550, Reproduction/Developmental Toxicity Screening Test
Deviations:
not specified
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1,8-diazabicyclo[5.4.0]undec-7-ene
EC Number:
229-713-7
EC Name:
1,8-diazabicyclo[5.4.0]undec-7-ene
Cas Number:
6674-22-2
Molecular formula:
C9H16N2
IUPAC Name:
2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine
Details on test material:
- Name of test material (as cited in study report): 1,8-Diazabicyclo-5,4,0-undecene-7
- Analytical purity:>=98%

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: Approximately 11 weeks.
- Housing: Pre-mating animals were housed in groups of 5 animals/sex/cage in Macrolon plastic cages (MIV type, height 18 cm). During mating, females were caged together with males on a one-to-one-basis in Macrolon plastic cages (MIII type, height 18 cm). Post-mating, males were housed in their home cage (Macrolon plastic cages, MIV type, height 18 cm) with a maximum of 5 animals/cage. Females were individually housed in Macrolon plastic cages (MIII type, height 18 cm). During lactation, pups were kept with the dam until termination in Macrolon plastic cages (MIII type, height 18 cm). During locomotor activity monitoring of the dams the pups were kept warm in their home cage using bottles filled with warm water. In order to avoid hypothermia of pups, pups were not left without their dam or a bottle filled with warm water for longer than 30-40 minutes. During locomotor activity monitoring, animals were housed individually in a Hi-temp polycarbonate cage (48.3 x 26.7 x 20.3 cm).
- Diet (e.g. ad libitum): Free access to pelleted rodent diet
- Water (e.g. ad libitum): Free access to tap-water.
- Acclimation period: At least 5 days prior to start of treatment.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24°C
- Humidity (%): 40 to 70%,
- Air changes (per hr): approximately 15 room air changes/hour
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Formulations (w/w) were prepared daily within 30 minutes prior to dosing and were homogenized to a visually acceptable level. Adjustment was made for the density of the test substance.
On the first day of dosing, the pH value of Groups 2-4 formulations were determined. Based on information that the test substance may react with glass, the formulations were prepared in plastic vials.
Formulations were placed on a magnetic stirrer during dosing.

VEHICLE
Water
Details on mating procedure:
Following a minimum of 14 days of exposure for the males and females, one female was cohabitated with one male of the same treatment group,
avoiding sibling mating. Detection of mating was confirmed by evidence of sperm in the vaginal lavage or by the appearance of an intravaginal copulatory plug. This day was designated Day 0 post-coitum. Once mating occurred, the males and females were separated.
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. Samples of formulations were analyzed for homogeneity (highest and lowest concentration) and accuracy of preparation (all concentrations). Stability in vehicle over 30 minutes at room temperature 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.
Females were exposed for 43 to 57 days
Frequency of treatment:
Once daily, seven days per week.
Details on study schedule:
Not applicable.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 15, 50, 150 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
5 animals per sex per dose group.
Control animals:
not specified
Details on study design:
- Dose selection rationale:
The doses selected for this study are based on results from a 14-day dose range finding study where the doses were administered were 0, 15, 40, 100 and 200 mg/kg bw/day. At 200 mg/kg bw/day, slight body weight loss or reduced gains were seen along with changes in clinical pathology parameters. Reddish foci on the stomach glandular mucosa were seen for all animals at this dose level during the macroscopic examination. Therefore, 200 mg/kg was considered to be in excess of the MTD for the main study. No adverse effects were noted at 100 mg/kg bw/day. Based on these data, 15, 50 and 150 mg/kg bw/day were chosen for the main study.

-Rationale for animal assignment:
Prior to commencement of treatment, by computer-generated random algorithm according to body weight, with all animals within ± 20% of the sex mean.
Positive control:
No data.

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Mortality/viability were examined at least twice daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At least once daily from start of treatment onwards, detailed clinical observations were conducted for all animals. Once prior to start of treatment and at weekly intervals during the treatment period this was also performed outside the home cage in a standard arena.

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 AND COMPOUND INTAKE (if feeding study):
Weekly, except for males and females which were housed together for mating and for females without evidence of mating. Food consumption of mated females was measured on Days 0, 4, 7, 11, 14, 17 and 20 postcoitum and on Days 1 and 4 of lactation.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study):
Subjective appraisal was maintained during the study, but no quantitative investigation was introduced as no treatment related effect was suspected.

OTHER:
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Prior to scheduled post-mortem examination.
- Anaesthetic used for blood collection: Yes, isoflurane.
- Animals fasted: Yes, for a maximum of 20 hours.
- How many animals: 5 animals per sex per group.
- Parameters checked: White blood cells (WBC) and Differential leucocyte count, including Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, Red blood cells, Reticulocytes, Red blood cell distribution width (RDW), Haemoglobin, Haematocrit, Mean corpuscular volume (MCV), Mean corpuscular haemoglobin (MCH), Mean corpuscular haemoglobin concentration (MCHC) and Platelets.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to scheduled post-mortem examination.
- Animals fasted: Yes, for a maximum of 20 hours.
- How many animals: 5 animals per sex per group.
- Parameters checked: Alanine aminotransferase (ALAT), Aspartate aminotransferase (ASAT), Alkaline Phosphatase (ALP), Total protein, Albumin, Total Bilirubin, Bile acids, Urea, Creatinine, Glucose, Cholesterol, Sodium, Potassium, Chloride, Calcium and Inorganic Phosphate (Inorg. Phos).

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: The selected males were tested during Week 4 of treatment and the selected females were tested towards the end of the scheduled lactation period (all before blood sampling).
- Battery of functions tested: hearing ability, pupillary reflex, static righting reflex and grip strength.
Oestrous cyclicity (parental animals):
Male number paired with, mating date, confirmation of pregnancy, and delivery day were recorded. Pregnant females were examined to detect signs of difficult or prolonged parturition, and cage debris of pregnant females was examined to detect signs of abortion or premature birth. Any deficiencies in maternal care (such as inadequate construction or cleaning of the nest, pups left scattered and cold, physical abuse of pups or apparently inadequate lactation or feeding) were examined.
Sperm parameters (parental animals):
Parameters examined in [all/P/F1/F2] male parental generations:
Testes, epidymides.
Litter observations:
Each litter was examined to determine the mortality and viability, where the numbers of live and dead pups on Day 1 of lactation and daily thereafter were determined.
Detailled clinical observations were conducted at least once daily.
Body weights of live pups were measured on days 1 and 4 of lactation.
Sex was determined for all pups on days 1 and 4 of lactation.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals were necropsied following completion of the mating period (a minimum of 28 days of dose administration).
- Maternal animals: Females who delivered were necropsied on lactation Days 5-7. Females who failed to deliver were necropsied post-coitum on days 25-28 (females with evidence of mating) or approximately 21 days after the last day of the mating period (females without evidence of mating).

GROSS NECROPSY
- All animals were subjected to macroscopic examination of the cranial, thoracic and abdominal tissues and organs, with special attention being paid to the reproductive organs.

HISTOPATHOLOGY / ORGAN WEIGHTS
Alanine aminotransferase (ALAT), Aspartate aminotransferase (ASAT), Alkaline Phosphatase (ALP), Total protein, Albumin, Total Bilirubin, Bile acids, Urea, Creatinine, Glucose, Cholesterol, Sodium, Potassium, Chloride, Calcium and Inorganic Phosphate (Inorg. Phos).
Postmortem examinations (offspring):
SACRIFICE
Pups surviving to planned termination were killed by decapitation between Days 5-7 of lactation.

GROSS NECROPSY
All pups were sexed and descriptions of all external abnormalities were recorded. The stomach was examined for the presence of milk. If possible, defects or cause of death were evaluated.

HISTOPATHOLOGY / ORGAN WEIGTHS
Adrenal glands, Spleen, Brain, Testes, Epididymides, Thymus, Heart, Uterus (including cervix), Kidneys, Prostate, Liver, Seminal vesicles including coagulating glands, Ovaries and Thyroid including parathyroid.
Statistics:
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.
The following additional methods of statistical analysis were used:
Motor activity data was subjected to the Kruskal-Wallis nonparametric ANOVA test to determine intergroup differences followed by the Wilcoxon test to compare the treated groups to the control group.
All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance.
Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables. Test statistics were calculated on the basis of exact values for means and pooled variances. Individual values, means and standard deviations may have been rounded off before printing. Therefore, two groups may display the same printed means for a given parameter, yet display different test statistics values.
Reproductive indices:
Mating Index, Fertility index, Conception index, Gestation index, Viability index.
Offspring viability indices:
Percentage live males at First Litter Check, Percentage live females at First Litter Check, percentage of postnatal loss Days 0-4 of lactation, viability index.

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:
effects observed, treatment-related
Description (incidence and severity):
: stomach histopathology at 150 mg/kg bw/d
Other effects:
not specified

Reproductive function / performance (P0)

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

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No mortality occurred during the study period. No toxicologically significant clinical signs were noted up to 150 mg/kg bw/d. At 150 mg/kg bw/d, salivation was noted for six males and four females over a few days towards the end of the treatment period. This may be related to the taste of the test substance, and was considered to be a physiological response rather than a sign of systemic toxicity. Hunched posture and rales were also noted for a few animals on a few occasions. As inflammatory changes were observed in the stomach for animals at this dose level, it is possible these symptoms were indicative of discomfort due to local stomach effects of the test substance. Hunched posture and/or laboured respiration were noted for individual animals at 15 and 50 mg/kg bw/d over 1-3 days. Due to the transient nature and limited occurrence, these signs were not considered to be toxicologically relevant. Broken tail apex was an incidental finding noted for single males in the control and 50 mg/kg bw/d groups which had no relationship to treatment.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
No toxicologically relevant changes in body weights and body weight gain were noted up to 150 mg/kg bw/d. Individual animals at 150 mg/kg bw/d lost weight over a single time point during the mating and post coitum periods, respectively. Since this occurred for individual animals and was transient for the female, this was not considered to be indicative of systemic toxicity. Body weight gains were significantly lower for males at 50 mg/kg bw/d on Day 8 of the pre-mating period. As the difference from controls was only slight and occurred in the absence of a dose response, it was not considered to be toxicologically relevant.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No toxicologically relevant effects on reproductive parameters were noted. The mating, fertility and conception indices, precoital time, and numbers of corpora lutea and implantation sites were unaffected by treatment up to 150 mg/kg bw/d.
ORGAN WEIGHTS (PARENTAL ANIMALS)
Absolute and relative kidney weights were dose dependently higher for females of treated groups than controls, but only reached statistical significance at 150 mg/kg bw/d. The same relationship was not observed for males. However, in the absence of any effects on relevant clinical pathology parameters or treatment-related findings noted in the kidneys during the microscopic examination, the increased weights were not considered to be biologically relevant. There were no other effects on organ weights or organ to body weight ratios at any dose level tested.
GROSS PATHOLOGY (PARENTAL ANIMALS)
Dark red foci on the stomach glandular mucosa were noted for 5 males at 150 mg/kg bw/d. In addition, irregular surface and dark red discoloration of the glandular mucosa were noted for a single female and dark red discoloration of the mesenteric lymph node was noted for a single male at this dose level. An isolated, reddish focus on the stomach glandular mucosa was also seen for a single control male, however, due to the increased incidence, the foci seen for males at 150 mg/kg bw/d were considered to be treatment related. Incidental findings noted for control and/or treated animals included a bent tail, reddish or dark red foci on the thymus, pelvic dilation of the kidneys, dark red foci on the lungs, a tan focus or greenish discoloration of the clitoral gland, and alopecia on the foreleg. These findings did not show a dose related trend and were not considered to be toxicologically relevant. One female at 50 mg/kg bw/d was found with two mummified fetuses in the cervix at the macroscopic examination. As there were no developmental or reproductive findings noted at any dose level, this was not considered to be treatment related.
HISTOPATHOLOGY (PARENTAL ANIMALS)
Findings attributed to the test article were limited to the stomach and spleen, mostly for animals at 150 mg/kg bw/d.
Stomach:
Most stomach observations were confined to animals given 150 mg/kg bw/d.
-Minimal to moderate hemorrhage was observed 0/6, 1/5, 1/5, and 7/8 males in the respective 0, 15, 50 and 150 mg/kg bw/d dose groups. Minimal or slight hemorrhage was present in the glandular mucosa of 1/5 15 mg/kg bw/d and 2/5 150 mg/kg bw/d females.
-Moderate degeneration of the glandular mucosa was present in 1/8 150 mg/kg bw/d males. Minimal degeneration was present in the glandular mucosa of 1/5 150 mg/kg bw/d females.
-Minimal or slight inflammation was present in 7/8 males and 1/5 females at 150 mg/kg bw/d.
-Minimal or slight hyperplasia of non-glandular epithelium was present in 4/8 males and 2/5 females at 150 mg/kg bw/d.
-Minimal hyperkeratosis was observed in 3/8 males and 2/5 females at 150 mg/kg bw/d.
Spleen:
The average severity grades of splenic hematopoiesis were 2.0, 2.4, 1.8 and 1.2 in the respective 0, 15, 50 and 150 mg/kg bw/d dose groups for males. Females at 150 mg/kg bw/d were comparable to controls. In consideration that female 150 mg/kg bw/d animals were comparable to controls and that any significant blood loss from the stomachs of 150 mg/kg bw/d males should have resulted in increased levels of normally occurring hematopoiesis, the decrease in average severity may be spurious.
No test article related abnormalities were seen in the reproductive organs.
There were 3/10 150 mg/kg bw/d males with seminiferous tubular degeneration, however, all were unilateral. One was centrally located slight and focal. The other two were focal, minimal (barely noticeable), and consisted of a single centrally located cross sectional tubule (comprised of sertoliform cells as are often seen in association with the rete). The testes from these two animals were essentially normal. PAS stains demonstrated the presence of all sperm development stages in all control and 150 mg/kg bw/d males. Degeneration was not attributed to the test article.

OTHER FINDINGS (PARENTAL ANIMALS)
HAEMATOLOGY
There were no toxicologically relevant effects on haematology parameters up to 150 mg/kg bw/d. Activated partial prothrombin time (APTT) was increased for females at 150 mg/kg bw/d. However, this was attributable to relatively high values obtained for 2 females, and in the absence of corroborating effects seen in any other parameters, this was not considered to be toxicologically relevant. Minor statistically significant differences seen between controls and animals receiving 15 and 50 mg/kg bw/d occurred in the absence of a dose response and were not considered to be biologically relevant.
CLINICAL CHEMISTRY
There were no toxicologically relevant effects on clinical biochemistry parameters up to 150 mg/kg bw/d. At 150 mg/kg bw/d, cholesterol was higher for males, though in the absence of any relevant effects on the liver seen for any other parameter, this was ultimately not considered to be toxicologically relevant. There was a slight trend toward lower glucose for animals of all treatment groups, though the difference from controls was not statistically significant and was not considered toxicologically relevant. Calcium was significantly lower for females at 50 mg/kg bw/d, but was not considered to be toxicologically relevant since the difference from controls was only slight and occurred in the absence of a treatment related distribution.

NEUROBEHAVIOUR
Hearing ability, pupillary reflex, static righting reflex and grip strength were normal in all animals. The variation in motor activity did not indicate a relation with treatment. Males at 15 mg/kg bw/d had significantly higher total movement and ambulatory counts. However, in the absence of a dose response and any relevant clinical signs noted like hyperactivity, the effects were not considered to be treatment related. All groups showed a similar habituation profile with very high activity in the first interval that decreased over the duration of the test period.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Remarks:
parental toxicity
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: At 150mg/kg bw/day, parental effects on the stomach were observed at macroscopic and microscopic examination.
Dose descriptor:
NOAEL
Remarks:
reproductive toxicity
Effect level:
150 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No reproductive toxicity at the highest dose level of 150 mg/kg bw/d.

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 specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings:
not specified

Details on results (F1)

VIABILITY (OFFSPRING)
One pup of the control group and two, one and two pups of the 15, 50 and 150 mg/kg bw/day groups were found dead during the first days of lactation. No toxicological relevance was attributed to these dead/missing pups since the mortality incidence did not show a dose-related trend and remained within the range considered normal for pups of this age.

CLINICAL SIGNS (OFFSPRING)
There were no clinical signs noted for any pup.

BODY WEIGHT (OFFSPRING)
Body weights of pups were unaffected by treatment up to 150 mg/kg bw/day.

GROSS PATHOLOGY (OFFSPRING)
The only macroscopic finding noted was cannibalism (with all organs present), noted for a single pup that was dead at the first litter check at 50 mg/kg bw/day. This was not related to treatment with 1,8-Diazabicyclo-5,4,0-undecene-7.

Effect levels (F1)

Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Generation:
F1
Effect level:
150 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects on developmental parameters were observed at the highest dose level tested.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

No toxicologically relevant effects on gestation index and duration, parturition, maternal care and early postnatal pup development (mortality, clinical signs, body weight and macroscopic examination) were observed. The gestation index and duration of gestation were unaffected up to 150 mg/kg bw/day. The gestation index was 100, 90, 100 and 100% for females in the control, 15, 50 and 150 mg/kg bw/day groups, respectively. No signs of difficult or prolonged parturition were noted among the pregnant females. Examination of cage debris of pregnant females did not reveal signs of abortion or premature birth and no deficiencies in maternal care were observed. The number of dead and living pups at first litter check, postnatal loss and viability index were unaffected by treatment, and clinical signs, body weight and external macroscopic examination did not reveal treatment-related findings. There was a (statistically) significantly lower ratio of male to female pups (compared to controls) seen at 50 mg/kg bw/d. This was attributable to a comparatively high ratio of male to female pups (63/37) seen for controls, therefore the difference at 50 mg/kg bw/d was not due to treatment. In teh absence of any effects of treatment, a reproductive NOAEL of 150 mg/kg bw/d is determined for this study.

Applicant's summary and conclusion

Conclusions:
In conclusion, treatment with 1,8-Diazabicyclo-5,4,0-undecene-7 by oral gavage in male and female Wistar Han rats at dose levels of 15, 50 and 150 mg/kg bw/day revealed parental toxicity at 150 mg/kg bw/day. The effects were local and limited to the stomach, and may have been caused by the strong alkaline corrosivity of the test substance. No reproduction and developmental toxicity was observed for treatment up to 150 mg/kg body weight/day.
Based on the results of the present study, the No Observed Adverse Effect Level (NOAEL) for Parental toxicity was 50 mg/kg bw/day. The NOAEL for reproductive and developmental toxicity was 150 mg/kg bw/day.
Executive summary:

In this OECD -422 screening study, groups of rats were exposed to DBU via oral gavage at concentrations of 0 (vehicle controls), 15, 50 and 150 mg/kg bw/d. Males were exposed for 29 days (2 weeks prior to mating, during mating, and up to termination). Females were exposed for between 43 and 57 days (during 2 weeks prior to mating, during mating, gestation and during 4 days of lactation). he following observations and examinations were evaluated: mortality / viability, clinical signs (daily), functional observations and locomotor activity (males: Week 4, females: end of lactation), body weight and food consumption (at least at weekly intervals), clinical pathology (males: Week 4, females: end of lactation), macroscopy at termination, organ weights and histopathology on a selection of tissues, and reproduction/ developmental parameters, consisting of mating, fertility and conception indices, precoital time, number ofcorpora luteaand implantation sites, gestation index and duration, parturition, maternal care, sex ratio and early postnatal pup development (mortality, clinical signs, body weights and macroscopy). Formulations were analyzed during the study to assess accuracy, homogeneity and stability. At the highest dose level of 150 mg/kg bw/d, local effects on the stomach were seen at necropsy, including dark red foci and irregular mucosal surface. Histopathology revealed findings including haemorrhage and degeneration of the glandular mucosa, inflammation, hyperplasia and hyperkeratosis. All effects of treatmnet were local, limited to the stomach and attributable to the strong alkaline corrosivity of the test substance. No toxicologically significant changes were noted in any of the remaining parental parameters investigated in this study (i.e. clinical appearance, functional observations, body weight, food consumption, clinical laboratory investigations, macroscopic examination, organ weights, and microscopic examination). No effects of treatment on the stomach were noted at 15 and 50 mg/kg bw/d. No reproduction or developmental toxicity was observed up to the highest dose level tested (150 mg/kg bw/d). Based on these results of this study, the NOAEL for parental toxicity is considered to be 50 mg/kg bw/d; the NOAEL for reproductive and developmental toxicity is 150 mg/kg bw/d (the highest dose tested).