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EC number: 635-156-4 | CAS number: 109293-98-3
- 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
Repeated dose toxicity: dermal
Administrative data
- Endpoint:
- short-term repeated dose toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1995-09-26 until 1995-10-20
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study conducted in compliance to GLP and according to current guidelines.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 996
- Report date:
- 1996
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- sodium 2-{N-[(3,5-difluorophenyl)carbamoyl]ethanehydrazonoyl}nicotinate
- EC Number:
- 635-156-4
- Cas Number:
- 109293-98-3
- Molecular formula:
- C15 H12 F2 N4 O3 .Na
- IUPAC Name:
- sodium 2-{N-[(3,5-difluorophenyl)carbamoyl]ethanehydrazonoyl}nicotinate
- Reference substance name:
- Diflufenzopyr sodium salt
- IUPAC Name:
- Diflufenzopyr sodium salt
- Test material form:
- solid: particulate/powder
- Remarks:
- migrated information: powder
Constituent 1
Constituent 2
Test animals
- Species:
- rabbit
- Strain:
- New Zealand White
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan UK Ltd, Bicester, Oxon, England
- Age at study initiation: approximately 14 weeks
- Weight at study initiation: 2.2 to 2.7 kg
- Housing: individually, in Macrolon size 3 plastic cages
- Diet: standard laboratory diet SDS Rabbit Diet SQC, ad libitum
- Water: ad libitum
- Acclimation period: 13 days
ENVIRONMENTAL CONDITIONS
- Temperature: 18 to 21°C
- Humidity: 41 to 72%
- Photoperiod: 12/12 (hours dark / hours light)
- Air changes (per hr): approximately 19
Administration / exposure
- Type of coverage:
- occlusive
- Vehicle:
- water
- Details on exposure:
- TEST SITE
- Area of exposure: dorsal region
- % coverage: 10%
- Type of wrap if used: Impervious bandage "Elastoplast"
REMOVAL OF TEST SUBSTANCE
The test substance remained on the back of each rabbit for approximately 6 hours each day after which time the dressings were removed and the treated skin washed with warm (30 to 40 °C) water and gently blotted dry.
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2 mL/kg bw
- Constant volume or concentration used for each dose group: yes
- For solids, paste formed: yes
VEHICLE
distilled water to for moistening the powder and to ensure good contact with the skin.
USE OF RESTRAINERS FOR PREVENTING INGESTION: no - Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- not performed
- Duration of treatment / exposure:
- 6 h per day for 21 days
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 100, 300, 1000 mg/kg bw/day
Basis:
nominal per unit body weight
- No. of animals per sex per dose:
- 5 animlas per sex per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- The appropriate weight of test substance was spread evenly over the prepared skin of Group 2 to 4 rabbits inclusive. As the test substance is a powder, it was moistened using distilled water to ensure good contact with the skin. The control group was treated in a similar manner receiving water alone.
The treatment site was occluded by covering with an impervious bandage consisting of "Elastoplast" adhesive dressing backed with impervious "Sleek" plaster.
The test substance remained on the back of each rabbit for approximately 6 hours each day after which time the dressings were removed and the treated skin washed with warm (30 to 40 °C) water and gently blotted dry. Each animal received a constant dosage based on its most recently recorded body weight. Animals were treated once daily for at least twenty-one consecutive days. Treatment of all animals not scheduled for sacrifice on Day 22 was continued up to 24 hours prior to sacrifice. - Positive control:
- not applicable
Examinations
- Observations and examinations performed and frequency:
- Clinical signs
All animals were observed three times daily for signs of ill health, behavioural changes or toxicosis. Any observed changes were recorded.
All animals were checked early in each working day and again in the late afternoon to look for dead or moribund animals. This allowed a post mortem examination to be undertaken during the working part of that day.
Local dermal irritation
Local irritation was recorded immediately prior to the first daily application of the test substance and subsequently daily. Reactions (erythema and oedema) resulting from treatment were assessed on a numerical basis according to a Draize scoring system as follows:
Erythema and eschar formation:
No erythema 0
Slight erythema 1
Well-defined erythema 2
Moderate erythema 3
Severe erythema (beet redness) to slight eschar formation (injuries in depth) 4
Oedema formation:
No oedema 0
Slight oedema 1
Well-defined oedema (area well defined by definite raising) 2
Moderate oedema (raised approximately 1 millimetre) 3 Severe oedema (raised more than 1 millimetre and extending beyond
the area of exposure) 4
Any other lesion not covered by this scoring system, was described.
Bodyweight
All rabbits were weighed prior to dosing on Day 1 (Week 0) and subsequently at weekly intervals throughout the study.
Food consumption
The quantity of food consumed by each rabbit was measured at weekly intervals throughout the study.
Removal of blood samples
Food was withdrawn overnight prior to collection of samples. Blood was withdrawn from the median artery of the ear of all rabbits prior to termination (Week 3). Further removal of blood samples for re-analysis was carried out for individual animals, and the results of these analyses are presented in the appendices.
The collected blood samples were divided as follows:
EDTA anticoagulant tubes for haematological investigations
Citrate anticoagulant tubes for coagulation test
Heparin anticoagulant microtainer tubes for biochemical tests
Haematology
Packed cell volume (PCV)
Haemoglobin (Hb)
Red cell count (RBC)
Mean corpuscular haemoglobin concentration
Mean corpuscular volume
Mean corpuscular haemoglobin
Total white blood cell (WBC) count
Differential WBC count
Neutrophils
Lymphocytes
Eosinophils
Basophils
Monocytes
Large unstained cells
Cell morphology: the most common morphological changes (anisocytosis, micro/macrocytosis, variation in colour, hypo/hyperchromasia, left shift, atypical/blast cells) were recorded.
Platelet count
Thrombotest (TT)
Biochemistry
The following parameters were analysed with a Hitachi 737 Clinical Chemistry Analyser
Glucose
Total protein
Albumin (Alb)
Globulin (Glob)
Urea nitrogen
Creatinine
Alkaline phosphatase
Alanine aminotrnasferase
Aspartate aminotransferase
Bilirubin
Sodium
Potassium
Calcium
Chloride
Inorganic phosphorus
Cholesterol - Sacrifice and pathology:
- Termination
All animals surviving treatment were randomly killed on Day 22, Day 23 or Day 24 by means of an intravenous overdose of pentobarbitone sodiu and a complete autopsy undertaken. Specified organs were weighed and relevant tissue samples were fixed for microscopic examination.
Organ weight
The following organs from each animal were dissected free of fat and weighed:
adrenals
ovaries
brain
spleen
kidneys testes (with epididymides)
Macroscopic pathology
The macroscopic appearance of the tissues of all rabbits was recorded and samples of the following tissues were preserved in 10% buffered formalin:
adrenals
aorta
brain (medullary, cerebellar
and cortical sections)
caecum colon duodenum
eyes (Davidson's fluid as fixative)
gall bladder
heart
ileum
jejunum
kidneys
larynx
liver
lungs
lymph nodes (cervical and mesenteric)
mammary glands
oesophagus
ovaries
pancreas
pharynx
pituitary
prostate
salivary
gland
sciatic nerve
skeletal muscle
skin (treated and untreated)
spleen
sternum (for bone and marrow sections)
stomach
testes (including epididymis)
thymus (where present)
thyroid (with parathyroid)
tongue
trachea
urinary bladder
uterus (with cervix)
vagina
any macroscopically abnormal tissue
Microscopic pathology
Fixed tissue samples required for microscopic examination were prepared by embedding in paraffin wax - sections were cut at 4 µm and stained with haematoxylin and eosin.
Microscopic examination of prepared slides (from tissues indicated under "Macroscopic pathology" were carried out for all rabbits of Group 1 (control group) and Group 4 (high dosage group) killed on Day 22/23/24. - Statistics:
- All statistical analyses were carried out separately for males and females.
The following sequence of statistical tests were used for bodyweight gains, food consumption, organ weight and clinical pathology data:
If the data consisted predominantly of one particular value (relative frequency of the mode exceeded 75%), the proportion of values different from the mode were analysed by Fisher's exact test followed by Mantel's test for a trend in proportions.
Otherwise:
Bartlett's test was applied to test for heterogeneity of variance between treatments. If significant heterogeneity was found at the 1% level, a logarithmic transformation was tried to see if a more stable variance structure could be obtained.
If no significant heterogeneity was detected (or if a satisfactory transformation was found), a one-way analysis of variance was carried out followed by Williams' test for a dose related response.
If significant heterogeneity of variance was present and could not be removed by a logarithmic transformation, the Kruskal-Wallis analysis of ranks was used. This analysis was followed by the non-parametric equivalent of Williams' test (Shirley's test).
Covariate analysis of organ weight data (with final bodyweight as covariate) was also performed using adjusted weights for organs where a correlation between organ weight and bodyweight was established at the 10% level of significance.
Significant differences between control animals and those treated with the test substance were expressed at the 5% (* p <0.05) or 1% (** p <0.01) level.
Results and discussion
Results of examinations
- Details on results:
- CLINICAL SIGNS
There were no mortalities. No treatment-related clinical signs were noted for any of the animals throughout the study.
DERMAL REACTIONS
No dermal reactions were seen during the first five days of the study. Dermal irritation, accompanied by yellow staining and cracking, developed during the latter part of Week 1 and during Weeks 2 and 3 for all treatment groups, and the incidence and severity was dosage related. For some animals treated at the low dosage of 100 mg/kg/day dermal irritation (slight to well defined erythema accompanied by slight to well defined oedema) was recorded. Irritation was accompanied by yellow staining and cracking. Most rabbits of the intermediate dosage of 300 mg/kg/day, dermal irritation (slight to moderate erythema accompanied by slight to well defined oedema) was observed. Dermal irritation was accompanied by yellow staining and cracking and occasionally by sloughing. At the high dosage of 1000 mg/kg/day dermal irritation (slight to moderate erythema accompanied by slight to moderate oedema) was recorded. Dermal irritation was accompanied by yellow staining and cracking and occasionally by sloughing.There were no dermal reactions seen for any animals from the control group.
BODYWEIGHT
There were no statistically significant differences from control noted for bodyweight gains in any of the treatment groups. Bodyweight gains showed considerable variation for all groups of rabbits. This is not uncommon for laboratory rabbits and in the absence of any dosage relationship, differences from control were considered to reflect variation.
FOOD CONSUMPTION
There were no statistically significant differences from control noted for the food consumption in any of the treatment groups. Food consumption for low dosage group female rabbits was slightly higher than control and lower than control for intermediate dosage group male rabbits. These small differences from control were considered to reflect variation and not an effect of treatment.
HAEMATOLOGY
There were no differences from control in the haematological parameters measured that were considered to be related to treatment. Statistically significantly higher than control monocyte levels were recorded for male rabbits of the high dosage group. The magnitude of this change was small and a treatment related effect was considered unlikely. nLymphocyte levels were statistically significantly lower than control for female rabbits treated at 1000 mg/kg/day. However, there was wide variation for individual values and the total white blood cell count was not affected. A treatment-related effect was considered unlikely.
BIOCHEMISTRY
There were no differences from control in the biochemical parameters measured.
ORGAN WEIGHTS
There were no differences from control in the organ weights measured.
MACROSCOPIC PATHOLOGY
The macroscopic examination performed at termination revealed yellow staining of the skin in some rabbits at all dosage levels.
MICROSCOPIC PATHOLOGY
Minimal or trace diffuse acanthosis was seen in the majority of male and female rabbits from all treated groups.
A related minimal or trace diffuse inflammation of the superficial dermis was observed in a proportion of male and female rabbits of the 1000 and 300 mg/kg/day treatment groups and male rabbits of the 100 mg/kg/day treatment group. These changes were considered to be dose-related.
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects observed.
- Dose descriptor:
- NOEL
- Effect level:
- < 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effects observed.
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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