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EC number: 221-882-5 | CAS number: 3268-49-3
- 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:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- acute toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 402 (Acute Dermal Toxicity)
- Version / remarks:
- adopted 09 Oct 2017
- Deviations:
- yes
- Remarks:
- occlusive dressing, no stepwise dosing
- GLP compliance:
- not specified
- Test type:
- standard acute method
- Limit test:
- yes
- Species:
- rabbit
- Strain:
- New Zealand White
- Sex:
- male/female
- Type of coverage:
- occlusive
- Vehicle:
- unchanged (no vehicle)
- Details on dermal exposure:
- TEST SITE
- Area of exposure: clipped dorsal trunk
- Type of wrap if used: The test material was applied to the test site and the exposed skin was covered with gauze and impervious sheeting. The materials were held in place using an elastic bandage around the trunk.
- Duration of exposure:
- 24 h
- Doses:
- 0.25, 0.5, 1.0 mL/kg bw (males), corresponding to 259, 518 and 1036 mg/kg bw and 0.5, 1.0 mL/kg bw (females), corresponding to 518 and 1036 mg/kg bw
- No. of animals per sex per dose:
- 4
- Control animals:
- no
- Details on study design:
- - Duration of observation period following administration: 14 days
- Frequency of observations: during exposure and daily thereafter
- Frequency of weighing: before dosing, at 7 and 14 days post dosing
- Necropsy of survivors performed: yes - Sex:
- male
- Dose descriptor:
- LD50
- Effect level:
- 736 mg/kg bw
- Based on:
- test mat.
- 95% CL:
- 446 - 1 191
- Remarks on result:
- other: dosel levels in mg/kg bw calculated with a density of 1036 mg/mL
- Sex:
- female
- Dose descriptor:
- LD50
- Effect level:
- 818 mg/kg bw
- Based on:
- test mat.
- 95% CL:
- 508 - 1 347
- Remarks on result:
- other: dosel levels in mg/kg bw calculated with a density of 1036 mg/mL
- Mortality:
- 0.25 mL/kg bw (corresponding to 259 mg/kg bw): 1/4 males died on Day 9.
0.5 mL/kg bw (corresponding to 518 mg/kg bw): no mortality occurred.
1.0 mL/kg bw (corresponding to 1036 mg/kg bw): 4/4 males and 3/4 females died (males: death within 3 h - 5 days; females: death within 1 day). - Clinical signs:
- Local signs: Marked erythema, edema and necrosis in all animals of all dose groups, which persisted 14 days. Desquamation and fissuring were seen at 7 days in females at 1 mL/kg bw (1036 mg/kg bw).
Clinical signs: Salivation, sluggishness, and unsteady gait. Survivors recovered from these effects by 2 days. - Body weight:
- Body weight gain was unaffected by treatment.
- Gross pathology:
- The main necropsy finding was light to dark red mottling of the lungs. Sacrificed survivors had no gross pathological changes observed.
- Interpretation of results:
- Category 3 based on GHS criteria
- Conclusions:
- CLP: Acute Dermal 3, H311 according to Regulation (EC) No. 1272/2008
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 406 (Skin Sensitisation)
- Version / remarks:
- adopted 17 Jul 1992
- Deviations:
- yes
- Remarks:
- no challenge control, limited information on materials and methods
- GLP compliance:
- yes
- Type of study:
- guinea pig maximisation test
- Species:
- guinea pig
- Strain:
- Dunkin-Hartley
- Sex:
- male/female
- Details on test animals and environmental conditions:
- TEST ANIMALS
- Source: Covance, Inc., Denver, Pennsylvania, USA
- Age at study initiation: 5-7 weeks
- Housing: individually in suspended, stainless steel cages with wire mesh bottoms
- Diet: Certified Guinea Pig Diet No. 5026 (PMI Nutrition International, St. Louis, Missouri), ad libitum
- Water: tap water, ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16-25
- Humidity (%): 20-62
- Photoperiod (hrs dark / hrs light): 12/12 - Route:
- intradermal and epicutaneous
- Vehicle:
- propylene glycol
- Concentration / amount:
- intradermal induction on Day 1: 5% in propylene glycol
epicutaneous induction on Day 7: 0.2 mL unchanged - Day(s)/duration:
- intradermal induction: single treatment on Day 0; epicutaneous induction: 24 h exposure on Day 6
- Adequacy of induction:
- other: concentration chosen based on the results of a preliminary range-finding study in which 100% produced a score of 0.5 in 2/6 animals
- No.:
- #1
- Route:
- epicutaneous, occlusive
- Vehicle:
- unchanged (no vehicle)
- Concentration / amount:
- 0.1 mL
- Day(s)/duration:
- Day 21, 48 h
- Adequacy of challenge:
- other: concentration chosen based on the results of a preliminary range-finding study in which 100% produced a score of 0.5 in 2/6 animals
- No.:
- #2
- Route:
- epicutaneous, occlusive
- Vehicle:
- propylene glycol
- Concentration / amount:
- 25%
- Day(s)/duration:
- Day 21, 48 h
- Adequacy of challenge:
- other: The concentration was chosen due to excess irritation in the control group after the first challenge.
- No. of animals per dose:
- 20 (10 male and 10 female)
- Details on study design:
- RANGE FINDING TESTS:
Induction and maximum non irritant concentration for challenge was determined in a pre-test: 5% MTPA in propylene glycol administered intradermally produced local necrosis. 25% topical application produced no irritation, and up to 100% only produced a score of 0.5 in 2 of 6 animals.
MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 2 (intradermal and epicutaneous, respectively)
- Exposure period: single injection (intradermal) and 24 h (epicutaneous)
Intradermal (3 pairs of injections):
Injection 1: 50% complete Freund's adjuvant (FCA) in distilled water
Injection 2: 5% test substance in propylene glycol
Injection 3: 5% test substance in 50% aqueous FCA
Epicutaneous: 7 days after the injections, 0.2 mL of undiluted test substance were applied on a 2 x 4 inch patch of filter paper and applied to the reclipped areas which had received the intradermal injections. The patches were covered by impermable plastic and secured with an elastic adhesive bandage wound around the animals torso. After 48 h occluded contact the skin was wiped free of excess test material with gauze soaked in 0.9% saline.
- Control group: Not included in the study.
B. CHALLENGE EXPOSURE
- No. of exposures: 2
- Day of challenge: 2 weeks after epidermal induction (Day 20)
- Exposure period: 24 h
- Test groups: test substance
- Control group: Not included in the study.
- Concentrations: 0.1 mL undiluted test item
- Evaluation (hr after challenge): 24 and 48 h - Challenge controls:
- No challenge control group was included.
- Positive control substance(s):
- yes
- Remarks:
- a-hexylcinnamaldehyde
- Positive control results:
- Two positive control groups were included. Both groups were induced intradermally with 50% FCA in distilled water, 30% a-hexylcinnamaldehyde (HCA) in propylene glycol, and 30% HCA in 50% aqueous FCA. Epicutaneous induction was with a 48 h occluded contact with undiluted HCA. Animals were challenged with both 50% HCA in propylene glycol and undiluted HCA. Challenge with undiluted HCA induced a skin sensitisation of a score of 1 or greater in 40% of the animals. The severity indices were 0.6 (24 h) and 0.35 (48 h). Challenge with 50% HCA induced a positive response in 90% of the animals with severity indices of 1.1 (24 h) and 0.9 (48 h).
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- induction: 5% intradermal and 0.2 mL unchanged epicutaneous induction, challenge with 100% epicutaneous induction
- No. with + reactions:
- 3
- Total no. in group:
- 19
- Remarks on result:
- other: 1/10 females died on Day 10
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- induction: 5% intradermal and 0.2 mL unchanged epicutaneous induction, challenge with 100% epicutaneous induction
- No. with + reactions:
- 5
- Total no. in group:
- 19
- Remarks on result:
- other: 1/10 females died on Day 10
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- negative control
- Dose level:
- induction with vehicle, untreated during challenge
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Remarks on result:
- other: 4/10 animals gave a result of score 1. In view of this, a score of 2 or greater was used as basis for a positive response.
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- positive control
- Dose level:
- induction: 30% intradermal and 0.2 mL unchanged epicutaneous induction, challenge with 100% epicutaneous induction
- No. with + reactions:
- 1
- Total no. in group:
- 10
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- positive control
- Dose level:
- induction: 30% intradermal and 0.2 mL unchanged epicutaneous induction, challenge with 100% epicutaneous induction
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- induction: 5% intradermal and 0.2 mL unchanged epicutaneous induction, challenge with 25% epicutaneous induction
- No. with + reactions:
- 2
- Total no. in group:
- 19
- Remarks on result:
- other: re-challenge, 1st reading
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- induction: 5% intradermal and 0.2 mL unchanged epicutaneous induction, challenge with 25% epicutaneous induction
- No. with + reactions:
- 4
- Total no. in group:
- 19
- Remarks on result:
- other: re-challenge, 2nd reading
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- positive control
- Dose level:
- induction: 30% intradermal and 0.2 mL unchanged epicutaneous induction, challenge with 50% epicutaneous induction
- No. with + reactions:
- 2
- Total no. in group:
- 10
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- positive control
- Dose level:
- induction: 30% intradermal and 0.2 mL unchanged epicutaneous induction, challenge with 50% epicutaneous induction
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Interpretation of results:
- study cannot be used for classification
- Conclusions:
- Based on the experimental findings, the test item causes erythema, edema and necrosis to the skin. However, due to the highly skin irritating properties, a distinct conclusion on skin sensitising effects cannot be drawn. Therefore the skin sensitisation study test result is considered to be inconclusive due to irritating effects of the test item to the skin.
Results of pilot study:
Intradermal injections of 5% MTPA produced local
necrosis and the concentration was considered adequate for
the main study. Topical application of 25% produced no
local irritation and 50, 70, 100% produced a score of
0.5 in 2 or 3 of 6 animals. Therefore undiluted MTPA was used for the
main study epicutaneous induction and challenge.
Table 1: Results of main study - Incidences of skin responses at
challenge and in irritation control animals
Compound | Group | No. of animals | Time | Erythema Score | Edema | Necrosis | ||||
0 | 0.5 | 1 | 2 | 3 | ||||||
Test item, 100% | Challenge | 19 | 24 | 14 | 1 | 1 | 0 | 3 | 5 | 3 |
19 | 48 | 8 | 5 | 1 | 0 | 5 | 11 | 4 | ||
Test item, 25% | Re-challenge | 19 | 24 | 12 | 4 | 0 | 0 | 2 | 3 | 0 |
19 | 48 | 3 | 8 | 3 | 0 | 4 | 13 | 2 | ||
Test item, 100% | Irritation | 10 | 24 | 8 | 0 | 0 | 0 | 2 | 2 | 2 |
10 | 48 | 6 | 2 | 0 | 0 | 0 | 4 | 1 | ||
Test item, 25% | Irritation | 10 | 24 | 5 | 5 | 0 | 0 | 0 | 3 | 0 |
10 | 48 | 1 | 5 | 4 | 0 | 0 | 6 | 0 | ||
HCA, 100% | Challenge | 10 | 24 | 2 | 4 | 3 | 1 | 0 | 2 | 0 |
10 | 48 | 5 | 3 | 2 | 0 | 0 | 0 | 0 | ||
HCA, 100% | Irritation | 10 | 24 | 8 | 2 | 0 | 0 | 0 | 0 | 0 |
10 | 48 | 10 | 0 | 0 | 0 | 0 | 0 | 0 | ||
HCA, 50% | Challenge | 10 | 24 | 0 | 2 | 6 | 2 | 0 | 1 | 0 |
10 | 48 | 0 | 2 | 8 | 0 | 0 | 0 | 0 | ||
HCA, 50% | Irritation | 10 | 24 | 4 | 5 | 1 | 0 | 0 | 0 | 0 |
10 | 48 | 6 | 4 | 0 | 0 | 0 | 0 | 0 |
HCA: a-hexylcinnamaldehyde
One female of the MTPA sensitization group died on day 10 of the study.
The irritation reaction was unexpectedly high compared to the pre-study.
In summary, based on the scores of 2 or greater with
epicutaneous challenge at 25% the test
item produced sensitization in 22% of the guinea pigs; therefore,this material was classified as a "mild sensitizer" based on the Magnusson and
Kligman allergenicity rating criteria.
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- skin irritation: in vivo
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with national standard methods with acceptable restrictions
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
- Version / remarks:
- adopted 28 Jul 2015
- Deviations:
- yes
- Remarks:
- no erythema and edema values for individual animals reported, only average scores given, occlusive application
- GLP compliance:
- not specified
- Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: 2.0 - 3.0 kg - Type of coverage:
- occlusive
- Preparation of test site:
- clipped
- Vehicle:
- unchanged (no vehicle)
- Controls:
- no
- Amount / concentration applied:
- TEST MATERIAL
- Amount applied: 0.5 mL - Duration of treatment / exposure:
- 4 h
- Observation period:
- 17 days
Reading time points: 1, 24, 48 and 72 h, and 7, 10, 14 and 17 days - Number of animals:
- 6 (3 male and 3 female)
- Details on study design:
- TEST SITE
- Area of exposure: clipped dorsal trunk skin.
- Type of wrap if used: The area was covered with a gauze patch and loosely covered with impervious sheeting.
REMOVAL OF TEST SUBSTANCE
- Occlusive materials were removed and any excess sample wiped away with a moistened gauze swab.
- Time after start of exposure: 4 h
OBSERVATION TIME POINTS : 1, 24, 48 and 72 h, and 7, 10, 14 and 17 days
SCORING SYSTEM:
- Method of calculation: Draize scoring system - Irritation parameter:
- erythema score
- Basis:
- other: average score over all animals
- Time point:
- 24/48/72 h
- Score:
- 2.3
- Max. score:
- 4
- Reversibility:
- fully reversible within: 17 days
- Irritation parameter:
- edema score
- Basis:
- other: average score over all animals
- Time point:
- 24/48/72 h
- Score:
- 2.9
- Max. score:
- 4
- Reversibility:
- fully reversible within: 17 days
- Irritant / corrosive response data:
- An hour after removal of the occlusive dressing there was mild to moderate erythema (score 1-2) and well defined to severe edema (score 3-4). On study Days 1-3 mild to severe erythema (score 1-4) was observed, which began to resolve between 3 and 7 days and had disappeared in half of the animals by Day 14 and in all animals by Day 17. Mild to severe edema (score 1-4) was observed in the animals up to study Day 3. One week after patch removal up to study Day 10 slight to moderate edema was observed (score 0-2). 14 days after patch removal, only slight edema (score 0-1) was observed, which was fully reversible until study termination. In addition, desquamation and scab formation were seen in all animals from Day 7-17.
- Interpretation of results:
- study cannot be used for classification
- Conclusions:
- The test conditions (occlusive conditions) may have led to more detrimental skin reactions than those specified in current guidelines. Individual animal data for erythema and edema were not reported.
Data source
Referenceopen allclose all
- Reference Type:
- publication
- Title:
- Cutaneous toxicology of 3-(Methylthio)propionaldehyde
- Author:
- Ballantyne B, Cawley TJ, Blaszcak DL , 0
- Year:
- 2 000
- Bibliographic source:
- J.Toxicol.-Cut. & Ocular Toxicol., 19 (2&3), 117-13
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 999
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
- Version / remarks:
- adopted 12 May 1981
- Deviations:
- yes
- Remarks:
- limited study duration including 9 days treatment instead of 21/28 days, treatment 5 days/week instead of daily application, test material not fully characterised
- GLP compliance:
- yes
- Limit test:
- yes
Test material
- Reference substance name:
- 3-(methylthio)propionaldehyde
- EC Number:
- 221-882-5
- EC Name:
- 3-(methylthio)propionaldehyde
- Cas Number:
- 3268-49-3
- Molecular formula:
- C4H8OS
- IUPAC Name:
- 3-(methylthio)propionaldehyde
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: 165.3 - 195.5 g (males) and 182.5 - 216.0 g (females)
- Housing: individually in stainless steel wire mesh cages
- Diet: Certified Rodent Diet No. 5000 (PMI Nutrition International, St. Louis, Missouri), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 26
- Humidity (%): 24 - 70
Administration / exposure
- Type of coverage:
- occlusive
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- TEST SITE
- Area of exposure: The doses were applied to the clipped dorsal trunk skin.
- Type of wrap if used: The treated areas were covered with a layer of 8-ply gauze and impervious plastic, which was secured with an adhesive elastic bandage.
REMOVAL OF TEST SUBSTANCE
- Washing: The test sites were wiped free of excess test material using gauze soaked in saline.
- Time after start of exposure: 6 h
TEST MATERIAL
- Amount applied: 0.05, 0.2 and 0.5 mL/kg bw/day, corresponding to 52.7, 210.8 and 527 mg/kg bw/day
- Constant volume or concentration used: no
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 6 h
- Frequency of treatment:
- 6 hours/day for 9 days (5 days in first week, 4 days in second week)
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0.05 other: mL/kg bw
- Remarks:
- corresponding to 52.7 mg/kg bw/day
- Dose / conc.:
- 0.2 other: mL/kg bw
- Remarks:
- corresponding to 210.8 mg/kg bw/day
- Dose / conc.:
- 0.5 other: mL/kg bw
- Remarks:
- corresponding to 527 mg/kg bw/day
- No. of animals per sex per dose:
- Main group: 10
Recovery group: 5 (control and high dose group only) - Control animals:
- yes
- Details on study design:
- - Dose selection rationale:
Dose levels were chosen based on a preliminary range-finding study, which was performed in 3 rats/sex with treatment for 5 consecutive days. 1/3 males and 1/3 females treated at 1.0 mL/kg bw/day died on study Day 4. There were no clinical signs of toxicity and no abnormalities in the Irwin Screen. Local skin irritation, seen at 0.5 and 1.0 mL/kg bw/day, was mainly mild erythema. Body weight losses at 0.5 mL/kg bw/day and 1.0 mL/ kg bw/day were significantly greater than for the control group. Except for the 1.0 mL/kg bw/day males, all groups gained weight by the fifth day of dosing. Based on these findings, it was considered that applied doses of 0.05, 0.2, and 0.5 mL/kg bw/day were appropriate for the full 9-day study.
- Fasting period before blood sampling for clinical biochemistry: not specified
- Post-exposure recovery period in satellite groups: 28 days
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily during the exposure period, once weekly during the recovery period
- Cage side observations included: local skin lesions and signs of toxic or pharmacological effects and mortality
DERMAL IRRITATION: Yes
- Time schedule for examinations: daily during the exposure period, once weekly during the recovery period
BODY WEIGHT: Yes
- Time schedule for examinations: on study Days 1, 3, 5, 8 and 10 during the exposure period and on Day 15 and weekly thereafter during the recovery period.
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes. Food consumption was measured for a week prior to dosing, over Days 1-3, 3-5, 5-8 and 8-10 during the exposure period and for recovery animals over six daily intervals.
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION: Yes
- Time schedule for examinations: Prior to dosing, over Days 1-3, 3-5, 5-8 and 8-10 during the exposure period and for recovery animals over six daily intervals.
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood was collected before sacrifice from the retro-orbital venous plexus and used for chemical pathological measurements.
- Anaesthetic used for blood collection: no data
- Animals fasted: no data
- How many animals: all animals
- Parameters checked: hemoglobin concentration, hematocrit, erythrocyte count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet and reticulocyte counts, total and differential leukocyte counts, prothrombin time, and activated partial thromboplastin time.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood was collected before sacrifice from the retro-orbital venous plexus and used for chemical pathological measurements.
- Anaesthetic used for blood collection: no data
- Animals fasted: no data
- How many animals: all animals
- Parameters checked: urea nitrogen, glucose, total protein, albumin, globulin, bilirubin, sodium, potassium, calcium, chloride, inorganic phosphorus, aspartate and alanine aminotransferases, alkaline phosphate, lactate and sorbitol dehydrogenases, creatine kinase, and y-glutamyl transferase.
URINALYSIS: Yes
- Time schedule for collection of urine: Urine was collected over a 2 h interval from trays under the animal’s cage, and over 16 h from animals in metabolism cages.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data
- Parameters checked: Appearance, microscopy, pH, protein, ketones, bilirubin, occult blood, urobilinogen, glucose, creatinine, specific gravity, osmolality, and N-acetyl-ß-D-glucosaminidase (NAG) activity.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Before dosing, after the fifth dosing and before necropsy. Recovery animals were also evaluated the day following the cessation of dosing and prior to sacrifice.
- Dose groups that were examined: all groups
- Type of test: Irwing Screen, functional observation battery - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes. Necroscopic examination was conducted on all animals sacrificed by CO2 inhalation at the ends of the dosing and recovery periods to detect any indications of gross pathological change. Complete macroscopic postmortem examinations were conducted on all animals.
- The following organs were removed for weighing: brain, adrenal glands, liver, kidneys, ovaries, and testes.
HISTOPATHOLOGY: Yes. Histopathological evaluation of selected tissues (brain, kidneys, nerves, skin, spinal cord and testes) were performed on controls and high dose animals. Tissues and organs were removed, fixed in 10% neutral-buffered formalin, and then processed for light microscopic examination.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Dermal irritation:
- effects observed, treatment-related
- Description (incidence and severity):
- Local signs of irritation were barely perceptible erythema in a few of the low-dose animals. Most mid- and high-dose animals showed very slight to slight erythema. By Day 18, all high-dose recovery animals were free of skin irritation.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weight gains of the high-dose males and females were lower than for the controls over the treatment period. At the end of the dosing period (Day 12) high-dose males had mean body weights 7% lower than controls, and high-dose females 5% lower. Body weights for the mid- and low-dose groups were comparable to the controls. Gains during the recovery period were comparable for control and high-dose animals.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- effects observed, treatment-related
- Description (incidence and severity):
- The mean food consumption per bw. in all treated groups of males was 10 to 15% (p<0.01) higher than in controls from Day 5 until Day 10 but not dose-related. The effect was considered to be non-adverse.
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Treatment related histopathologic findings in the skin of the high-dose animals consisted of an occasional trace to mild inflammatory cell infiltrates in the dermis. The effect was considered adverse.
- Neuropathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Mild to moderate hyperkeratosis and acanthosis were observed in all animals of all dose groups at the treated skin site and acute inflammatory cell infiltration was noted in high dose-groups animals only. The effects were considered treatment-related and toxicologically relevant.
- Histopathological findings: neoplastic:
- not examined
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- systemic
- Effect level:
- 527 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effect observed
- Remarks on result:
- other: corresponding to 0.5 mL/kg bw/day
- Key result
- Dose descriptor:
- LOAEL
- Remarks:
- local
- Effect level:
- 527 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- dermal irritation
- histopathology: non-neoplastic
- Remarks on result:
- other: corresponding to 0.5 mL/kg bw/day
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- local
- Effect level:
- 210.8 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effect observed
- Remarks on result:
- other: corresponding to 0.2 mL/kg bw/day
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- Application of the test material to the skin of Sprague Dawley rats for a period of 9 days produced mild local skin reactions at 0.2 mL/kg bw/day (corresponding to 210.8 mg/kg bw/day) and mild to moderate local skin reactions at 0.5 mL/kg bw/day (corresponding to 527 mg/kg bw/day). The findings of the high dose group persisted until study Day 17. Based on these findings, a LOAEL for local toxicity of 527 mg/kg bw/day was derived and a NOAEL for local toxicity of 210.8 mg/kg bw/day. The NOAEL for systemic toxicity was 0.5 mL/kg bw/day (corresponding to 527 mg/kg bw/day).
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