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EC number: 436-690-9 | CAS number: 220727-26-4
- 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:
- 28 Feb - 02 Jul 2014
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 015
- Report date:
- 2015
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- (2001)
- Deviations:
- yes
- Remarks:
- six dams were dosed at a lower dose level than intended on first day of dosing (63% of nominal concentration)
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- (1998)
- Deviations:
- yes
- Remarks:
- six dams were dosed at a lower dose level than intended on first day of dosing (63% of nominal concentration)
- Qualifier:
- according to guideline
- Guideline:
- other: Japanese Ministry of Agriculture, Forestry and Fisheries Testing guidelines for Toxicology studies, 12 NohSan No 8147 (2000)
- Deviations:
- yes
- Remarks:
- six dams were dosed at a lower dose level than intended on first day of dosing (63% of nominal concentration)
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- THE DEPARTMENT OF HEALTH OF THE GOVERNMENT OF THE UNITED KINGDOM
- Limit test:
- no
Test material
- Details on test material:
- - Name of test material (as cited in study report): Y-15099
- Physical state: pale yellow liquid
- Analytical purity: 95.4%
- Lot/batch No.: 13NSUN161
- Expiration date of the lot/batch: 18 Dec 2017
- Storage condition of test material: at room temperature in the original container protected from light under nitrogen headspace
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Sprague-Dawley Crl:CD® (SD) IGS BR
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Limited, Margate, Kent, UK
- Weight at study initiation: 228 - 308 g
- Housing: The animals were housed individually in solid-floor polypropylene cages with stainless steel lids furnished with softwood flakes. Environmental enrichment was provided in the form of wooden chew blocks and cardboard fun tunnels (Datesand Ltd., Cheshire, UK).
- Diet: pelleted diet (Rodent 2018C Teklad Global Certified Diet, Harlan UK, Oxon, UK), ad libitum
- Water: mains drinking water, ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 23 Mar 2014 To: 10 Apr 2014
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: desiccated Arachis oil BP
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test material was prepared at the appropriate concentrations as a solution in dessicated Arachis oil BP. Test material formulations were proven to be stable for at least twenty days. Formulations were therefore prepared within the stability period and stored at approximately 4 °C in the dark under nitrogen headspace.
VEHICLE
- Concentration in vehicle: 6, 30 and 150 mg/mL
- Amount of vehicle: 5 mL/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The test material concentration in the test samples was determined by gas chromatography (GC) using an external standard technique. The test material gave a chromatographic profile consisting of a single peak. The formulations investigated during the study were found to comprise test material in the range of 96 to 104%, and thus, the required content limit of ±10% with reference to the nominal content was met. An exception was recorded on the first day of dosing when six female animals of the low dose group were exposed to 63% of the nominal concentration only. The formulations were found to be homogeneously prepared and sufficient formulation stability under storage conditions was approved.
- Details on mating procedure:
- Animals were delivered in two batches containing females prior to Day 2 of gestation. The day that positive evidence of mating was observed was designated Day 0 of gestation.
- Duration of treatment / exposure:
- Day 5-19 of gestation
- Frequency of treatment:
- daily, 7 days/week
- Duration of test:
- until Day 20 of gestation
- No. of animals per sex per dose:
- 24 females/group with
24 pregnant females in the control group
21 pregnant females in the low dose group
22 pregnant females in the mid dose group
23 pregnant females in the high dose group - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels and treatment volume were chosen based on the available data from a 28 Day study (RCC study Number: 808378, November 2001).
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were examined for overt signs of toxicity, ill-health or behavioral changes once daily during the gestation period. Additionally, during the dosing period, observations were recorded immediately before and soon after dosing and one hour post dosing.
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded on Day 3 (before the start of treatment) and on Days 5, 6, 7, 8, 11, 14 and 17 of gestation. Body weights were also recorded for surviving animals at terminal kill (Day 20).
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: Food consumption was recorded for each surviving individual animal at Day 3, 5, 8, 11, 14, 17 and 20 of gestation.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Water intake was observed daily by visual inspection of the water bottles for any overt changes.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on Day 20 of gestation
- Organs examined: All animals were subjected to a full external and internal examination and any macroscopic abnormalities were recorded. The ovaries and uteri of pregnant females were removed and examined. The uteri of any apparently non-pregnant females were immersed in 0.5% ammonium polysulphide solution to reveal evidence of implantation. - 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 sex: Yes
- External fetal appearance: Yes
- Fetal weight: Yes
- Placental weight: 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:
- The following parameters were analyzed statistically, where appropriate, using the test methods outlined below: female body weight change, food consumption and gravid uterus weight: Shapiro Wilk normality test and Bartlett’s test for homogeneity of variance and one way analysis of variance, followed by Dunnett’s multiple comparison test or, if unequal variances were observed, an alternative multiple comparison test. Caesarean necropsy parameters and fetal parameters: Kruskal-Wallis non-parametric analysis of variance; and a subsequent pairwise analysis of control values against treated values using the Mann-Whitney ‘U’ test, where significance was seen. Fetal evaluation parameters, including skeletal or visceral findings: Kruskal-Wallis non-parametric analysis of variance and Mann-Whitney ‘U’ test. Probability values (p) are presented as follows: p<0.01 = **, p<0.05 = *, p=0.05 (not significant).
- Indices:
- Pre-implantation loss (%) = [(number of corpora lutea - number of implantations) / number of corpora lutea] x 100
Post-implantation loss (%) = [(number of implantations - number of live fetuses) / number of implantations] x 100
Sex ratio (% male fetuses) = (number of male fetuses / total number of fetuses) x 100
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes. Remark: (non-adverse)
Details on maternal toxic effects:
There were no treatment-related deaths during the study period. One female of the low dose was killed on Day 6 of gestation due to a decline in clinical condition. Clinical signs prior to death included hunched posture, piloerection, laboured and noisy respiration, decreased respiratory rate and staining around the snout. At necropsy, macroscopic findings were consistent with physical trauma following dosing procedure and thus, the death of this animal was considered unrelated to treatment with the test material.
There were no clinical signs considered to be related to the toxicity of the test material at any dose level. Increased post-dose salivation was seen in two females of the high dose group on Days 6 and 7 of gestation (one animal on each day). No such effects were detected in females of the low and medium dose groups. Observations of this nature are commonly observed following the oral administration of an unpalatable test material formulation, and in isolation, are considered of no toxicological importance. One female of the medium dose group showed signs of chromodaccryorrhea (Day 13 of gestation) and swollen snout and right side of the face (Days 13 to 16 of gestation); these observations were considered to be associated with a physical injury attained during the course of the study and hence are considered unrelated to treatment with the test material. A female of the low dose group showed signs of noisy respiration between Days 6 to 9 of gestation. In isolation, this was considered not to be related to treatment with the test material. No toxicologically significant effects of treatment with the test material on body weight development were detected at any dose level. Females of the high dose group showed slight group mean body weight loss over the first day of dosing, but without achieving statistical significance when compared with controls. Subsequent improvement in body weight was apparent for these females such that the mean gains from Day 8 of gestation were comparable with controls. Group mean cumulative body weight gains for these females were statistically significantly lower than controls over Days 5 to 7 (p<0.01), 5 to 8 (p<0.01) and 5 to 11 (p<0.05) of gestation. Since the initial effect on body weight development was minimal with full recovery evident thereafter, this finding was considered not to be of any toxicological significance. There was no effect of treatment with the test material on body weight development in females given the test material at 150 or 30 mg/kg bw/day. There was no detrimental effect of treatment with the test material food intake at any dose level. Over Days 5 to 8 of gestation, group mean food consumption in females of the low and medium dose groups was slightly but statistically significantly higher than controls (p<0.05 and p<0.01, respectively). In contrast, the mean food intake in females of the high dose group over the corresponding period was similar to controls. Over the remaining days, food intake across all treated groups was similar to controls. Daily visual inspection of water bottles did not reveal any overt intergroup differences. There were no macroscopic findings for any of the animals surviving to the scheduled necropsy on Day 20 of gestation with exception of one female (see above).
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- >= 750 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- >= 750 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes. Remark: (non-adverse)
Details on embryotoxic / teratogenic effects:
In total, out of a total number of 24 females per dose group, 24, 21, 22 and 23 females from the control, low, medium and high dose groups, respectively, were found to be pregnant at scheduled necropsy on Day 20 of gestation. One female of the low dose group that was killed in extremis on Day 6 of gestation was also pregnant. The incidence and distribution of non-pregnant females was considered to be within the background ranges for this strain of animals. There were no treatment-related effects on in utero offspring survival, as assessed by the mean numbers of early or late resorptions, live litter size and post-implantation losses. Pre-implantation losses and sex ratios across all treated groups were similar to controls. Fetal or placental weights were also unaffected by treatment with the test item. For all dose groups, there were no statistically significant treatment-related trends in the proportion of fetuses (or litters) with evidence of external, visceral or skeletal anomalies. At the high dose group, major malformations were confined to one fetus showing microphthalmia. This abnormality is known to occur spontaneously in this strain of rat, and due to its isolated nature in this study, it was considered unlikely to be related to treatment with the test item. At the low dose group, one fetus was noted with an absent kidney and ureter. Since this finding was not present in any of the fetuses from the medium or high dose groups, it was considered unrelated to treatment with the test item. Other external, visceral and skeletal anomalies were either similar to controls and/or commonly observed for this type of study.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- 750 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- other: No effects noted, highest test group
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
- Lowest effective dose / conc.:
- 750 mg/kg bw/day (nominal)
- Treatment related:
- no
Any other information on results incl. tables
Table 1: Summary of female performance
Category |
Number of females at dose level (mg/kg bw/day) |
|||
0 (Control) |
30 |
150 |
750 |
|
Initial Group Size |
24 |
24 |
24 |
24 |
Pregnant |
24 |
22 |
22 |
23 |
Number with Fetuses on Day 20 of Gesation |
24 |
21 |
22 |
23 |
Table 2: Group mean litter data values
Dose level (mg/kg bw/day) |
|
Number of Corpora Lutea |
Number of Implants |
Number of Embryonic/Fetal Deaths |
Implantation Loss (%) |
Number of Live Implants |
Male Fetuses (%) |
Mean Male Fetal Weight (g) |
Mean Female Fetal Weight (g) |
Mean Fetal Weight (g)
|
Mean Placental Weight (g) |
Litter Weight (g) |
Total Placental Weight (g) |
|||||
Early |
Late |
Total |
Pre |
Post |
Male |
Female |
Total |
|||||||||||
0 |
Mean SD N |
14.0 4.0 24 |
13.4 4.0 24 |
0.2 0.6 24 |
0.0 0.0 24 |
0.2 0.6 24 |
5.7 10.0 24 |
1.3 3.6 24 |
6.7 2.5 24 |
6.5 2.7 24 |
13.2 3.9 24 |
52.8 15.5 24 |
4.222 0.256 24 |
3.936 0.248 23 |
4.092 0.262 24 |
0.589 0.178 24 |
53.575 15.381 24 |
7.173 1.911 24 |
30 |
Mean SD N |
15.4 1.9 21 |
14.4 1.6 21 |
0.2 0.5 21 |
0.1 0.4 21 |
0.3 0.6 21 |
6.2 4.9 21 |
2.6 4.6 21 |
6.3 2.2 21 |
7.7 2.0 21 |
14.0 1.6 21 |
44.8 13.3 21 |
4.200 0.242 21 |
3.999 0.215 21 |
4.091 0.227 21 |
0.557 0.049 21 |
57.445 7.256 21 |
7.814 1.086 21 |
150 |
Mean SD N |
15.1 1.3 22 |
14.3 1.8 22 |
0.2 0.5 22 |
0.1 0.4 22 |
0.3 0.7 22 |
5.6 5.7 22 |
2.0 4.3 22 |
7.6 2.4 22 |
6.4 1.8 22 |
14.0 1.5 22 |
53.8 14.7 22 |
4.204 0.333 22 |
3.980 0.321 22 |
4.095 0.308 22 |
0.549 0.050 22 |
57.090 6.798 22 |
7.630 0.811 22 |
750 |
Mean SD N |
14.4 3.1 23 |
13.5 3.5 23 |
0.1 0.3 23 |
0.1 0.3 23 |
0.4 0.7 23 |
8.6 14.4 23 |
2.8 4.6 23 |
6.9 2.1 23 |
6.3 2.2 23 |
13.1 3.4 23 |
54.4 15.0 23 |
4.210 0.399 23 |
3.923 0.171 22 |
4.108 0.410 23 |
0.562 0.083 23 |
52.762 12.663 23 |
7.158 1.730 23 |
SD: Standard deviation
N: number of pregnant animals
Applicant's summary and conclusion
- Conclusions:
- The oral (gavage) administration of the test item to pregnant female Sprague-Dawley rats, at dose levels of 30, 150 or 750 mg/kg bw/day was well tolerated. No toxicological relevant effects were recorded, thus a dose level of 750 mg/kg bw/day is considered to be the No Observed Adverse Effect Level (NOAEL) for maternal and developmental toxicity.
- Executive summary:
The test item was administered by gavage to three groups of 21, 22 and 23 pregnant female Sprague-Dawley Crl:CD® (SD) IGS BR rats, during gestation days 5-19, at dose levels of 30, 150 or 750 mg/kg bw/day, respectively. A control group of 24 pregnant female rats was dosed with vehicle alone (dessicated Arachis oil BP). Clinical signs, body weight development, dietary intake and water consumption were monitored during the study period. On day 20 of gestation the animals were euthanized and examined for maternal and fetal parameters. There were no adverse effects found for all parameters examined in maternal animals. Based on the number of implantations, number of total litter losses by resorption, mortality, gravid uterus weight, number of corpora lutea, placenta weight clinical signs, body weight, and gross pathology of maternal animals the NOAEL for maternal toxicity was found to be 750 mg/kg bw/day. Examination of fetus litter size and weights, offspring viability (number alive and number dead), sex ratio, grossly visible abnormalities, external, head, soft tissue and skeletal abnormalities showed only incidental malformations in each one low and high dose fetuses. Thus, the NOAEL for developmental toxicity in rats for the test item was found to be 750 mg/kg bw/day.
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