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EC number: 410-690-9 | CAS number: 103055-07-8 CGA 184699
- 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:
- 23 Jan 1989 to 7 Feb 1989
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 989
- Report date:
- 1989
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 1981
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.31 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 1988
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- N-[2,5-dichloro-4-(1,1,2,3,3,3-hexafluoropropoxy)-phenyl-aminocarbonyl]-2,6-difluorobenzamide
- EC Number:
- 410-690-9
- EC Name:
- N-[2,5-dichloro-4-(1,1,2,3,3,3-hexafluoropropoxy)-phenyl-aminocarbonyl]-2,6-difluorobenzamide
- Cas Number:
- 103055-07-8
- Molecular formula:
- C17 H8 Cl2 F8 N2 O3
- IUPAC Name:
- 1-[2,5-dichloro-4-(1,1,2,3,3,3-hexafluoropropoxy)phenyl]-3-(2,6-difluorobenzoyl)urea
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl: CD® (SD) BRVAF/Plus(tm) rats
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: Approx. 10 weeks of age at start of mating
- Housing: Rats were housed in hanging polycarbonate cages with solid bottoms containing approximately a one inch layer of hardwood chip bedding. Animals were housed in cages of approximately 62 sq. in. floor space prior to and after mating and approximately 143 sq. in. floor space during mating. Animals were caged individually except at the time of mating.
- Diet: Ad libitum, rodent chow
- Water: Ad libitum, tap water
- Acclimation period: at least 12 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24
- Humidity (%): 40-60
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: 23 Jan 1989 to 26 Oct 1989
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: Aqueous 3% cornstarch and 0.5% Tween 80
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test substance was mixed with an aqueous 3% cornstarch and 0.5% Tween 80. The dose suspensions were prepared weekly by a weight/volume method and stored refrigerated.
VEHICLE
- Amount of vehicle: 5 mL/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of all dose suspension preparations were taken for analytical determination of concentration and homogeneity. Analyses indicated that the mean measured concentrations of the test substance were within 10% of the intended concentrations for all preparations of the 20, 100 and 200 mg/mL suspensions. Analyses of dose suspensions for concentrations was based on six samples per suspension. The relative standard deviations ranged from 1.4 to 7.9% indicating adequate homogeneity.
- Details on mating procedure:
- - Impregnation procedure: Cohoused
- If cohoused: One or two females with each proven male breeder
- Length of cohabitation: Overnight
- Proof of pregnancy: Presence of sperm or a copulatory plug referred to as day 0 of pregnancy - Duration of treatment / exposure:
- Day 6 through 15 p.c.
- Frequency of treatment:
- Once daily
- Duration of test:
- Untill Day 21 p.c.
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
- Control animals:
- yes, concurrent vehicle
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS:
- Time schedule: Daily
BODY WEIGHT:
- Time schedule for examinations: Day 0, 6, 7, 9, 12, 16 and 21 of gestation
FOOD CONSUMPTION
- Time schedule for examinations: Day intervals 0-6, 6-9, 9-12, 12-16 and 16-21 of gestation
POST-MORTEM EXAMINATIONS:
- Sacrifice on gestation day 21
- Organs examined: The oral cavity and all organs of the thoracic and abdominal cavities. The ovaries and uterus with cervix were immediately removed, trimmed, weighed intact and examined
- 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
- Soft tissue examinations: Yes
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter - Statistics:
- Incidence data for each dose group, such as clinical observations were analysed by the Fisher exact probability test (Siegel, 1956) with Bonferroni’s correction for multiple comparisons to a single control level (Ingelfinger et al., 1983). Enumerative data for each litter, such as the percent incidence of foetal variations and malformations and the number of corpora lutea per dam, were analysed by the nonparametric Mann-Whitney U two-sample rank test (Goldstein, 1967). Quantitative or continuous data, such as body and food consumption were analysed by one-way analysis of variance (Steel and Torrie, l960) and the Dunnett’s t-test (Dunnett, 1964). The level of significance selected for all statistical tests was p < 0.05 but values also significant at p < 0.01 are indicated
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, non-treatment-related
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- No statistically significant reductions in mean absolute body weights or mean corrected body weights occurred at any dose level. The gain in body weight at 100 mg/kg bw/day was statistically reduced before, but not after, the start of treatment. The change in corrected body weight at 100 mg/kg bw/day was also statistically reduced for gravid days 0-21 but not from the start of treatment, gravid days 6-21. The statistically significant changes in mean body weights at 100 mg/kg/day were not considered treatment-related. The mean gain in body weight was reduced at 1000 mg/kg/ day after one day of treatment and was statistically reduced for the gravid day interval 7-9.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- A statistically significant reduction in food consumption occurred over gravid days 6-9 at 1000 mg/kg/day.
- 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
- Endocrine findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- 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:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Statistically significant reductions in the mean number of implants/dam at 100 mg/kg/day were not considered to be adverse.
- 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
- Other effects:
- not examined
Effect levels (maternal animals)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- General toxicity
- Effect level:
- 500 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- Maternal developmental toxicity
- Effect level:
- > 1 000 mg/kg bw/day
- Based on:
- test mat.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The mean number of live foetuses per dam was slightly but statistically reduced at 100 and 1000 mg/kg/day but considered to be non-treatment related
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Anogenital distance of all rodent fetuses:
- not examined
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Malformations were observed in 19 foetuses. All of these malformations were considered to have occurred spontaneously. At 0 mg/kg/day, 6 foetuses from 5 litters were considered to be malformed. The most severely affected was a foetus (202/17 F; litter/foetus-sex) with absence of a lumbar vertebral centrum, absence of lumbar vertebrae and sacral vertebrae, and absence of the tail. Two foetuses from two litters had absence of a lumbar vertebra (213/2 F; 214/7 F). Two foetuses from one litter (223/14 and 16 F) had moderate dilation of a kidney pelvis. The sixth foetus (212/8 F) had moderate dilation of a kidney pelvis and extreme dilation of an ureter. At 100 mg/kg/day, six foetuses from four litters were considered malformed. The most severely affected was a foetus (258/4 F) that had incomplete situs inversus of the abdomen and thorax with only one lung lobe on the left side, moderate dilation of both kidney pelvis, and extreme convolution of both ureters. A second foetus in the same litter (258/16 M) had moderate dilation of both kidney pelvis. One foetus (254/5 F) had no anus and a rudimentary tail. One foetus from litter 257 (12 F) had umbilical eventration. A second foetus from litter 257 (8 M) had moderate dilation of a kidney pelvis. The sixth foetus (250/15M) had umbilical eventration. At 500 mg/kg/day, three foetuses from two litters were considered malformed. One foetus (283/2 H) had an absence of a lumbar vertebra. In litter 286 one foetus (1 F) had moderate dilation of both kidney pelvis and one foetus (9 F) had moderate dilation of one kidney pelvis. At 1000 mg/kg bw/day four foetuses from four litters were considered malformed. One foetus (322/3 F) had situs inversus of the abdomen and thorax, two foetuses (325/11 F; 335/1 F) had extreme dilation and convolution of both ureters and a fourth foetus (342/4 F) had moderate dilation of a kidney pelvis
- Visceral malformations:
- no effects observed
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The reduction at 100 mg/kg/day reflected a slight reduction in the number of corpora lutea (developed before treatment) and at 1000 mg/kg/day the <4% reduction in mean number of live foetuses compared to concurrent controls exceeded the mean values for controls from the previous five studies.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
Analytical verification:
Table 1. Analysis of the dosing suspensions
Date prepared and analysed |
Concentration expected |
Number of samples |
Mean concentration (mg/mL) |
Range (mg/mL) |
Standard deviation |
Relative standard deviation (%) |
1-20-89 |
20 |
6 |
18.4 |
16.9-19.6 |
1.3 |
7.0 |
|
100 |
6 |
97 |
93-101 |
3 |
3.1 |
|
200 |
6 |
198 |
189-205 |
5 |
2.7 |
1-27-89 |
20 |
6 |
18.1 |
16.0-19.9 |
1.4 |
7.9 |
|
100 |
6 |
98 |
93-104 |
5 |
4.7 |
|
200 |
6 |
194 |
166-206 |
14 |
7.4 |
2-3-89 |
20 |
6 |
18.5 |
17.5-19.2 |
0.7 |
3.9 |
|
100 |
6 |
|
89-102 |
5 |
5.2 |
|
200 |
6 |
202 |
199-207 |
3 |
1.4 |
Table 2. Intergroup comparison of maternal body weight gain (g)
Days |
Dose level of mg test substance technical/kg/day |
|||
0 |
100 |
500 |
1000 |
|
7-9 |
11 |
9.4 |
13 |
3.4* |
Number# |
22 |
23 |
19 |
25 |
#Number of females with live fetuses in utero at termination.
*Statistically significant difference from control group mean, p<0.05 (Dunnett’s t-test)
Table 3. Intergroup comparison of maternal food consumption (g/day)
Interval (days) |
Dose level of mg test substace technical/kg/day |
|||
0 |
100 |
500 |
1000 |
|
6-9 |
24 |
23 |
24 |
21* |
Number# |
22 |
23 |
19 |
25 |
#Number of females with live fetuses in utero at termination.
*Statistically significant difference from control group mean, p<0.05 (Dunnett’s t-test)
Table 4. Intergroup comparison of selected intrauterine data
Parameter |
Dose level of mg test substance technical/kg/day |
|||
0 |
100 |
500 |
1000 |
|
Mean number of implants per dam |
16.5 |
15.4* |
16.4 |
16.2 |
Mean number of implants per dam |
15.9 |
15.0* |
15.7 |
15.3* |
*Statistically significant difference from control group mean, p<0.05 (two-tailed)
Table 5. Historical control data of selected intrauterine data
Parameter |
Study number (start date) |
||||
12 (11/4/88) |
11 (22/6/87) |
10 (16/3/87) |
9 (22/7/85) |
8a(14/5/85) |
|
Mean number of implants per dam |
15.8 |
14.4 |
14.2 |
14.7 |
15.6 |
Mean number of live fetuses per dam |
15.0 |
13.8 |
12.8 |
14.2 |
14.2 |
Table 6. Intrauterine data for gravid intergroup comparison of maternal food consumption (g/day).
|
Dose level of mg test substance technical/kg/day |
|||||||
|
0 |
100 |
500 |
1000 |
||||
Dams with implants |
22 |
23 |
19 |
25 |
||||
Dams with live fetuses |
22 |
23 |
19 |
25 |
||||
Dams with resorptions |
10 |
8 |
10 |
17 |
||||
Dams with affected implantsa |
14 |
11 |
12 |
17 |
||||
|
Meanb |
SD |
Mean |
SD |
Mean |
SD |
Mean |
SD |
Corpora lutea/dam Implants/dam |
17.5 16.5 |
3.2 2.6 |
16.5 15.4* |
1.9 1.9 |
18.5 16.4 |
3.1 2.6 |
18.1 16.2 |
3.1 1.3 |
Implantation indexc(%) Pre implantation lossd(%) |
95.3 4.7 |
13.1 13.1 |
93.8 6.2 |
10.2 10.2 |
89.3 10.7 |
12.0 12.0 |
91.1 8.9 |
11.6 11.6 |
Implant viability indexe(%) Post implantation lossf(%) |
95.7 4.3 |
8.1 8.1 |
97.5 2.5 |
3.7 3.7 |
95.8 4.2 |
4.9 4.9 |
94.4 5.6 |
5.3 5.3 |
Live fetuses/dam Dead fetuses/dam |
15.9 0.0 |
2.9 0.0 |
15.0* 0.0 |
1.8 0.0 |
15.7 0.0 |
2.6 0.0 |
15.3* 0.0 |
1.4 0.0 |
Resorptions/dam - early - mid - late |
0.5 0.1 0.0 |
0.6 0.5 0.0 |
0.3 0.1 0.0 |
0.5 0.3 0.0 |
0.3 0.2 0.2 |
0.5 0.4 0.5 |
0.5 0.4 0.0 |
0.7 0.7 0.0 |
Malformed live foetusesg(%) Affected implantsh(%) |
1.6 5.9 |
3.3 8.0 |
1.7 4.1 |
3.9 4.9 |
1.1 5.3 |
3.9 5.1 |
1.1 6.6 |
2.6 6.3 |
Sex ratio (%)i |
50.2 |
15.2 |
45.7 |
12.4 |
45.6 |
13.1 |
49.3 |
12.2 |
Mean body weights (grams)/live foetus Reproductive tract weight (grams)/dam |
5.2 108.03 |
0.2 18.0 |
5.4 105.61 |
0.4 11.25 |
5.2 107.66 |
0.3 17.79 |
5.4 108.00 |
0.3 10.70 |
a Affected implants includes dead fetuses, resorptions and malformed live fetuses
b Values determined on a per litter basis
c (implants/corpora lutea)x 100
d 100 – implants index
e (viable implants/total implants) x 100
f 100 – implant viability index
g (fetuses with observations classified as malformations/total live fetuses) x 100
h [ (dead fetuses + resorptions + malformed live fetuses) /total implants] x 100
i (live female fetuses/total live fetuses) x 100
* Significantly different from 0 mg/kg /day dose level, p< 0.05, two-tailed
Applicant's summary and conclusion
- Conclusions:
- Minimal maternal toxicity was evident at 1000 mg/kg bw/day and consisted of transient reductions in body weight gained and food consumed. No embryofoetal toxicity or teratogenic effects were apparent at any of the dose levels tested. The NOAEL in this study for maternal toxicity was 500 mg/kg bw/day and for developmental toxicity was 1000 mg/kg bw/day.
- Executive summary:
The test substance was tested for embryotoxic and teratogenic action in accordance with OECD 414 and performed under GLP principles. The test substance was administered to Crl: CD® (SD) BRVAF/Plus™ rats by oral gavage as a suspension in aqueous 3% corn starch and 0.5% Tween 80 to groups of 25 mated females at dosages of 0, 100, 500 or 1000 mg/kg/day. The females were treated for 10 consecutive days from gestation day 6 through 15. The dose was based on each female’s gravid day 6 body weight. The females were monitored daily for clinical signs. Body weights and food consumption were recorded for selected intervals during gestation. The dams were sacrificed on gravid day 21; the status of the reproductive tract determined; and the foetuses examined for external, soft and tissue skeletal variations and malformations.
Results showed that treatment with the test substance caused minimal maternal toxicity at 1000 mg/kg/day indicated by a short period (gravid days 6-9) of slightly reduced body weight gain and food consumption. No embryofoetal and teratogenic toxicity was apparent at any dose level.
In conclusion, minimal maternal toxicity was evident at 1000 mg test substance/kg/day and consisted of transient reductions in body weight gained and food consumed. No embryofoetal toxicity or teratogenic effects were apparent at any of the dose levels tested. The NOAEL in this study for maternal toxicity was 500 mg/kg bw/day and for developmental toxicity was 1000 mg/kg bw/day.
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