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EC number: 267-510-5 | CAS number: 67874-81-1
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 03 November 2015 to 21 December 2015
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 016
- Report date:
- 2016
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: OECD guideline 422
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- [3R-(3α,3aβ,6α,7β,8aα)]-octahydro-6-methoxy-3,6,8,8-tetramethyl-1H-3a,7-methanoazulene
- EC Number:
- 267-510-5
- EC Name:
- [3R-(3α,3aβ,6α,7β,8aα)]-octahydro-6-methoxy-3,6,8,8-tetramethyl-1H-3a,7-methanoazulene
- Cas Number:
- 67874-81-1
- Molecular formula:
- C16H28O
- IUPAC Name:
- [3R-(3α,3aβ,6α,7β,8aα)]-octahydro-6-methoxy-3,6,8,8-tetramethyl-1H-3a,7-methanoazulene
- Test material form:
- liquid
Constituent 1
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): Cedramber
- Physical state: clear liquid
- Storage condition of test material: 15 - 25°C, protected from light
- Analytical purity: 97.88%
- Lot/batch No.: 0006870782
- Expiration date of the lot/batch: 06-Jun-2017
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approximately 9 weeks (males) or 8 weeks (females) of age
- Weight at study initiation: Mean body weight one day before the start of treatment was 299 grams for males and 185 grams for females.
- Housing: The rats were housed in makrolon cages with a bedding of wood shavings (Lignocel, Rettenmaier & Söhne GmbH & Co, Rosenberg, Germany) and strips of paper (Enviro-dri, Shepherd Specialty Papers, Michigan, USA) and a wooden block (ABEDD, Vienna, Austria) as environmental enrichment. During the premating period the animals were housed four rats to a cage (separated by sex). For mating, one male and one female were housed together. Mated females were housed individually.
- Diet: the rats receive a cereal-based (closed formula) rodent diet (VRF1 (FG)) from a commercial supplier (SDS Special Diets Services, Witham, England)., ad libitum.
- Water: Tap-water, ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 45-65%
- Air changes (per hr): about 10
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- The diets were mixed in a mechanical blender. Fresh batches of the experimental diets were prepared on 29 October 2015 and on 27 November 2015) and stored in a freezer (<-18°C) in plastic bags in portions sufficient for three to four days. The diets were provided as a powder in stainless steel cans, covered by a perforated stainless steel plate to prevent spillage. The food in the cans was replaced twice per week with fresh portions from the freezer.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- From both batches of diets prepared in the study (29 October 2015 and on 27 November 2015) samples were taken and stored in a freezer (≤ -18°C). The content of the test substance at each dietary level was determined in the batches prepared on 29 October 2015 and 27 November 2015. The homogeneity (and content) of the test substance in the experimental diets was assessed in the first batch (29 October 2015), by analysing five samples (taken at different locations in the feed container) of each test diet in duplicate. One sample of the control diet was analysed. To demonstrate the stability of the test substance under experimental conditions, samples of the batch of test diets prepared on 29 October 2015 (low-dose diet, mid-dose diet and high-dose diet) were analyzed at t=0 and analyzed after storage in the animal room (in an open container) for 4 days, and after storage in a freezer (<-18 °C) for at least 5 weeks.
The concentration of the test substance in diet was determined using the following procedure: The test substance was extracted from diet using extraction solvent (150 μl undecane in 2.5 liter dichloromethane) under shaking and ultrasonic treatment. Subsequently the extracts were 50-fold diluted with extraction solvent and centrifuged. The method of analysis was Gas Chromatography – Mass Spectrometry (GC-MS). Quantification was obtained by comparison of the peak area of the test substance in the extracts with those in calibration samples containing known amounts of the test substance and internal standard (undecane).
Before analysis of study samples, the analytical method was validated by analyzing three spiked samples per dose level, to conform to the following criteria:
- Linearity: the correlation coefficient of the calibration curve should be greater than or equal to 0.996;
- Recovery: the mean recovery of the test substance from the diet should be between 85% and 115% at each of the dose levels of the study;
- Repeatability: the relative standard deviation in the percentage recovery, when the recovery test is performed three times at each of the dose levels to be used in the toxicity study, should be less than 10%.
With respect to specificity: the signal obtained for samples should be corrected for the signal obtained with blank samples in case the signal obtained for blank samples is ≥ 5% of the signal obtained for low-dose samples. - Details on mating procedure:
- At the end of the premating period, each female was caged with one male from the same dose group. Animals were caged together until mating occurred. During the first week of the mating period, all males successfully mated with their assigned female and therefore no male needed to be replaced. Every consecutive morning during the mating period, vaginal smears were made for determination of the presence of sperm. The day on which sperm was detected in the vaginal smear was considered as gestation day 0. Upon evidence of copulation the females were caged individually for the birth and rearing of their pups. Dams were allowed to raise their litter until sacrifice four or six days after giving birth. Males were killed after at 28 days of exposure
- Duration of treatment / exposure:
- Males 28 days. Females received substance during a premating period of 2 weeks and during mating (1 week), gestation and lactation until 4-6 days after delivery.
- Frequency of treatment:
- Continuously
- Duration of test:
- Until 4-6 days after delivery.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg diet
- Dose / conc.:
- 1 500 mg/kg diet
- Remarks:
- Males: ca. 79 mg/kg bw/day; Females: ca. 99 mg/kg bw/day
- Dose / conc.:
- 3 000 mg/kg diet
- Remarks:
- Males: ca. 166 mg/kg bw/day; Females: ca. 203 mg/kg bw/day
- Dose / conc.:
- 6 000 mg/kg diet
- Remarks:
- Males: ca. 330 mg/kg bw/day; Females: ca. 406 mg/kg bw/day
- No. of animals per sex per dose:
- 12
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: The dose levels were selected in consultation with the sponsor and are based on the results of a 2-weeks dose-range finding study with the test substance in rats.
Examinations
- Maternal examinations:
- - General clinical observations: Each animal was observed daily in the morning hours by cage-side observations. On working days, all cages were checked again in the afternoon for dead or moribund animals to minimize loss of animals from the study. All abnormalities, signs of ill health or reactions to treatment were recorded.
- Neurobehavioral testing (FOB and spontaneous motor activity): In addition to the above daily general clinical observations, detailed clinical examinations outside the home cage were performed on all rats of all groups prior to the first exposure and then once weekly throughout the study. In the last week of the study the detailed clinical examinations were part of the Functional Observational Battery tests (FOB) in the animals concerned. Signs noted included but were not limited to changes in skin and fur, piloerection, changes in the eyes, gait (including posture), and presence of clonic or tonic movements, stereotypies and bizarre behaviour. In the week prior to sacrifice, FOB tests and spontaneous motor activity were performed in 5 males/group on day 24 of the study and in 5 females with a litter/group on PN day 4. For females both tests were performed after sacrifice of their pups on PN day 4. During neurobehavioural testing, the observer was unaware of the treatment of the animals.
- Body weight: Body weights of male and female animals were recorded shortly before the start of the treatment (to enable randomization) and at the start of the study (day 0). Subsequently males were weighed weekly until sacrifice. Females were weighed once per week during the premating and mating period. Mated females were weighed on days 0, 7, 14 and 20 during presumed gestation and on day 0 and 4 of lactation. The animals were weighed on their scheduled necropsy date in order to calculate the organ to body weight ratios.
- Food consumption: Food consumption was measured per cage for the same periods as the body weight are measured, except during the mating period when food intake was not registered. The results are expressed in g per animal per day. Food was refreshed twice weekly.
- Intake of test substance: The intake of the test substance per kg body weight per day was calculated from the nominal dietary concentrations, the food consumption and the body weight of each study phase period for males and females separately.
- Hematology: Hematology was conducted in samples collected prior to the end of the premating period (on day 13) in 5 rats/sex/group. The rats were fasted overnight (water was freely available). Blood was taken by orbita punction whilst under CO2/O2 anesthesia. EDTA was used as anticoagulant. In each sample the following determinations were carried out: Hemoglobin, packed cell volume, red blood cell count, reticulocytes, total white blood cell count, differential white blood cell counts (neutrophils, lymphocytes, eosinophils, basophils, monocytes), prothrombin time, thrombocyte count, mean corpuscular volume (MCV; calculated), mean corpuscular hemoglobin (MCV; calculated), mean corpuscular hemoglobin concentration (MCHC; calculated)
- Clinical chemistry: Clinical chemistry was conducted in the same rats as indicated above (hematology). Blood was collected in heparinized plastic tubes and plasma was prepared by centrifugation. In each plasma sample the following determinations were carried out: Alkaline phosphatase activity (ALP) , aspartate aminotransferase activity (ASAT), alanine aminotransferase activity (ALAT), gamma glutamyl transferase activity (GGT), total protein, albumin, ratio albumin to globulin (calculated), urea, creatinine, glucose (fasting), bilirubin (total), cholesterol (total), triglycerides, phospholipids, calcium (Ca), sodium (Na), potassium (K), chloride (Cl), inorganic phosphate (PO4).
- Gross necropsy and histology of maternal animals: All female parent animals were sacrificed by exsanguination from the abdominal aorta whilst under CO2/O2 anesthesia at necropsy and then examined grossly for pathological changes. The dams were sacrificed on day 4 of lactation or one day thereafter (those selected for FOB/motor activity testing. High-dose female 89 was sacrificed at day 6 of lactation. Pups were sacrificed by gradual CO2 anesthesia, followed by irreversible hypothermia. The dams and the various lots were sacrificed between 14 – 21 December 2015. Samples of the following tissues and organs of all parent animals were preserved in a neutral aqueous phosphate buffered 4% solution of formaldehyde; except for the testes and the epididymides which were preserved in Bouin's fixative. Organs with asterisk were weighed (paired organs together) as soon as possible after dissection to avoid drying. all gross lesions, ovaries (after counting the corpora lutea), uterus (after counting of the implantation sites). In addition, the following organs of five parent animals/group were preserved. The organs with an asterisk were weighed (paired organs together) (five animals/group) as soon as possible after dissection to avoid drying: Adrenals*, heart*, kidneys*, lungs, spleen*, stomach, thymus*, thyroid, urinary bladder, brain* (including sections of cerebrum, cerebellum, medulla/pons), bone marrow (femur), liver*, mesenterial and axillary lymph nodes, peripheral nerve (sciatic or tibial), small and large intestines (including Peyer’s patches), spinal cord (cervical, mid-thoracic, and lumbar), trachea. Tissues for microscopic examination were embedded in paraffin wax, sectioned at 5 μm, and stained with hematoxylin and eosin. Microscopic examination was performed on the preserved organs of all animals of the control (group 1) and high-dose group (group 4). Rats of all dose groups organs showing gross lesions were microscopically examined. - Ovaries and uterine content:
- Ovaries and uterus were examined. Corpora lutea and the implantation sites were counted.
- Fetal examinations:
- - Parturition and litter evaluation: At the end of the gestation period (GD 21), females were examined twice daily for signs of parturition. Any difficulties occurring during parturition were recorded. To keep nest disturbance to a minimum the litters were examined only once daily for dead pups.
- Litter size, sexes and weight: The total litter size and numbers of each sex as well as the number of stillbirths, live- and dead pups and grossly malformed pups were evaluated on days 0 and 4 of lactation. The pups were individually weighed on days 0 and 4 of lactation. Mean pup weight was calculated per sex and for both sexes combined.
- Signs and pathology of pups: Any abnormal behavior of pups was recorded on day 0 and 4 of lactation. Grossly malformed pups were examined macroscopically. A necropsy was performed on stillborn pups and pups dying during the study; macroscopic abnormalities were recorded. At necropsy of the surviving dams, pups were examined externally for gross abnormalities and killed by hypothermia whilst under CO2/O2 anesthesia. The pups were discarded right after necropsy. No further examinations took place. - Statistics:
- The data were analysed using appropriate methods. Tests were generally performed as two-sided tests with results taken as significant where the probability of the results is p<0.05 (*) or p<0.01 (**). Continuous data were subjected to the “Decision tree for continuous data” and dichotomous data were subjected to the “Decision tree for dichotomous data”
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- One female (number 47) in the low-dose group had encrustations of the skin in the neck region from premating until gestation. These observations and common observations for this strain and therefore not considered to be treatment related. During the end of the gestation period and the start of the lactation period, a few rats in the low, mid and high dose had sparsely haired area(s) and one rat in the high dose had ventral encrustations during lactation (female number 89). This observation is common for this strain and therefore not considered to be treatment related. Around the time of delivery piloerection was observed in one female rat in the high dose and two in the mid dose. This was due to delivery and not considered related to the treatment.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- No mortality and morbidity was observed during premating, mating, or gestation and lactation.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- In females no changes were observed in body weight and body weight gain in any of the doses groups in the premating period, gestation period and lactation period. In addition, no changes were observed in the total body weight gain during the pre-mating period.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No changes were observed in food consumption in any of the dose groups.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- In female rats no changes were observed in red blood cells and coagulation parameters in any of the dose groups. Also no changes were observed in total and differential white blood cell counts.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In females in the high-dose a statistically significant decrease in bilirubin was observed. In females that received the low-dose ALP concentrations were statistically significantly decreased. Because the findings were not dose-dependent and observed in only one sex, these findings are considered chance findings. In females in the high-dose group, phospholipids concentration and phosphate concentration were statistically significantly increased. Since these findings were slightly outside the historical control range, these effects were considered slight and not adverse.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- Clinical observations, Functional Observation Battery (FOB) and motor activity assessment (MAA) did not indicate any neurotoxic potential of the test substance in rats.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- No effects were observed on all organ weights of females of all groups.
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- At necropsy no treatment related macroscopic changes were observed. The few gross changes observed represented background pathology in rats of this strain and age and occurred only incidentally or at random incidence in the different groups.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Organs and tissues did not reveal treatment related histopathological changes. The histopathological changes observed were about equally distributed amongst the different treatment groups or occurred in one or a few animals only. They are common findings in rats of this strain and age or occurred as individual chance findings. Therefore, they were not considered to be related to treatment.
- Histopathological findings: neoplastic:
- no effects observed
Maternal developmental toxicity
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed - Details on maternal toxic effects:
- All females were pregnant (12 females for each dose group). There were no relevant differences in pre-coital time, male and female mating indices, or female fertility indices and the duration of gestation between the groups. No effects were found on the mean number of corpora lutea and implantation sites between the group. Pre-implantation loss was not affected by the treatment.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 406 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: No toxic effects observed at any dose level tested.
- Remarks on result:
- other: corresponding to NOAEL ≥ 6000 mg test substance/kg diet
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Body weight and body weight change of the pups did not differ between de groups on PN day 0 and PN day 4 for males and females separately or when added both sexes together.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined - Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- In all groups all pups were live born, no stillborn pups were observed.
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- There were no statistically significant differences observed in the sex ratio between all groups.
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- no effects observed
- Description (incidence and severity):
- Nno differences were observed in the number pups found dead (between LD 1 and LD 4) between the control and experimental groups.
- External malformations:
- not examined
- Skeletal malformations:
- not examined
- Visceral malformations:
- not examined
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The incidence of clinical observations in pups was limited to 4 female pups in the control and mid-dose groups and 4 male pups in the low-, mid-, and high-dose groups.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 406 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No toxic effects observed at any dose level tested.
- Remarks on result:
- other: corresponding to NOAEL ≥ 6000 mg test substance/kg diet
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
|
Mean (range) substance intake (mg Cedramber/kg body weight/day |
||
|
Low dose |
Mid dose |
High dose |
Premating females |
99.27 - 106.75 |
203.81 - 214.43 |
406.65 - 407.57 |
Gestation females |
99.43 - 108.38 |
204.06 - 222.34 |
411.74 – 418.74 |
Lactation females |
173.74 |
366.26 |
759.56 |
-Test substance analysis:
Content:
The concentration of the test substance was close to intended (85-115%) for the diets prepared on 29 October 2015. The measured concentrations in the diets prepared on 27 November 2015 were slightly lower than intended (-11%, -22%, -19% as compared to the nominal concentration for the low-, mid-, and high-dose respectively).
Homogeneity:
The test substance was considered to be homogeneously distributed in the diets.
Stability:
After storage in an open container in the animal room for 4 days, the test substance was considered stable (relative differences upon storage were -2%, -11% and -15% for the low dose, mid-dose and high-dose groups, respectively). Re-analysis at 7 December 2015 of the high-dose samples (after subsequent storage in the freezer for 5 weeks) showed a relative difference of -20%. After storage in a closed container freezer for at < -18 °C for 5 weeks the low-dose and mid dose were considered stable after storage. The high-dose was slightly lower than intended (-21%). These concentrations were accepted and no corrections with respect to the analysis were made in the test item intake calculations.
Applicant's summary and conclusion
- Conclusions:
- Based on the absence of effects on developmental parameters, the NOAEL for developmental toxicity was stablished at ≥ 6000 mg test substance per kg diet (corresponding to a dose of 406 mg/kg body weight for females).
- Executive summary:
The possible effects of the test substance on general toxicity, reproductive performance and development of pups was examined according to OECD 422 and in compliance with GLP.Groups of 12 male and female Wistar rats were exposed via the diet to levels of 0, 1500, 3000 and 6000 mg/kg diet during a premating period of 2 weeks and during mating, gestation until day 4 of lactation. Female rats and pups were sacrificed at or shortly after day 4 of lactation. Male rats were sacrificed after the mating period. The content, homogeneity and stability of the test substance in the carrier were accepted. Stability in a freezer resulted in slightly lower concentrations. No mortality and morbidity was observed in this study. No treatment related clinical signs were noted in female rats. Neurobehavioural observations and motor activity assessment did not indicate specific neurotoxic effects of the test substance. In females no treatment related effects were observed in body weight and body weight change. No treatment related changes were observed in food consumption in any of the dose groups. No treatment-related effects were observed on hematology and clinical chemistry parameters. No treatment-related effects were observed on organ weight. There were no effects of the test substance on female fertility and reproductive performance. The number of pregnant females, pre-coital time, mating index, fertility index, duration of gestation, number of corpora lutea, implantation sites and pre-implantation loss were comparable among the groups. There were no differences in prenatal loss. There were no differences in mean pup weight and pup clinical signs between all dose groups. Based on the absence of effects on developmental parameters, the NOAEL for developmental toxicity was stablished at ≥ 6000 mg test substance per kg diet (corresponding to a dose of 406 mg/kg body weight for females).
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