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EC number: 201-983-0 | CAS number: 90-30-2
- 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
![](https://echa.europa.eu./o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 016
- Report date:
- 2016
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.31 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- BASF SE, Experimental Toxicology and Ecology, 67056 Ludwigshafen, Germany
- Limit test:
- no
Test material
- Reference substance name:
- N-1-naphthylaniline
- EC Number:
- 201-983-0
- EC Name:
- N-1-naphthylaniline
- Cas Number:
- 90-30-2
- Molecular formula:
- C16H13N
- IUPAC Name:
- N-phenylnaphthalen-1-amine
- Details on test material:
- - Stability: The stability under storage conditions over the test period was guaranteed
- Physical state/appearance: solid/white to light red
- Storage conditions: ambient temperature
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: 10-12 weeks
- Weight at study initiation: 141.2 - 192.8 g
- Housing: individually in Polycarbonate cages type III supplied by TECHNIPLAST, Hohenpeißenberg, Germany and BECKER & CO., Castrop-Rauxel, Germany (floor area about 800 cm²). Dust-free wooden bedding was used in this study. For enrichment, wooden gnawing blocks were offered (Typ NGM E-022, supplied by Abedd® Lab. and Vet. Service GmbH, Vienna, Austria).
- Diet: ad libitum, Kliba maintenance diet mouse/rat “GLP”, meal, supplied by Provimi Kliba SA, Kaiseraugst, Switzerland
- Water: ad libitum
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The oily test substance preparations were prepared at the beginning of the administration period and thereafter at intervals, which took into account the period of established stability. The preparations were kept at room temperature. For the test substance preparations the specific amount of test substance was weighed, topped up with corn oil in a calibrated beaker and intensely mixed with a magnetic stirrer until it was completely dissolved (40°C for a maximum of about one hour). During administration (after the preparations had reached room temperature), the preparations were kept homogeneous with a magnetic stirrer. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of the test substance preparations were sent to the analytical laboratory once during the study period (at the beginning of administration) for verification of the concentrations. The samples were also used to verify the homogeneity of the low- and the high-concentrations (15 and 150 mg/kg bw/d). Three samples (one from the top, middle and bottom in each case) were taken from the beaker with a magnetic stirrer running.
- Details on mating procedure:
- The animals were paired by the breeder (“time-mated”); the day of evidence of mating (= detection of vaginal plug/sperm) was referred to as GD 0. The animals arrived on the same day (GD 0) at the experimental laboratory. The following day was designated as “GD 1”.
- Duration of treatment / exposure:
- From implantation to one day prior to the expected day of parturition (GD 6 to GD 19)
- Frequency of treatment:
- daily
- Duration of test:
- Until GD 20
Doses / concentrationsopen allclose all
- Dose / conc.:
- 15 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 150 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, concurrent vehicle
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS
A check for dead animals was made twice a day on working days or once a day on Saturdays, Sundays or on public holidays (GD 0-20). A cage-side examination was conducted at least once daily for any signs of morbidity, pertinent behavioral changes and signs of overt toxicity. If such signs occurred, the animals were examined several times daily (GD 0-20).
BODY WEIGHT
All animals were weighed on GD 0, 1, 3, 6, 8, 10, 13, 15, 17, 19 and 20. The body weight change of the animals was calculated based on the obtained results. Furthermore, the corrected body weight gain was calculated after terminal sacrifice (terminal body weight on GD 20 minus weight of the unopened uterus minus body weight on GD 6).
FOOD CONSUMPTION
The consumption of food was recorded for the intervals GD 0-1, 1-3, 3-6, 6-8, 8-10, 10-13, 13-15, 15-17, 17-19 and 19-20.
WATER CONSUMPTION
Water consumption was recorded for the intervals GD 0-1, 1-3, 3-6, 6-8, 8-10, 10-13, 13-15, 15-17, 17-19 and 19-20.
HAEMATOLOGY
In the morning of GD 20 blood was taken from the retro-bulbar venous plexus from fasted animals. The following parameters were determined in blood with EDTA-K3 as anticoagulant using a particle counter (Advia 120 model; Bayer, Fernwald, Germany): leukocyte count, erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, differential blood count, reticulocytes, heinz bodies
CLINICAL CHEMISTRY
An automatic analyzer (Cobas c501; Roche, Mannheim, Germany) was used to examine the following clinicochemical parameters: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyltransferase, inorganic phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol
POST-MORTEM EXAMINATIONS
On GD 20, the dams were sacrificed. After the dams had been sacrificed, they were necropsied and assessed for gross pathology. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: number of dead fetuses - Fetal examinations:
- At necropsy each fetus was weighed, sexed, and external tissues and all orifices were examined macroscopically. The sex was determined by observing the distance between the anus and the base of the genitalia. Furthermore, the viability of the fetuses and the condition of placentas, umbilical cords, fetal membranes, and fluids were examined. The placentas were weighed and their individual weights were recorded. Thereafter, the fetuses were sacrificed. After these examinations, approximately one half of the fetuses per dam were eviscerated, skinned and fixed in ethanol; the other half was placed in Harrison’s fluid for fixation.
- Soft tissue examinations: The fetuses fixed in Harrison’s fluid were examined for any visceral findings according to the method of BARROW and TAYLOR. After this examination these fetuses were discarded.
- Skeletal examinations: The skeletons of the fetuses fixed in ethanol were stained according to a modified method of KIMMEL and TRAMMELL. Thereafter, the skeletons of these fetuses were examined under a stereomicroscope. After this examination the stained fetal skeletons were retained individually. - Statistics:
- - Water consumption, food consumption, body weight, body weight change, corrected body weight gain (net maternal body weight change), carcass weight, weight of unopened uterus, number of corpora lutea, number of implantations, number of resorptions, number of live fetuses, proportions of preimplantation loss, proportions of post-implantation loss, proportions of resorptions, proportion of live fetuses in each litter, litter mean fetal body weight, litter mean placental weight were evaluated by simultaneous comparison of all dose groups with the control group using the DUNNETT-test (two-sided) for the hypothesis of equal means.
- Female mortality, females pregnant at terminal sacrifice, number of litters with fetal findings were evaluated by pairwise comparison of each dose group with the control group using FISHER'S EXACT test (one-sided) for the hypothesis of equal proportions.
- Proportions of fetuses with malformations, variations and/or unclassified observations in each litter were evaluated by pairwise comparison of each dose group with the control group using the WILCOXON-test (one-sided) for the hypothesis of equal medians.
- For blood parameters with bidirectional changes a non-parametric one-way analysis was performed using the KRUSKAL-WALLIS test. If the resulting p-value was equal or less than 0.05, a pairwise comparison of each dose group with the control group was performed using WILCOXON-test (two-sided) for the hypothesis of equal medians
Only pregnant dams were used for the calculations of mean maternal water consumption, food consumption, body weight and body weight change. Only pregnant dams with scheduled sacrifice (GD 20) were used for the calculation of mean gravid uterine weights, corrected (net) body weight gain and summary of reproduction data. One female in group 0 (0 mg/kg bw/d), two females in group 1 (15 mg/kg bw/d) and three females in group 2 (50 mg/kg bw/d) were not pregnant. - Indices:
- The conception rate (in %) = number of pregnant animals / number of fertilized animals x 100
The preimplantation loss (in %) = number of corpora lutea – number of implantations / number of corpora lutea x 100
The postimplantation loss (in %) = number of implantations – number of live fetuses / number of implantations x 100
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Some (20 out of 25) females of the high-dose group (150 mg/kg bw/d) and five females of the mid-dose group (50 mg/kg bw/d) showed transient salivation during the treatment period. Salivation persisted in the respective animals only for some minutes after daily dosing (i.e. up to 10 minutes) and was initially observed on GD 8. This effect was assessed as treatment-related. No further clinical signs or changes of general behavior, which may be attributed to the test substance, were detected in any female at dose levels of 15, 50 or 150 mg/kg bw/d during the entire study period.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- There were no test substance-related or spontaneous mortalities in any females of the test groups (0, 15, 50 or 150 mg/kg bw/d).
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The mean body weights of the dams in test group 3 (150 mg/kg bw/d) were in general comparable to the controls throughout the entire study period. The body weight change of the high-dose dams was statistically significantly reduced on GD 6-8 (approx. 41% below control). If calculated for the entire treatment period (GD 6-19) or the entire study period (GD 0-20), the high-dose dams gained 9% or 8% less weight, respectively, in comparison to the concurrent control group. This effect was assessed as test substance- related. The mean body weights and the mean body weight gains of the low- and mid-dose dams (15 or 50 mg/kg bw/d) were generally comparable to the controls throughout the entire study period.
The corrected body weight gain (terminal body weight on GD 20 minus weight of the unopened uterus minus body weight on GD 6) was distinctly and statistically significantly lower in test group 3 (150 mg/kg bw/d - about 26% below the concurrent control value). Furthermore, the carcass weight of the high-dose dams was also statistically significantly reduced in comparison to the control group (about 5% below controls). These effects are assessed as test substance-related signs of maternal toxicity. The corrected body weight gain of test groups 1 and 2 (15 or 50 mg/kg bw/d) revealed no difference of any biological relevance to the corresponding control group. Moreover, carcass weights remained also unaffected by the treatment. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- The mean food consumption of the dams in test group 3 (150 mg/kg bw/d) was statistically significantly reduced at the beginning of the treatment period (GD 6-13; up to 16% below control), but recovered afterwards. If calculated for the entire treatment period (GD 6-19) or the entire study period (GD 0-20), the high-dose dams consumed 9% or 7% less food, respectively, in comparison to the concurrent control group. This effect was assessed as test substance-related. The mean food consumption of the dams in test groups 1 and 2 (15 and 50 mg/kg bw/d) was generally comparable to the concurrent control group throughout the whole study period.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Description (incidence and severity):
- The mean water consumption of the dams in test group 3 (150 mg/kg bw/d) was statistically significantly increased from GD 10 onwards until scheduled sacrifice on GD 20. If calculated for the entire treatment period (GD 6-19) or the entire study period (GD 0-20), the high-dose dams consumed 24% or 19% more water in comparison to the concurrent control group. This effect was assessed as test substance-related. The mean water consumption of the dams in test groups 1 and 2 (15 and 50 mg/kg bw/d) was generally comparable to the concurrent control group throughout the whole study period.
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- At gestation day 20 in dams of test group 3 (150 mg/kg bw/d) red blood cell (RBC) counts, hemoglobin and hematocrit values as well as mean corpuscular hemoglobin concentration (MCHC) were decreased, whereas relative reticulocyte counts were increased. Additionally, in dams of test group 3 (150 mg/kg bw/d) platelet counts were higher and relative eosinophil counts were lower compared to controls. Both means were within historical control ranges (platelets 844-1110 giga/L; relative eosinophils 0.8-1.7 %) and therefore these alterations were regarded as incidental and not treatment-related. No Heinz bodies were found in individuals of any test group.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- At gestation day 20 in dams of test groups 1, 2 and 3 (15, 50 and 150 mg/kg bw/d) total bilirubin concentrations were higher compared to controls. The values in test group 1 were within the historical control range (bilirubin 0.95-1.85 μmol/L) those of test groups 2 and 3 were above this range. In test group 2 higher bilirubin levels were the only relevantly altered clinical pathology parameter. Therefore, the total bilirubin increase in test groups 1 and 2 were regarded as treatment-related but not adverse (ECETOC Technical Report No. 85, 2002). In dams of test group 3 (150 mg/kg bw/d) cholesterol levels were decreased. In dams of test group 3 (150 mg/kg bw/d) alanine aminotransferase (ALT) activities and urea levels were increased and total protein, albumin, globulin and creatinine levels were lower compared to controls. Urea levels were already increased in dams of test groups 1 and 2 (15 and 50 mg/kg bw/d). However, all changed values were within historical control ranges (ALT 0.68-1.20 μkat/L; urea 4.52-7.14 mmol/L; total protein 55.10-62.64 g/L; albumin 30.69-38.59 g/L; globulins 21.10-26.90 g/L; creatinine 22.8-29.3 μmol/L). Therefore, all mentioned alterations in this paragraph were regarded as incidental and not treatment-related.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- The mean gravid uterus weights of the animals of test group 1-3 (15, 50 and 150 mg/kg bw/d) were not influenced by the test substance. The differences between these groups and the control group revealed no dose-dependency and were assessed to be without biological relevance.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No test substance-related or spontaneous findings occurred at necropsy in any dam.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Details on maternal toxic effects:
- The conception rate reached 88% in the mid-dose group (50 mg/kg bw/d), 92% in the low-dose group (50 mg/kg bw/d), 96% in the control and 100% in the high-dose group (150 mg/kg bw/d). With these rates, a sufficient number of pregnant females were available for the purpose of the study. There were no test substance-related and/or biologically relevant differences between test groups 0, 1, 2 and 3 (0, 15, 50 and 150 mg/kg bw/d) with regard to conception rate, the mean number of corpora lutea and implantation sites or the values calculated for the pre- and the postimplantation losses, the number of resorptions and viable fetuses. All observed differences were considered to reflect the normal range of fluctuations for animals of this strain and age.
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 50 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- food consumption and compound intake
- haematology
- water consumption and compound intake
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- The mean fetal weights were similar in all test groups (15, 50 and 150 mg/kg bw/d) and did not show any biologically relevant differences.
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- The sex distribution of the fetuses in test groups 1-3 (15, 50 and 150 mg/kg bw/d) was comparable to the control fetuses.
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- no effects observed
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- One fetus of test group 1 (15 mg/kg bw/d) had an external malformation (anal atresia). The total incidences of external malformations in treated animals did not differ significantly from the control group and was comparable to the historical control data.
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Skeletal malformations were detected in test groups 0 (severely malformed vertebral column in one female, misshapen turbositas deltoidea in one male), 2 (severely malformed skull bones in one male) and 3 (misshapen scapulae in two females) (0, 50 or 150 mg/kg bw/d). The total incidences of skeletal malformations in treated animals did not differ significantly from the control group and was comparable to the historical control data.
For all test groups, skeletal variations of different bone structures were observed, with or without effects on corresponding cartilages. The observed skeletal variations were related to several parts of fetal skeletons and appeared without a relation to dosing. The overall incidences of skeletal variations were comparable to the historical control data. For a better overview, all skeletal variations with statistically significant differences between control and the treated groups were compiled. All incidences were expressed on a fetus per litter basis and any statistically significant differences was determined. A few variations - affecting some elements of the vertebral column and ribs - were, at the top dose (150 mg/kg bw/d) and/or at the mid dose (50 mg/kg bw/d), present at statistically significantly incidences above the historical control range. An association with the treatment cannot be ruled out. The other findings were not considered to be treatment-related, because there is no dose-response.
Additionally, some isolated cartilage findings without impact on the respective bony structures, which were designated as unclassified cartilage observations, occurred in all test groups. The observed unclassified cartilage findings were related to the skull, the ribs and the sternum and did not show any relation to dosing. - Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Two soft tissue variations were detected in test groups 0, 1 and 3 (0, 15 and 150 mg/kg bw/d), i.e. dilated renal pelvis and dilated ureter. The incidences of these variations were neither significantly different from control nor dose-dependent and, therefore, not considered biologically relevant. All of them can be found in the historical control data at higher incidences.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- 150 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effects, highest dose tested
Overall developmental toxicity
- Developmental effects observed:
- no
Any other information on results incl. tables
Assessment of all fetal external, soft tissue and skeletal observations
Soft tissue malformations did not occur in any of the fetuses in this study. There were noted external and skeletal malformations in test groups 0, 1, 2 and 3 (0, 15, 50 and 150 mg/kg bw/d). The distribution of malformations about the groups was not related to the doses. Two fetuses were multiple-malformed. One female control group fetus had several skeletal malformations concerning the vertebral column and male mid-dose fetus (50 mg/kg bw/d) had several skeletal malformations concerning the skull. No ontogenetic pattern is recognizable for the individual malformations nor was there any cluster of any of these individual malformations seen in the other offspring of the test groups. Other malformations, such as anal atresia, misshapen scapula and misshapen tuberositas deltoidea, observed in test groups 0, 1 or 3, were scattered observations in individual fetuses of these test groups, are common for this rat strain and most of them can be found in the historical control data at comparable or higher frequency.
Total fetal malformations:
Test group 0 0 mg/kg bw/d |
Test group 1 15 mg/kg bw/d |
Test group 2 50 mg/kg bw/d |
Test group 3 150 mg/kg bw/d |
||
Litter Fetuses | N N |
24 246 |
22 229 |
22 219 |
25 262 |
Fetal incidence | N (%) | 2 (0.8) | 1 (0.4) | 1 (0.5) | 2 (0.8) |
Litter incidence | N (%) | 2 (8.3) | 1 (4.5) | 1 (4.5) | 1 (4.0) |
Affected fetuses/litter | Mean% | 0.9 | 0.6 | 0.4 | 0.7 |
mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent
External variations did not occur in any of the fetuses in this study. A spontaneous origin is assumed for two soft tissue variations which were observed in fetuses of test groups 0, 1 and 3. A broad range of skeletal variations are equally distributed among the different test groups including control, if normal biological variation is taken into account, and can be found in the historical control data at similar frequencies. At 150 mg/kg bw/d altered rib cages (wavy ribs) were noted in 25 pups out of 13 litters. This resulted in a statistically significantly increased rate of 22.8% affected fetuses per litter. In addition incomplete ossification of the cervical arch (cartilage present) in 7 pups out of 3 litters (150 mg/kg bw/d) and 5 pups out of 4 litters (50 mg/kg bw/d) resulted in significantly increased rates of 5% or 3.7% affected fetuses per litter, respectively. The increase in the mid dose group is only slightly above the historical control range (0.0 - 3.2%).
Occurrence of statistically significantly increased skeletal variations (expressed as mean percentage of affected fetuses/litter):
Finding | Test group 0 0 mg/kg bw/d |
Test group 1 15 mg/kg bw/d |
Test group 2 50 mg/kg bw/d |
Test group 3 150 mg/kg bw/d |
Historical control data Mean % (range) |
Supraoccipital hole(s) | 0.0 | 2.7 | 2.2* | 1.1 | 6.9 (0.0 – 30.1) |
Incomplete ossification of cervical arch; cartilage present | 0.0 | 0.8 | 3.7* | 5.0* | 0.3 (0.0 – 3.2) |
Unossified sternebra; unchanged cartilage | 1.7 | 4.1 | 6.6* | 4.8 | 6.1 (0.0 – 20.7) |
Wavy rib | 8.0 | 5.2 | 1.7 | 22.8* | 4.3 (0.0 – 8.7) |
* = p ≤ 0.05 (Wilcoxon-test [one-sided]) ** = p ≤ 0.01 (Wilcoxon-test [one-sided])
Those minor changes in connection with significant maternal toxicity in the high-dose group represent either minor departures from normal morphology not affecting morphology or slight delays of ossification. In the literature (Price CJ, Strong PL, Marr MC, Myers CB, Murray FJ. (1996); Nishimura M, Iizuka M, Iwaki S, Kast A. (1982); Hayasaka I, Tamaki F, Uchiyama K, Kato Z, Murakami K. (1985)) wavy ribs are described as a common reversible finding during postnatal development. As additionally the total incidence of skeletal variations is equally distributed among the different test groups including the control group, the single changes were considered to be a possible effect of treatment, but not as an adverse effect.
Total fetal variations:
Test group 0 0 mg/kg bw/d |
Test group 1 15 mg/kg bw/d |
Test group 2 50 mg/kg bw/d |
Test group 3 150 mg/kg bw/d |
||
Litter Fetuses | N N |
24 246 |
22 229 |
22 219 |
25 262 |
Fetal incidence | N (%) | 128 (52) | 120 (52) | 111 (51) | 141 (54) |
Litter incidence | N (%) | 24 (100) | 22 (100) | 22 (100) | 25 (100) |
Affected fetuses/litter | Mean% | 52.1 | 52.3 | 50.3 | 53.3 |
mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent
Unclassified external and unclassified soft tissue observations did not occur in any fetuses of this study. A spontaneous origin was assumed for the unclassified skeletal cartilage observations which were observed in several fetuses of all test groups (0, 15, 50 and 150 mg/kg bw/d). The distribution and type of these findings do not suggest any relation to treatment. Finally, fetal examinations revealed that there is no other effect of the compound on the respective morphological structures up to a dose of 150 mg/kg bw/d.
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of this prenatal developmental toxicity study, the oral administration of the test item to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) caused maternal toxicity (increased water consumption, reduced food consumption, decreased body weight gain and a regenerative anemia) in the high dose group (150 mg/kg bw/d). In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity was 50 mg/kg bw/d. Single variations - affecting some elements of the vertebral column and ribs - were, at the top dose (150 mg/kg bw/d) and/or at the mid dose (50 mg/kg bw/d), present at incidences outside the historical control range. Those minor changes in connection with significant maternal toxicity in the high dose group are assessed as a possible effect of the treatment, but not as adverse. The no observed effect level (NOEL) for prenatal developmental toxicity was therefore 15 mg/kg bw/d; the NOAEL was 150 mg/kg bw/d, the highest dose tested.
- Executive summary:
The test item was examined for its prenatal developmental toxicity in pregnant Wistar rats. The test substance was administered as an oily preparation to groups of 25 time-mated female Wistar rats by gavage at dose levels of 0, 15, 50 and 150 mg/kg body weight/day (mg/kg bw/d) on gestation days (GD) 6 through 19. The control group was dosed with the vehicle in parallel (corn oil). A standard dose volume of 4 mL/kg body weight was used for each test group. At terminal sacrifice on GD 20, 22-25 females per group had implantation sites. Water consumption, food consumption and body weights of the animals were recorded regularly throughout the study period. The state of health of the animals was checked each day. On GD 20, blood samples were obtained from all females by retrobulbar venous puncture following isoflurane anesthesia. After blood sampling all females were sacrificed by decapitation (under isoflurane anesthesia) and assessed by gross pathology (including weight determinations of the unopened uterus and placentas). For each dam, corpora lutea were counted and number and distribution of implantation sites (differentiated between resorptions, live and dead fetuses) were determined. The fetuses were removed from the uterus, sexed, weighed and further investigated for external findings. Thereafter, one half of the fetuses of each litter were examined for soft tissue findings and the remaining fetuses for skeletal (inclusive cartilage) findings. The following test substance-related adverse effects/findings were noted:
Test group 3 (150 mg/kg bw/d):
Dams
• Increased mean water consumption from GD 10 onwards until scheduled sacrifice on GD 20. If calculated for the administration period (GD 6-19) the dams consumed 24% more water.
• Reduced food consumption on GD 6-13 (up to 16% below control). If calculated for the administration period (GD 6-19) the dams consumed 9% less food.
• Reduced body weight change on GD 6-8 (approx. 41% below control). If calculated for the administration period (GD 6-19) the dams gained 9% less weight.
• Distinctly lower corrected (net) body weight gain (about 26% below control). Furthermore, the carcass weight was also reduced (about 5% below controls).
• Decreased red blood cell (RBC) counts, hemoglobin and hematocrit values as well as decreased mean corpuscular hemoglobin concentration (MCHC) in the dams.
• Decreased cholesterol levels in the dams.
• Increased relative reticulocyte counts and bilirubin levels in the dams.
Fetuses
• No test substance-related adverse effects in fetuses.
Test group 2 (50 mg/kg bw/d):
• No test substance-related adverse effects in dams, gestational parameters or fetuses.
Test group 1 (15 mg/kg bw/d):
• No test substance-related adverse effects in dams, gestational parameters or fetuses.
Under the conditions of this prenatal developmental toxicity study, the oral administration of the test item to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) caused maternal toxicity (increased water consumption, reduced food consumption, decreased body weight gain and a regenerative anemia) in the high dose group (150 mg/kg bw/d). In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity was 50 mg/kg bw/d. Single variations - affecting some elements of the vertebral column and ribs - were, at the top dose (150 mg/kg bw/d) and/or at the mid dose (50 mg/kg bw/d), present at incidences outside the historical control range. Those minor changes in connection with significant maternal toxicity in the high dose group are assessed as a possible effect of the treatment, but not as adverse. The no observed effect level (NOEL) for prenatal developmental toxicity was therefore 15 mg/kg bw/d; the NOAEL was 150 mg/kg bw/d, the highest dose tested.
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