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EC number: 947-899-4 | CAS number: -
- 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
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Remarks:
- (Lack of data on test substance).
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 995
- Report date:
- 1995
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- yes
- Remarks:
- (lack of data on test substance)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 189200-42-8
- Cas Number:
- 189200-42-8
- IUPAC Name:
- 189200-42-8
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD BR VAF/Plus
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Inc., Stone Ridge, NY, USA
- Age at study initiation: approximately 9 - 10 weeks
- Weight at study initiation: 200 - 274 g (female)
- Housing: The animals were housed in suspended stainless steel and wire mesh cages with absorbent paper below the cages. The females were housed separately during the study period except during mating.
- Diet: Purina Certified Rodent Chow No. 5002, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 13 d
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.0 - 24.4
- Humidity (%): 40 - 70
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES:
From: 03 Oct 1994
To: 08 Nov 1994
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: polyethylene glycol (PEG 400)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The undiluted test substance was thoroughly mixed in vehicle prior to dispensing. The dosing solutions were prepared weekly.
VEHICLE
- Lot/batch no. (if required): 122H1109
- Physical state: colorless liquid - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis for homogenity of the test substance dilutions were performed on the lowest and the highest concentrations expected during the course of the study. The relative standard deviation ranged from 0.72 to 3.19%. Concentrations were analysed in the first and the third dosing mixture preparation. The analytical results for all test solutions were within 7% of the nominal concentrations for weeks 1 and 3.
- Details on mating procedure:
- - Impregnation procedure: cohoused
- M/F ratio per cage: 1/1
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy
After confirmation of pregnancy, each mated female was returned to its cage and new females were placed into the males' cages until a required number of pregnant females was obtained. - Duration of treatment / exposure:
- gestation days (GD) 6 - 15
- Frequency of treatment:
- daily, 7 d/week
- Duration of test:
- 21 d (GD 0 - 21)
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 25 females per dose, 50 males in total
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Rationale for animal assignment: Mated females were assigned to dose groups in the order of mating. Accordingly, the first confirmed mated female was assigned to Group 1, the next to Group 2 and so on until all mated animals for a given day were assigned to dose groups. On subsequent days, the next group in sequence was filled by the first confirmed mated female on that day and so on. Assignments were made until all groups were filled with confirmed mated females.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily during the treatment period and once daily at all other times during the study period
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to selection and daily during gestation
BODY WEIGHT: Yes
- Time schedule for examinations: prior to selection and on GD 0, 6, 9, 12, 15, 18 and 21
FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Time schedule for examinations: concurrently with body weight examinations
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on GD 21
- all females were examined by gross necropsy - 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 - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter - Statistics:
- Bartlett's Test was performed to determine if the dose groups had equal variance (1% level of significance). If equal, the testing was done using parametric methods, otherwise nonparametric techniques were used. Parametric procedures: a standard one way ANOVA (F distribution) was used. If significant differences among the means were indicated, Dunnett's Test was used to determine which treatment groups differed significantly from control. In addition to the ANOVA, a standard regression analysis for linear response in the dose groups was performed that also tested for linear lack of fit in the model. Nonparametric procedures: the test of equality of means was performed using the Kruskal-Wallis Test. If significant differences among the means were indicated, Dunn's Summed Rank Test was used to determine which treatment groups differed significantly from the control. In addition, Jonckheere's Test for monotonic trend in the dose response was performed. All tests were conducted at the 5% and 1% level of significance.
Fetal weight was analyzed by a standard nested analysis of covariance (fetuses nested within dams and dams nested within doses and litter size (both sexes combined)). If differences in groups were identified, the Least Significant Difference technique was used to determine which groups differed from the control group. Male and female fetuses were tested separately (the covariate was combined sexes in each analysis). Fetal malformation and variation incidence data were analyzed for statistical significance as follows: a standard chi-square analysis was performed to determine if the proportions of incidences differ between the groups tested. If any one cell had an expected value less than 5, this step was not reported. Next, each treatment group was compared to the control group using a 2x2 Fisher Exact Test. Thirdly, Armitage's test for linear trend in the dosage groups was performed. All tests were reported at the 5% or 1% level of significance. - Indices:
- Preimplantation loss = (no. of Corpora Lutea - no. of Implantation Sites) / no. of Corpora Lutea * 100
Postimplantation loss = (no. of Implantation Sites - no. of live foetuses) / no. of Implantation Sites * 100
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:
Mortality:
No treatment-related mortality occurred. On GD 7, one female of the 500 mg/kg bw/d group was found dead. At necropsy, discolored and consolidated lungs were the only findings. The death of this female was probably a result of an accidental gavage error.
Clinical signs:
No treatment-related clinical signs were observed during the study period. The most frequently observation was soft stool, that occurred in treated and control animals and was therefore considered as a response to the vehicle rather than to the test substance. Other findings were scabs, little sign of stool, rales and alopecia in one or more groups. One female of the high dose group had a subcutis mass in the cervical area on GD 21. In summary, these clinical findings were considered to be incidental and unrelated to treatment with the test substance.
Body weight:
Treatment with the test substance had no statistically significant effect on mean body weight and mean body weight change at any interval.
Food consumption:
There were no statistically significant differences in mean food consumption between treated and control animals at any interval.
Post-mortem examinations:
There were no necropsy findings that were considered to be treatment-related. One high dose female had a subcutaneous mass in the cervical area and one control and one high dose female had dilated renal pelvis. In summary, these necropsy findings were considered to be incidental and unrelated to treatment.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- systemic
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: No adverse effects observed up to and including the highest tested dose level
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
Fetal body weight:
There were no statistically significant differences between treated and control mean fetal body weights of either sex (see Table 1).
Implantation data:
There were no statistically significant differences in the mean live fetuses, mean live male or female fetuses, mean resorptions, mean implantation sites, mean corpora lutea, mean total dead fetuses, mean fetuses per implantation sites, mean dead fetuses per implantation sites, mean resorptions per implantation sites, % pre-implantation loss, % post-implantation loss, mean malformed fetuses, mean fetuses with variations, or mean affected (resorptions + dead + malformed fetuses per litter) fetuses between treated and control groups. (see Table 1)
Fetal observations:
No biologically or statistically significant differences in total or individual variations or malformations were observed between the litters of test substance groups and control group (see Table 2). In the control, 100, 500 and 1000 mg/kg bw/d group, 5, 2, 6 and 1 fetuses, respectively, were stunted.
External observations regarded as malformations were found in one fetus of the 100 mg/kg bw/d group (agnathia, astomia, low set ears, anophthalmia) and single findings of cleft palate, syndactyly and kinked tail in three foetuses of separate litters of the 500 mg/kg bw/d group. External variations were not observed in any group.
Visceral observations regarded as malformations were limited to single occurrences of anophthalmia in one foetus each of the low and mid dose group, cleft palate and dilated brain ventricles in the 100 mg/kg bw/d group and two occurrences of folded retina in the control group. Visceral variations included a single or low incidence of dilated renal pelves, distended ureters and/or convoluted ureter.
Skeletal observations regarded as malformations were limited to multiple skull bones malformed in one foetus of the 100 mg/kg bw/d group, short pubis in one foetus of the 1000 mg/kg bw/d group and one less presacral vertebrae in one foetus of the control, two foetuses in the low dose and one foetus in the high dose groups. Skeletal variations were observed throughout the groups and consisted primarily of hypoplastic, misshapen or unossified stemebrae, hypoplastic skull bones or pubis and rudimentary or misshapen ribs.
In summary and without a clear pattern of response, all malformations were considered incidental and not to be treatment-related. Statistically significant differences in incidences of variations were limited to a decrease in hypoplastic skull bones of the mid dose group and a decrease in unossified stemebrae of the high dose group compared with controls. All variations were of no biological importance.
Skeletal ossification:
There were no statistically significant differences in mean ossification sites between treated and control groups.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- developmental
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: No adverse effects observed in the offspring up to and including the highest tested dose level
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
Table 1: Litter data and fetal body weight
|
Control |
dose groups [mg/kg bw/day] |
||
|
100 |
500 |
1000 |
|
No. of dams/litters examined |
25 |
21 |
23 |
25 |
Mean no. of Corpora Lutea |
16.8 |
16.8 |
17.7 |
16.8 |
± 2.28 |
± 2.50 |
± 3.50 |
± 1.82 |
|
n=25 |
n=20 |
n=23 |
n=25 |
|
Mean no. of Implantation Sites |
15.76 |
15.9 |
16.09 |
15.52 |
± 2.24 |
± 2.62 |
± 2.25 |
± 2.49 |
|
n=25 |
n=21 |
n=23 |
n=25 |
|
Mean no. of resorptions |
0.88 |
0.81 |
0.91 |
0.56 |
± 1.05 |
± 1.29 |
± 1.12 |
± 0.82 |
|
n=25 |
n=21 |
n=23 |
n=25 |
|
Pre-implantation loss [%] |
5.7 |
6.7 |
8 |
7.7 |
± 8.1 |
± 8.2 |
± 8.2 |
± 12.9 |
|
n=25 |
n=20 |
n=23 |
n=25 |
|
Post-implantation loss per litter [%] |
5.4 |
4.9 |
6 |
4.4 |
± 6.4 |
± 7.7 |
± 7.3 |
± 6.4 |
|
n=25 |
n=21 |
n=23 |
n=25 |
|
Mean no. of live fetuses |
14.88 |
15.1 |
15.13 |
14.88 |
± 2.19 |
± 2.64 |
± 2.46 |
± 2.64 |
|
n=25 |
n=21 |
n=23 |
n=25 |
|
Mean no. of dead fetuses |
0 |
0 |
0.04 |
0.08 |
|
|
± 0.21 |
± 0.28 |
|
n=25 |
n=21 |
n=23 |
n=25 |
|
Mean no. of female fetuses |
7.72 |
7.48 |
8.04 |
7.8 |
± 2.28 |
± 3.11 |
± 2.29 |
± 1.78 |
|
n=25 |
n=21 |
n=23 |
n=25 |
|
Mean no. of male fetuses |
7.16 |
7.62 |
7.09 |
7.08 |
± 1.93 |
± 2.25 |
± 2.09 |
± 2.58 |
|
n=25 |
n=21 |
n=23 |
n=25 |
|
Mean body weight (female fetuses) (g) |
5.04 |
5.05 |
5.06 |
5.2 |
± 0.44 |
± 0.32 |
± 0.46 |
± 0.37 |
|
n=188 |
n=157 |
n=185 |
n=195 |
|
Mean body weight (male fetuses) (g) |
5.33 |
5.27 |
5.39 |
5.44 |
± 0.52 |
± 0.39 |
± 0.38 |
± 0.38 |
|
n=175 |
n=160 |
n=163 |
n=177 |
Table 2: Fetal variations and malformations
|
Control |
dose groups [mg/kg bw/day] |
||
|
100 |
500 |
1000 |
|
No. of fetuses with external variations |
0 |
0 |
0 |
0 |
n=372 |
n=317 |
n=347 |
n=358 |
|
No. of fetuses with external malformations |
0 |
1 |
3 |
0 |
n=372 |
n=317 |
n=347 |
n=358 |
|
No. of fetuses with visceral or head variations |
0 |
0 |
1 |
2 |
n=187 |
n=161 |
n=173 |
n=186/187* |
|
No. of fetuses with visceral or head malformations |
2 |
2 |
1 |
0 |
n=187 |
n=161 |
n=173 |
n=186/187* |
|
No. of fetuses with skeletal variations |
45 |
39 |
29 |
35 |
n=185 |
n=156 |
n=176 |
n=185 |
|
No. of fetuses with skeletal malformations |
1 |
3 |
0 |
2 |
n=185 |
n=156 |
n=176 |
n=185 |
*186 visceral examinations performed, 187 head examinations performed
Applicant's summary and conclusion
- Conclusions:
- The test substance was not considered embryotoxic under the conditions of this study. Accordingly, the maternal and developmental NOAELs were established at 1000 mg/kg bw/d under the conditions of this study. The results indicate that test substance was not a selective developmental toxicant and was not embryotoxic or teratogenic under the conditions of this study.
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