Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
25 August 2015 - 14 April 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report date:
2016

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)
Version / remarks:
The pre-study chemistry Control samples from Day 8 and Day 15 were not analyzed, in error.
Amendment 2 to the Protocol re-scheduled the post dose observation and not the detailed physical examination and arena observation occasions during lactation, in error. The post dose observations were recorded on Day 6 of lactation, as the animals were not dosed on Day 8 and the detailed physical examination and arena observations were performed on Day 8 of lactation and not on Day 6, for logistical reasons.
Detailed physical and arena observation of some animals on Day 6 after mating and Day 1 of lactation were performed on some animals (Group 1F 85, 89, 90; Group 2F 106, 108; Group 3F 71, 76, 77; Group 4F 51, 52, 56 and Group 1F 81, 87; Group 2F 102, 104, 109, 110; Group 3F 75, 79; Group 4F 57-60) after dose administration, in error.
Group 2; Dam/Litter No. 107 - offspring body weights were not recorded on Day 4 of age, in error.
Total leucocyte count and mean cell volume in males and hematocrit, erythrocyte count and mean cell volume in females were recorded in Week 2 of recovery, in error and are not reported.

The urinary values for protein, sodium, potassium and glucose concentration, measured in Recovery Week 2 are reported as actual values and not as urinary concentrations, as the volume of the urine samples were not recorded, in error. Urinary chloride concentration was not measured in Recovery Week 2 in error, as it was not listed as a parameter to be measured in the Study Protocol.
These unforeseen events were considered to have not affected the integrity or validity of the study.
Deviations:
yes
Remarks:
See remarks. These deviations were considered to have not affected the integrity or validity of the study.
Qualifier:
according to guideline
Guideline:
other: OPPTS 870.3650, Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, July 2000.
Version / remarks:
The pre-study chemistry Control samples from Day 8 and Day 15 were not analyzed, in error.
Amendment 2 to the Protocol re-scheduled the post dose observation and not the detailed physical examination and arena observation occasions during lactation, in error. The post dose observations were recorded on Day 6 of lactation, as the animals were not dosed on Day 8 and the detailed physical examination and arena observations were performed on Day 8 of lactation and not on Day 6, for logistical reasons.
Detailed physical and arena observation of some animals on Day 6 after mating and Day 1 of lactation were performed on some animals (Group 1F 85, 89, 90; Group 2F 106, 108; Group 3F 71, 76, 77; Group 4F 51, 52, 56 and Group 1F 81, 87; Group 2F 102, 104, 109, 110; Group 3F 75, 79; Group 4F 57-60) after dose administration, in error.
Group 2; Dam/Litter No. 107 - offspring body weights were not recorded on Day 4 of age, in error.
Total leucocyte count and mean cell volume in males and hematocrit, erythrocyte count and mean cell volume in females were recorded in Week 2 of recovery, in error and are not reported.

The urinary values for protein, sodium, potassium and glucose concentration, measured in Recovery Week 2 are reported as actual values and not as urinary concentrations, as the volume of the urine samples were not recorded, in error. Urinary chloride concentration was not measured in Recovery Week 2 in error, as it was not listed as a parameter to be measured in the Study Protocol.
These unforeseen events were considered to have not affected the integrity or validity of the study.
Deviations:
yes
Remarks:
See remarks. These deviations were considered to have not affected the integrity or validity of the study.
Qualifier:
according to guideline
Guideline:
other: Official notice of J MHLW, METI and ME (31 March 2011), YAKUSHOKUHATSU No. 0331. 7, SEIKYOKU No. 5, KANPOKIHATSU No. 110331009.
Version / remarks:
The pre-study chemistry Control samples from Day 8 and Day 15 were not analyzed, in error.
Amendment 2 to the Protocol re-scheduled the post dose observation and not the detailed physical examination and arena observation occasions during lactation, in error. The post dose observations were recorded on Day 6 of lactation, as the animals were not dosed on Day 8 and the detailed physical examination and arena observations were performed on Day 8 of lactation and not on Day 6, for logistical reasons.
Detailed physical and arena observation of some animals on Day 6 after mating and Day 1 of lactation were performed on some animals (Group 1F 85, 89, 90; Group 2F 106, 108; Group 3F 71, 76, 77; Group 4F 51, 52, 56 and Group 1F 81, 87; Group 2F 102, 104, 109, 110; Group 3F 75, 79; Group 4F 57-60) after dose administration, in error.
Group 2; Dam/Litter No. 107 - offspring body weights were not recorded on Day 4 of age, in error.
Total leucocyte count and mean cell volume in males and hematocrit, erythrocyte count and mean cell volume in females were recorded in Week 2 of recovery, in error and are not reported.

The urinary values for protein, sodium, potassium and glucose concentration, measured in Recovery Week 2 are reported as actual values and not as urinary concentrations, as the volume of the urine samples were not recorded, in error. Urinary chloride concentration was not measured in Recovery Week 2 in error, as it was not listed as a parameter to be measured in the Study Protocol.
These unforeseen events were considered to have not affected the integrity or validity of the study.
Deviations:
yes
Remarks:
See remarks. These deviations were considered to have not affected the integrity or validity of the study.
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Justification for study design:
The oral gavage route of administration was chosen to simulate the conditions of potential human exposure and is the recommended route in the test guidelines.

Test material

1
Chemical structure
Reference substance name:
1-butoxy-3-(prop-2-en-1-yloxy)propan-2-ol
EC Number:
801-709-5
Cas Number:
53146-45-5
Molecular formula:
C10H20O3
IUPAC Name:
1-butoxy-3-(prop-2-en-1-yloxy)propan-2-ol
Specific details on test material used for the study:
Appearance: Brown liquid
Storage conditions: Room temperature, under nitrogen
Lot number: 15B26
Expiry date 01 August 2016
Purity (by GLC) 81.7%

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: Approximately 77 days for male, approximately 70 days for females.
- Weight at study initiation: Males 352 to 426 g, Females 226 to 289 g.
- Housing: Solid (polycarbonate) bottom cages with a stainless steel mesh lid were used during the acclimatisation, gestation, littering and lactation periods. Grid (polycarbonate) bottomed cages were used during pairing. Solid bottom cages contained softwood based bark-free fiber bedding.
- Diet (e.g. ad libitum): Certified pelleted diet, non-restricted (removed overnight before blood sampling for haematology or blood chemistry and during the period of urine collection).
- Water (e.g. ad libitum): Potable water from the public supply, non-restricted (except during urine collection).
- Acclimation period: 12 days before commencement of treatment.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24ºC
- Humidity (%): 40-70%
- Air changes (per hr): Filtered fresh air which was passed to atmosphere and not recirculated.
- Photoperiod (hrs dark / hrs light): 12 hours light : 12 hours dark.
- Environmental Enrichment: Aspen chew block, throughout the study (except during pairing and lactation) and plastic shelter, throughout the study (except during pairing and lactation)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
A daily record of the usage of formulation was maintained based on weights. This balance was compared with the expected usage as a check of correct administration. No significant discrepancy was found. Formulations were stirred using a magnetic stirrer before and throughout the dosing procedure.
An approximate volume of test formulation (1 mL, accurately weighed) was dissolved with the aid of swirling in a suitable volume of diluent. Where necessary the extract was diluted using diluent and a suitable volume of internal standard was added to the final dilution, to provide a solution containing the test item at an expected concentration within the range 40 µg/mL to 80 µg/mL.
The concentration of the test item in the final solution was quantified by GC using flame ionisation detection as detailed in the chromatographic section.

DIET PREPARATION
- Rate of preparation of diet (frequency): Weekly
Details on mating procedure:
- M/F ratio per cage: 1:1 from within the same treatment groups.
- Length of cohabitation: Up to two weeks
- Proof of pregnancy: Ejected copulation plugs in cage tray and sperm in the vaginal smear referred to as day 0 of pregnancy.
- After successful mating each pregnant female was caged (how): one female
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration of the test item in the final solution was quantified by GC using flame ionisation detection as detailed in the chromatographic section.
Duration of treatment / exposure:
Main study males: Two weeks pre-pairing, throughout pairing up to necropsy. A minimum of 5 weeks treatment in total.
Main study females: Two weeks before pairing, throughout pairing and gestation until Day 7 of lactation
Toxicity phase females: After minimum of five weeks.
Recovery phase animals: At least six weeks of treatment, followed by 14 days with no treatment (recovery phase commenced from the first main study Dam necropsy, on Day 8 post-partum).
Frequency of treatment:
Main study males: daily for two weeks before pairing, throughout pairing and up to necropsy after a minimum of five consecutive weeks.
Main study females: daily for two weeks before pairing, throughout pairing, gestation and until Day 7 of lactation.
Toxicity phase females: daily for a minimum of five consecutive weeks.
Recovery phase male and female: daily for a minimum of six consecutive weeks.
Details on study schedule:
Main study:
Females:
Week 2: mating
Days 4-6 of lactation: Sensory reactivity/Motor activity/grip strength
Day 8 of lactation: Haematology/blood chemistry
Day 8 lactation: Necropsy

Males:
Week 2: mating
Week 5: investigations Sensory reactivity/Motor activity/grip strength males groups 2 + 3 Haematology/blood chemistry and Urinalysis
Week 6: Necropsy
Necropsy - Litters Day 7 of age

Toxicity phase females (Toxicity phase females were not paired):
Week 5: investigations Haematology/blood chemistry and Urinalysis
Week 6: Necropsy

Recovery phase (Recovery phase animals were not paired):
Week 5: investigations Sensory reactivity/Motor activity/grip strength Groups 1 + 4 - M + F
Day 8 of lactation: Recovery starts after first Dam necropsy
Recovery behaviours Groups 1 + 4 M + F and Clinical pathology
After 2 weeks recovery: Necropsy
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Remarks:
Nominal concentration: 0 mg/mL
Formulated concentration: 0 mg/mL
Volume dose: 5 mL/kg
Dose / conc.:
25 mg/kg bw/day
Remarks:
Nominal concentration: 5 mg/mL
Formulated concentration: 6.1 mg/mL
Volume dose: 5 mL/kg
Dose / conc.:
105 mg/kg bw/day
Remarks:
Nominal concentration: 21 mg/mL
Formulated concentration: 25.62 mg/mL
Volume dose: 5 mL/kg
Dose / conc.:
450 mg/kg bw/day
Remarks:
Nominal concentration: 90 mg/mL
Formulated concentration: 109.8 mg/mL
Volume dose: 5 mL/kg
No. of animals per sex per dose:
Main study: 10 females/males at each dose
Toxicity phase: 5 females at Control and 450 mg/kg/day doses
Recovery phase: 5 females/males at Control and 450 mg/kg/day doses
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose levels were selected based on the results from the dose range finder study (Preliminary Toxicity Study by Oral Gavage Administration to CD Rats for 7 Days).
It was considered that a high dose level of 450 mg/kg/day and intermediate and low dose levels of 105 mg/kg/day and 25 mg/kg/day were suitable for this study for OECD 422 hazard classification for repeat dose toxicity studies.

Examinations

Parental animals: Observations and examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: least twice daily

BODY WEIGHT: Yes
- Time schedule for examinations:
Main study males, recovery phase animals and toxicity phase females: Week -1 Before dosing on the day that treatment commenced (Week 0) and weekly thereafter (including recovery phase). On the day of necropsy.
Main study females: Week -1 Before dosing on the day that treatment commenced (Week 0) and weekly before pairing. Days 0, 6, 13 and 20 after mating. Day 1, 4, 7 and 8 of lactation. On the day of necropsy.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
Main study males, recovery phase animals and toxicity phase females: Week -1 Weekly Food consumption was not recorded for main study phase males and females during the period when they were paired for mating (Week 3), but recommenced for males in Week 4. Food consumption was recorded continuously for toxicity phase females and recovery phase animals.
Main study females: Week -1, on the day that treatment commenced (Week 0). Weekly before pairing. Days 0-5, 6-12 and 13-19 after mating. Days 1-3 and 4-6 of lactation.
Oestrous cyclicity (parental animals):
Dry smears - main study: Daily smears were taken for 15 days before pairing. Smears were subsequently examined to establish the duration and regularity of the oestrous cycle.
Wet smears - main study: After pairing with the male, daily smearing was continued using pipette lavage, until evidence of mating was observed.
Terminal wet smears - toxicity phase: For four days up to and including the day of necropsy, using pipette lavage.
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: Clinical observations, Litter size, Sex ratio of each litter, Individual offspring body weights.

GROSS EXAMINATION OF DEAD PUPS:
yes: F1 offspring at Day 7 of age.

Postmortem examinations (parental animals):
See table 1.
Postmortem examinations (offspring):
Examined externally (including palate), if found to be normal offspring were discarded without further examination. Any externally abnormal offspring were also examined internally. Abnormal tissues were retained in an appropriate fixative.
Statistics:
The following data types were analyzed at each timepoint separately:
-Grip strength and motor activity
-Body weight, using absolute weights and gains over appropriate study periods
-Food consumption, over appropriate study periods during gestation and lactation Haematology, blood chemistry and urinalysis
-Estrous cycles
-Litter data
-Organ weights, both absolute and adjusted for terminal body weight
Offspring viability indices:
Post implantation survival index (%)
Live birth index (%)
Viability index (%)

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
One female (No. 60) receiving 450 mg/kg/day was humanely killed, following the death of her litter on Day 5 of age.
Microscopic examination of the mammary tissue of the adult revealed reduced secretory activity.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One female (No. 80) receiving 105 mg/kg/day Approximately five hours later, after treatment, the animal was found in respiratory distress (gasping) and had a red stained muzzle; one pup had been cannibalised. The female was considered to be in poor clinical condition andwas euthanized on welfare grounds at pre-Day 1 of lactation.
Macroscopic examination revealed fetal material or dark contents in the mouth, oesophagus, stomach, ileum, jejunum, lungs and bronchi and clear aerated fluid in the nasal turbinates and trachea; two placentas were found in the uterus. The cause of death was considered due to aspiration of fetal material and therefore not related to administration of the test item.

One female (No. 60) receiving 450 mg/kg/day was humanely killed, following the death of her litter on Day 5 of age.
Microscopic examination of the mammary tissue of the adult revealed reduced secretory activity
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
When compared with Control, overall body weight gain (Week 0-5) was marginally low, or low, in males treated at 105 or 450 mg/kg/day (91 or 80%, respectively). The body weight gain of males previously treated at 450 mg/kg/day was higher (162%) than Control, during the two week off-dose period.
Body weight gain in un-mated females and females during gestation and lactation were unaffected by treatment.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption of males was considered to be unaffected by treatment.
Food intake of unmated females at 450 mg/kg/day was low (85%) during the first week of treatment, when compared with Control; however there was no adverse effect on body weight gain.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Investigation of the cellular constituents of the blood in Week 5 and when compared with Control, indicated mild anaemia in treated males, but not in non-mated females treated at 450 mg/kg/day. Haematocrit, haemoglobin concentration and red cell count at 25, 105 or 450 mg/kg/day were all marginally low (94, 95 or 91%; 95, 94 or 90% and 92, 95 or 90%, respectively) and reticulocyte count at 105 or 450 mg/kg/day was marginally high (114 or 128%, respectively). In females, haemoglobin concentration was marginally low (92%), on Day 8 of lactation. Activated partial thromboplastin time was slightly short in males and non-mated females receiving 450 mg/kg/day (88% and 92%, respectively) and was short (87%) on Day 8 of lactation.
All other differences were minor, confined to one sex and included high lymphocyte count in males at 450 mg/kg/day (134%) and low mean cell volume in females at the same dose (92%).
Following two weeks respite from treatment, all parameters affected during treatment were comparable with Control and therefore showed full recovery
Description (incidence and severity):
The biochemical examination of the blood plasma in males and non-mated females in Week 5 and on Day 8 of lactation did not identify any toxicologically significant differences from Control that were clearly attributable to treatment.
All differences were confined to males. Such differences included the low triglyceride concentration at 105 or 450 mg/kg/day (72 or 56%) and low phosphorous concentration (80%), in which all individual values were lower than the Control range. Further investigation of these parameters, following two weeks respite from treatment, showed that the values were comparable with Control.
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
Investigation of the composition of the urine in Week 5 and when compared with Control, revealed high protein, glucose, sodium, potassium and chloride concentrations in males treated at 105 or 450 mg/kg/day and in females at 450 mg/kg/day.
Urinary volume was high in males and females treated at 450 mg/kg/day (165% or 193%, respectively) and pH was low in males treated at 25, 105 or 450 mg/kg/day (85, 85 or 77%, respectively).
Unfortunately, as the urinary volume was not recorded at the recovery phase investigation; the concentration of these parameters, relative to urinary output cannot be presented.
However, the data shows that concentrations of protein, glucose, sodium and potassium were comparable with Control, following two weeks respite from treatment. It was considered that chloride concentration would show similar recovery
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
It was considered that there was no effect of treatment at any dose on sensory reactivity and grip strength or motor activity.
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Findings considered to be related to treatment were seen in the skin.
Slight to moderate epidermal ulceration and/or necrosis and dermal inflammation were seen in four males receiving 450 mg/kg/day and one receiving 105 mg/kg/day, all of which correlated with findings seen at necropsy. In all cases, these changes were associated with one or more inflammatory and/or degenerative changes, including scabs, subcutaneous inflammation, epidermal hyperplasia, myofibre degeneration/necrosis of the panniculus carnosus, and dermal/subcutaneous oedema.
The toxicological significance of these changes is unclear.
Histopathological findings: neoplastic:
not examined
Other effects:
effects observed, treatment-related
Description (incidence and severity):
The toxicological significance of the changes in the skin is unclear, as it was only evident in males and not females.

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
It was considered that estrous cycles were not affected by treatment.
One animal receiving 25 mg/kg/day (No. 106) and two animals receiving 450 mg/kg/day (No’s 53 and 58) had irregular oestrus cycles and all other animals showed regular 4 or 5 day cycles; however, it was considered that there was no relationship with treatment.
Similar proportions of toxicity phase females in the Control and 450 mg/kg/day groups showed oestrus at the end of the treatment period and the pattern of recorded cycle stages suggested that animals were cycling normally
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
Pre-coital interval was not affected by treatment.
One Control female (No. 82) and one female receiving 450 mg/kg/day (No. 53) mated at the second oestrus occasion after pairing, all other females mated at the first oestrus occasion.
Mating performance and fertility was not affected by treatment.
The gestation length of all animals was within acceptable limits (22-23.5 days). All animals were pregnant.

Details on results (P0)

At 450 mg/kg/day: all or the majority of males and females, underactive behavior, with or without piloerection and/or partially closed eyelids that persisted in some at the end of the day; body temperature was noted to be low, following the first dose in females and the food intake of females only was low during the first week of treatment.

Overall male body weight gain during treatment was marginally low at 105 or 450 mg/kg/day and showed good, but partial recovery at the end of the recovery period; female body weight gain was unaffected. One male at 405 mg/kg/day was found with noisy respiration and piloerection on Day 21.
At the end of the treatment period, there was evidence of mild anaemia in treated males and activated partial thromboplastin time was slightly short in males and non-mated females and females with a litter and urinary protein, glucose, sodium, potassium and chloride concentrations were high in males and females treated at 450 mg/kg/day and in males at 105 mg/kg/day. All haematological and urinary parameters showed full recovery, following two weeks respite from treatment and there were no microscopic findings.
It was considered that there was no effect of treatment at any dose on sensory reactivity and grip strength or motor activity or food intake or on the biochemistry of the blood and there was no effect on estrous cycles (before pairing or immediately before termination (non-mated females)), pre-coital interval, mating performance, fertility or gestation length.
One female treated at 450 mg/kg/day was killed on Day 5 of lactation, following the death of her litter and microscopic examination revealed reduced secretory activity of the mammary glands, but in the absence of increased pup mortality in other litters no definite effect of treatment was inferred and one female treated at 105 mg/kg/day was killed shortly after littering, following aspiration of fetal material, again this death was considered not to be related with treatment.

The toxicological significance of the changes in the skin is unclear, as it was only evident in males and not females.

Effect levels (P0)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
450 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Dose descriptor:
NOAEL
Effect level:
25 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
clinical signs
Key result
Dose descriptor:
NOAEL
Effect level:
450 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive function (oestrous cycle)
reproductive function (sperm measures)
reproductive performance
Remarks on result:
not determinable due to absence of adverse toxic effects

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Description (incidence and severity):
There were no signs considered to be related to treatment.
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
All litters were raised to Day 7 of age, with the exception of on litter at 105 mg/kg/day, killed following the euthanasia of the dam (No. 80) and one litter at
450 mg/kg/day (Dam No. 60) that were not sufficiently suckled and died at five days of age and, in the absence of increased pup mortality in other study litters, no effect of parental treatment was inferred.
Litter size, sex ratio and survival indices were unaffected by treatment.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There was no effect of treatment on mean offspring body weight on Day 1 of age.
Offspring body weight gain from birth to Day 7 of age was slightly low, with parental treatment at 25, 105 or 450 mg/kg/day (male 89, 84 or 87%; female 85, 87 or 83%, respectively).
Gross pathological findings:
no effects observed
Description (incidence and severity):
Macroscopic observation of offspring that were humanely killed or found dead before Day 7 and those terminated on Day 7 of age revealed no findings considered to be related with treatment.
There was no effect of parental treatment on litter size or sex ratio and there were no macroscopic findings in the offspring considered to be treatment related.
Other effects:
no effects observed
Description (incidence and severity):
There was no effect of parental treatment on litter size or sex ratio and there were no macroscopic findings in the offspring considered to be treatment related.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
450 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
Parents treated only
Sex:
not specified
Remarks on result:
not determinable due to absence of adverse toxic effects

Overall reproductive toxicity

Key result
Reproductive effects observed:
no
Lowest effective dose / conc.:
450 mg/kg bw/day (nominal)
Treatment related:
no
Dose response relationship:
no

Applicant's summary and conclusion

Conclusions:
It was concluded that the No-Adverse-Effect-Level (NOAEL) for reproductive and developmental toxicity was 450 mg/kg/day.

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