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EC number: 468-710-7 | CAS number: 754-12-1
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- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
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- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
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- Additional toxicological data

Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Jan - May 2008
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 011
- Report date:
- 2011
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
Reference
- Name:
- Unnamed
- Type:
- Constituent
Test animals
- Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Covance Research, Kalamazoo, MI
- Age at study initiation: 5-9 months on gestation day 0
- Weight at study initiation: 2.9 - 4.5 kg on gestation day 0
- Housing: Individual in suspended stainless steel cages elevated above ground corncob bedding
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: 4-5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16-22
- Humidity (%): 30-70
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light):12
IN-LIFE DATES: From: Jan 2008 To: June 2008
Administration / exposure
- Route of administration:
- inhalation: gas
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Stainless steel and glass whole body exposure chambers (1500 to 2000 liters)
- Method of holding animals in test chamber: Individual cages
- Source and rate of air: HEPA and charcoal filtered
- System of generating test substance atmosphere: Metering of gas from headspace of storage cylinder controlled by appropriate valves and flow meters
- Temperature, humidity, in air chamber: 65.3°F to 66.1°F (18.5°C to 19.0°C), mean daily relative humidity ranged from 50.0% to 58.5% during the study
- Air change rate: At least 10/hour
TEST ATMOSPHERE
- Brief description of analytical method used: Samples taken at least hourly for analysis by gas chromatography
- Samples taken from breathing zone: Yes - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Gas chromatography
- Details on mating procedure:
- - Impregnation procedure: Purchased timed pregnant
- Duration of treatment / exposure:
- Gestation days 6-28
- Frequency of treatment:
- 6 hours a day
Doses / concentrationsopen allclose all
- Dose / conc.:
- 4 000 ppm
- Remarks:
- Group 2: Low dose.
- Dose / conc.:
- 5 500 ppm
- Remarks:
- Group 3: Mid dose.
- Dose / conc.:
- 7 500 ppm
- Remarks:
- Group 4: High dose.
- No. of animals per sex per dose:
- 24
- Control animals:
- yes, sham-exposed
- Details on study design:
- - Dose selection rationale: Based on rabbit teratogenicity range finding study which indicated significant maternal mortality at 10000 ppm and 50000 ppm.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS:
- Time schedule: Daily
DETAILED CLINICAL OBSERVATIONS:
- Time schedule: Daily
BODY WEIGHT:
- Time schedule for examinations: Daily
FOOD CONSUMPTION:
- Food consumption for each animal was determined and mean daily diet consumption was calculated as g food/kg body weight/day.
POST-MORTEM EXAMINATIONS:
- Sacrifice on gestation day # 29
- Organs examined: Heart, lungs, liver, kidney, brain
CAGE SIDE OBSERVATIONS:
- Time schedule: Daily
DETAILED CLINICAL OBSERVATIONS:
- Time schedule: Daily
BODY WEIGHT:
- Time schedule for examinations: GD 0, 4, 6-29 (daily)
POST-MORTEM EXAMINATIONS:
- Sacrifice on gestation day # 29
- Organs examined: Uterus, liver, kidney, brain, heart, lungs, all gross lesions - 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, all per litter
- Skeletal examinations: Yes, all per litter - Statistics:
- Two tailed for a minimum significance of 5% and 1% with means and standard deviations presented. All statistical tests were done by computer with appropriate programming. Data obtained from nongravid animals were excluded from statistical analyses. Due to the different rounding conventions inherent in the types of software used, the means, standard deviations and standard errors on the summary and individual tables may differ by ±1 in the last significant figure. Where applicable, the litter was used as the experimental unit.
Mean maternal body weights (absolute and net), body weight changes (absolute and net) and food consumption, gravid uterine weights, numbers of corpora lutea, implantation sites and viable fetuses and fetal body weights (separately by sex and combined) were subjected to a parametric one-way analysis of variance (ANOVA) (Snedecor and Cochran, 1980) to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunnett's test (Dunnett, 1964) was used to compare the test substance-exposed groups to the control group. Mean litter proportions (percent per litter) of prenatal data (viable and nonviable fetuses, early and late resorptions, total resorptions, pre- and postimplantation loss and fetal sex distribution), total fetal malformations and developmental variations (external, visceral, skeletal and combined) and each particular external, visceral and skeletal malformation or variation were subjected to the Kruskal-Wallis nonparametric ANOVA test (Kruskal and Wallis, 1952) to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunn’s test (Dunn, 1964) was used to compare the test substance-exposed groups to the control group. - Historical control data:
- Included in report
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Some of the animals which were found dead or killed in extremis (2 of 4 at 5500 ppm and and 3 of 7 at 7500 ppm) also exhibited labored and/or decreased respiration and/or hypoactivity prior to death or euthanasia.
No test substance related clinical findings were noted in females that survived to scheduled necropsy. - Dermal irritation (if dermal study):
- no effects observed
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- In total, 4 and 7 females in the 5500 and 7500 ppm groups, respectively, were found dead or euthanized in extremis. All other females survived to the scheduled necropsy.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Lower mean body weight gain was noted in the 7500 ppm group during gestation days 12-20 with corresponding occasional reductions in mean daily food consumption. Because several females died or were euthanized prior to the scheduled necropsy, mean net body weight and net body weight change in this group were not significantly different from the control group. Mean body weights in the 7500 ppm group were similar to the control group throughout the study. A slightly lower mean body weight gain and a mean body weight loss were observed in the 5500 ppm group during gestation days 12-20 and 20-29, resulting in a lower mean body weight gain when the entire exposure period (gestation days 6-29) was evaluated. A large mean net body weight loss was observed in this group.
Correspondingly lower mean food consumption was observed in this group during gestation days 20-29. However, mean body weights throughout the study and mean net body weight in the 5500 ppm group were similar to the control group. Slightly lower mean body weight gains were observed in the 4000 ppm group during gestation days 12-20 and 20-29, resulting in a lower mean body weight gain when the entire exposure period (gestation days 6-29) was evaluated.
However, because there were no test substance-related effects on mean food consumption, mean net body weight or net body weight change, and there were no clinical or macroscopic findings indicative of systemic toxicity observed in this group, the lower mean body weight gain noted in the 4000 ppm group was not considered adverse. - Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- See 'body weight and weight changes' field.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- Mean gravid uterine weights were unaffected by exposure to the test substance at all concentrations.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- All females found dead or euthanized in extremis were gravid with normally developing implantations or fetuses in utero.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Histological examination revealed these deaths were of undetermined causation (4/5 at 5500 ppm, 6/10 at 7500 ppm), due to subacute inflammation of the heart (1/5 at 5500 ppm and 3/10 at 7500 ppm) or a result of edema/hemorrhage of the lung (1/10 at 7500 ppm). Test substance exposure was also associated with subacute inflammation in the heart in the 2500 (n=8), 4000 (n=12), 5500 (n=10), and 7500 (n=15) ppm groups, coagulation necrosis of the heart in the 7500 (n=1) ppm group, and renal tubular necrosis in the 5500 n=3) and 7500 (n=1) ppm groups. At 5500 ppm, renal necrosis was noted in 2 animals that died or were euthanized. Although not dose related, these changes were considered adverse.
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not examined
Maternal developmental toxicity
- Number of abortions:
- effects observed, treatment-related
- Description (incidence and severity):
- One and 3 females in the 5500 and 7500 ppm groups, respectively, aborted on gestation day 26, 28 or 29. The abortions in the 5500 and 7500 ppm groups were attributed to the test substance; no test substance-related macroscopic findings were observed in these females.
- Early or late resorptions:
- effects observed, non-treatment-related
- Description (incidence and severity):
- One female at 5500 ppm had a late resorption and one female at 7500 ppm had an early resorption in utero.
- Changes in pregnancy duration:
- effects observed, treatment-related
- Description (incidence and severity):
- One female in the 7500 ppm group delivered on gestation day 29. The premature delivery in the 7500 ppm groups were attributed to the test substance; no test substance-related macroscopic findings were observed in these females.
- Other effects:
- no effects observed
- Description (incidence and severity):
- Corpea lutea were unaffected by exposure to the test substance at all concentrations.
Effect levels (maternal animals)
open allclose all
- Key result
- Dose descriptor:
- LOAEC
- Remarks:
- General toxicity
- Effect level:
- > 2 500 ppm
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- histopathology: non-neoplastic
- mortality
- Key result
- Dose descriptor:
- LOAEC
- Remarks:
- Maternal developmental toxicity
- Effect level:
- > 2 500 ppm
- Based on:
- test mat.
- Basis for effect level:
- effects on pregnancy duration
- number of abortions
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Mean fetal/pup weight by sex and with sexes combined were not affected by test substance exposure at any concentration.
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- Sex ratio were not affected by test substance exposure at any concentration.
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- Mean number and percent of live offspring were not affected by test substance exposure at any concentration.
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Description (incidence and severity):
- No test substance-related developmental variations were observed at any exposure level.
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- No test substance-related developmental variations were observed at any exposure level.
- Visceral malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- Test substance-related visceral malformations of the heart and/or great vessels were observed at frequencies above the WIL historical control values in the maternally toxic 5500 (2 fetus total; 2 litters) and 7500 (3 fetus total; 2 litters) ppm groups. These findings, were not statistically different from the concurrent study control group, consisted of bulbous aorta, stenotic pulmonary arch, interventricular septal defect (absent septa), absent tricuspid valve and/or interrupted aortic arch. No test substance-related developmental variations were observed at any exposure level.
- Other effects:
- not examined
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 750 ppm (analytical)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- visceral malformations
Fetal abnormalities
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- visceral/soft tissue: cardiovascular
- Description (incidence and severity):
- Exposure related visceral malformations in the heart and/or great vessels were observed in 2 fetus at 5500 and 3 fetus at 7500 ppm groups. These effects were not statistically significant and occurred at exposure levels that resulted in maternal lethality.
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
Table 1. Animals found dead, euthanized in extermis, aborted or delivered prior to scheduled necropsy
Dose (ppm) | 0 | 2500 | 4000 | 5500 | 7500 |
found dead | 0 | 0 | 0 | 3 (GD13, 14,27) | 6 (GD12(1),14(3),18(1),29(1)) |
euthanized in extremis | 0 | 0 | 0 | 1 (GD28) | 1 (GD16) |
Aborted | 0 | 0 | 0 | 1 (GD28) | 3 (GD26(2), 29(1)) |
Delivered | 0 | 0 | 0 | 0 | 1 (GD29) |
Attachment with body weight changes and food comsumption are included in the background information section below
Table 2. Incidence of selected histopathologic findicngs and cause of death in the rabbit
Exposure Level (ppm): | ||||||
0 | 2500 | 4000 | 5500 | 7500 | ||
Sample size | 24 | 24 | 24 | 24 | 24 | |
# animals adverse effects | 0 | 8 | 12 | 14 | 22 |
|
Heart |
|
|
|
|
| |
Inflammation, subacute | 0 | 8 | 12 | 10* | 15* | |
Minimal | - | 3 | 1 | 2 | 2 | |
Mild | - | 2 | 2 | 5 | 6 | |
Moderate | - | 3 | 8 | 3 | 6 | |
Severe | - | 0 | 1 | 0 | 1 | |
|
|
|
|
|
| |
Number of Deaths | 0 | 0 | 0 | 5 | 10 | |
Cause of Death |
|
|
|
|
| |
Undetermined | - | - | - | 4 | 6 | |
Heart Inflammation | - | - | - | 1 | 3 | |
Lung hemorrhage and edema | - | - | - | 0 | 1 |
Applicant's summary and conclusion
- Conclusions:
- Based on mortality, moribundity, abortions, premature delivery, lower mean body weight gain, mean body weight loss and/or lower food consumption observed at 5500 and 7500 ppm (25630 and 34950 mg/m3), an exposure concentration of 4000 ppm (18650 mg/m3) was considered to be the no-observed-adverse-effect level (NOAEC) for maternal lethality. Non statistically significant test substance-related visceral malformations in the heart and/or great vessels were observed in the 5500 (2 fetus) and 7500 ppm (3 fetus) groups only in the presence of maternal toxicity (mortality). Therefore, an exposure concentration of 7500 ppm was considered to be the NOAEL for embryo/fetal development when pregnant New Zealand White rabbits were exposed to the test substance via whole-body inhalation. These conclusions are drawn from the underlying data from this study which meets the requirements cited in OECD 414.
Histological evaluation of selected tissues (brain, heart, liver, lungs, kidneys) failed to reveal the cause of death in the majority of animals. However, cardiac inflammation were observed at 2500 ppm (11620 mg/m3) and higher. The significance of these findings is not understood. - Executive summary:
Administration of filtered air or test substance atmospheres to pregnant female New Zealand White [Hra:(NZW)SPF] rabbits, approximately 5.5 to 6 months of age, as 6-hour, daily whole-body exposures during the period of major organogenesis (gestation days 6 through 28) at concentrations of 2500, 4000, 5500, and 7500 ppm was associated with early death in the 5500 (n=5) and 7500 (n=10) ppm groups, and these deaths were of undetermined causation (4/5 at 5500 ppm, 6/10 at 7500 ppm), due to subacute inflammation of the heart (1/5 at 5500 ppm and 3/10 at 7500 ppm) or a result of edema/hemorrhage of the lung (1/10 at 7500 ppm). Test substance exposure was also associated with subacute inflammation in the heart in the 2500 (n=8), 4000 (n=12), 5500 (n=10), and 7500 (n=15) ppm groups, coagulation necrosis of the heart in the 7500 (n=1) ppm group, and renal tubular necrosis in the 5500 n=3) and 7500 (n=1) ppm groups. At 5500 ppm, renal necrosis was noted in 2 animals that died or were euthanized. Although not dose related, these changes were considered adverse.
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