Registration Dossier
Registration Dossier
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EC number: 235-985-8 | CAS number: 13080-86-9
Toxicological information
Acute Toxicity: oral
Administrative data
- Endpoint:
- acute toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1985
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Remarks:
- / Basic data given.
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- acute toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- other information
- Study period:
- 1985
- Reliability:
- 4 (not assignable)
- Rationale for reliability incl. deficiencies:
- documentation insufficient for assessment
- Remarks:
- No information available about the tested concentration.
- 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:
- no guideline followed
- Principles of method if other than guideline:
- Inhalation of substantially saturated vapor, single exposure for 6 hours, static conditions 25 °C
- GLP compliance:
- no
- Test type:
- acute toxic class method
- Limit test:
- yes
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Albino
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: 200 - 300 g
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25 - Route of administration:
- inhalation: vapour
- Type of inhalation exposure:
- not specified
- Vehicle:
- not specified
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The vapour was produced by enclosing the test substance in a sealed animal chamber for 18 h (static conditions). Oxygen was added as needed in order to maintain a chamber oxygen content of approximatively 20%
- Exposure chamber volume: 120 L
- Temperature in air chamber: 25 °C - Analytical verification of test atmosphere concentrations:
- not specified
- Duration of exposure:
- 6 h
- Concentrations:
- substantially saturated vapor
- No. of animals per sex per dose:
- 5
- Control animals:
- no
- Details on study design:
- - Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Weighing was performed in the beginning and on Day 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight - Sex:
- male/female
- Dose descriptor:
- LC50
- Based on:
- test mat.
- Exp. duration:
- 6 h
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Mortality:
- No mortality was observed during the observation period.
- Clinical signs:
- other: No clinical signs were observed.
- Body weight:
- All animals showed normal body weight gains during the observation period. (in males: mean body weight gain of 68 g and 120 g after 7 and 14 days, respectively; in females: mean body weight gain of 18 g and 29 g after 7 and 14 days, respectively)
- Gross pathology:
- No gross pathologic findings were observed.
- Interpretation of results:
- study cannot be used for classification
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- acute toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1985
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Remarks:
- / Basic data given.
- 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 in 2017
- GLP compliance:
- no
- Test type:
- standard acute method
- Limit test:
- no
- Species:
- rabbit
- Strain:
- New Zealand White
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: 2 - 3 kg
- Housing: Rabbits were immobilized during 24 h contact period - Type of coverage:
- occlusive
- Vehicle:
- corn oil
- Details on dermal exposure:
- TEST SITE
- Type of wrap if used: The test material was retained under impervious sheeting on the clipped, intact skin of the trunk.
REMOVAL OF TEST SUBSTANCE
- Washing (if done): Excess fluid was removed to diminish ingestion.
- Time after start of exposure: 24 h
TEST MATERIAL
- Amount(s) applied: not reported
- For solids, paste formed: yes, test substance was moistened with corn oil - Duration of exposure:
- 24 h
- Doses:
- 4 and 8 g/kg bw
- No. of animals per sex per dose:
- 5
- Control animals:
- no
- Remarks:
- not required
- Details on study design:
- - Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations of the skin were performed at 1 h, on Day 7 and 14, animals were weighed on Day 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight - Key result
- Sex:
- male/female
- Dose descriptor:
- LD50
- Effect level:
- > 8 000 mg/kg bw
- Based on:
- test mat.
- Mortality:
- There was no mortality during the study period.
- Clinical signs:
- The high dose administration (8 g/kg bw) resulted in erythema (Day 1) in all 10 animals (female/males), edema (Day 7) in 2 males and 2 females. Desquamation was apparent on the dosed skin from Day 7 till Day 14 in 2 males and in all 5 females. Administration of the lower dose (4 g/kg bw) produced erythema (Day 1) and desquamation (Day 7 - 14) in all 10 animals (females/males).
- Body weight:
- The high dose administration (8 g/kg bw) resulted in emaciation (Day 7) in 2 males and 1 female, who recovered at Day 14, while in 1 female it was observed at Day 14. Administration of the lower dose (4 g/kg bw) had no impact on the body weight of any animal during the study period.
- Gross pathology:
- Gross pathologic examination revealed slightly mottled and dark red lungs in 2 males and enlarged kidneys and spleens in 2 females after administration of the high dose (8 g/kg bw), while administration of the lower dose (4 g/kg bw) produced no gross pathologic findings.
- Interpretation of results:
- other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008
- Conclusions:
- CLP: not classified
Table 1: Body weight changes
|
Dose |
Body weight change |
|
Day 7 |
Day 14 |
||
Male |
8000 |
-597 to -289 (-381) |
-430 to -182 (-294) |
4000 |
-566 to -130 (-352) |
-344 to -57 (-191) |
|
Female |
8000 |
-606 to -2819 (-370) |
-632 to -57 (-317) |
4000 |
-466 to -247 (-348) |
-264 to -32 (-158) |
|
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- skin irritation: in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1985
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Remarks:
- / Basic data given.
- 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 in 2015
- GLP compliance:
- no
- Species:
- rabbit
- Strain:
- New Zealand White
- Type of coverage:
- semiocclusive
- Preparation of test site:
- clipped
- Vehicle:
- other: The test substance was moistened with corn oil.
- Controls:
- not required
- Amount / concentration applied:
- TEST MATERIAL
- Amount(s) applied: 0.5 g - Duration of treatment / exposure:
- 4 h
- Observation period:
- 7 days
- Number of animals:
- 3 males/ 3 females
- Details on study design:
- TEST SITE
- Area of exposure: 2.45 x 2.45 cm² on dorsal skin
- Type of wrap if used: The dose is applied to the clipped, intact skin under a gauze patch and is loosely covered with impervious sheeting.
REMOVAL OF TEST SUBSTANCE
- Washing: Excess test substance was removed after contact.
- Time after start of exposure: 4 h
OBSERVATION TIME POINTS
1, 24, 48, 72 h and 7 days
SCORING SYSTEM:
- Method of calculation: Draize scoring system - Irritation parameter:
- erythema score
- Basis:
- mean
- Remarks:
- of 6 animals
- Time point:
- 24/48/72 h
- Score:
- 0
- Max. score:
- 4
- Reversibility:
- other: reversibility: not applicable
- Irritation parameter:
- edema score
- Basis:
- mean
- Remarks:
- of 6 animals
- Time point:
- 24/48/72 h
- Score:
- 0
- Max. score:
- 4
- Reversibility:
- other: reversibility: not applicable
- Irritant / corrosive response data:
- No skin reaction was observed at any of the test sites of the 6 animals throughout the observation period.
- Other effects:
- Mortality/Clinical signs:
No mortality or clinical signs of toxicity were observed until the end of the observation period.
Sample residue was observed on 1/6 rabbits at 5 h. - Interpretation of results:
- other: CLP/ EU GHS criteria not met, classification not required according to Regulation (EC) No 1272/2008
- Conclusions:
- CLP: not classified
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- eye irritation: in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1985
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Remarks:
- / Basic data given.
- 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 405 (Acute Eye Irritation / Corrosion)
- Version / remarks:
- adopted in 2017
- GLP compliance:
- no
- Species:
- rabbit
- Strain:
- New Zealand White
- Vehicle:
- unchanged (no vehicle)
- Controls:
- not required
- Amount / concentration applied:
- TEST MATERIAL
- Amount(s) applied: 0.1 g (approx. 0.1 mL) - Duration of treatment / exposure:
- single application without washing
- Observation period (in vivo):
- 7 days
Reading time points: 1, 4, 24, 48, 72 h and Day 7 - Number of animals or in vitro replicates:
- 3 males/ 3 females
- Details on study design:
- SCORING SYSTEM:
Cornea:
(A) Opacity - degree of density (most dense area taken for reading)
No opacity: 0
Scattered or diffuse area, iris details clearly visible: 1
Easily discernible translucent areas, iris details slightly obscured: 2
Opalescent areas, iris details not visible. pupil size barely discernible: 3
Opaque, iris invisible: 4
(A) Area of cornea involved
One-quarter or less, but not zero: 1
Greater than one-quarter, but less than half: 2
Greater than half, but less than three-quarter: 3
Greater than three-quarter, up to whole area: 4
Iris:
(A)
Normal: 0
Folds above normal, congestion, swelling, circumcorneal injection (any or all), iris still reacting to light: 1
No reaction to light. hemorrhage, gross destruction: 2
Conjunctivae:
(A)
Vessels normal: 0
Vessels definitely injected above normal: 1
Diffuse, deep crimson red, individual vessels not readily discernible: 2
Diffuse beefy red: 3
(B)
No chemosis: 0
Any swelling above normal (includes nicitating membrane): 1
Obvious swelling with partial eversion of lids: 2
Swelling with lids about half closed: 3
Swelling with lids about half closed to completely closed: 4
(C)
No discharge: 0
Any amount of discharge different from normal: 1
Discharge with moistening of the lid, and hairs adjacent to lids: 2
Discharge with considerable moistening around the eyes: 3
TOOL USED TO ASSESS SCORE: Fluorescein sodium solution (2%) was used to determine corneal injury before dosing and at readings after one day. - Irritation parameter:
- cornea opacity score
- Basis:
- mean
- Remarks:
- of 6 animals
- Time point:
- 24/48/72 h
- Score:
- 0
- Max. score:
- 4
- Reversibility:
- other: not applicable
- Irritation parameter:
- iris score
- Basis:
- mean
- Remarks:
- of 6 animals
- Time point:
- 24/48/72 h
- Score:
- 0
- Max. score:
- 2
- Reversibility:
- other: not applicable
- Irritation parameter:
- conjunctivae score
- Basis:
- mean
- Remarks:
- of 6 animals
- Time point:
- 24/48/72 h
- Score:
- 0.06
- Max. score:
- 3
- Reversibility:
- fully reversible within: 48 h
- Remarks on result:
- other: 1 female showed conjunctivae (redness) scored 1 at 24 h
- Irritation parameter:
- chemosis score
- Basis:
- mean
- Remarks:
- of 6 animals
- Time point:
- 24/48/72 h
- Score:
- 0
- Max. score:
- 4
- Reversibility:
- other: not applicable
- Irritant / corrosive response data:
- 1 h after the application the test substance produced iritis (scored 1) in 1/6 animals persisting until the 24 h reading timepoint and slight conjunctival irritation in 4/6 animals (redness and chemosis, scored 1). The redness was then observed in all 6 animals at the 4 h reading time point but was reversible in 5/6 animals within 24 h, while for 1/6 animals (female) this was reversible at 48 h.
Discharge was observed 1 h after application of the test substance in all 6 animals. This reaction was reversible in 1 and 5 animals at 4 h and 24 h, respectively.
No corneal effects were apparent in any animal and time point. - Interpretation of results:
- other: CLP/ EU GHS criteria not met, classification not required according to Regulation (EC) No 1272/2008
- Conclusions:
- CLP: not classified
Table 1: Individual scores of eye irritation
Rabbit # |
Time [h] |
Conjunctivae |
Iris |
Cornea |
|
Redness |
Chemosis (swelling) |
||||
1 (m) |
1 |
1 |
1 |
0 |
0 |
4 |
1 |
0 |
0 |
0 |
|
24 |
0 |
0 |
0 |
0 |
|
48 |
0 |
0 |
0 |
0 |
|
72 |
0 |
0 |
0 |
0 |
|
mean |
0 |
0 |
0 |
0 |
|
2 (m) |
1 |
1 |
1 |
0 |
0 |
4 |
1 |
0 |
0 |
0 |
|
24 |
0 |
0 |
0 |
0 |
|
48 |
0 |
0 |
0 |
0 |
|
72 |
0 |
0 |
0 |
0 |
|
mean |
0 |
0 |
0 |
0 |
|
3 (m) |
1 |
0 |
0 |
0 |
0 |
4 |
1 |
0 |
0 |
0 |
|
24 |
0 |
0 |
0 |
0 |
|
48 |
0 |
0 |
0 |
0 |
|
72 |
0 |
0 |
0 |
0 |
|
mean |
0 |
0 |
0 |
0 |
|
4 (f) |
1 |
0 |
0 |
0 |
0 |
4 |
1 |
0 |
0 |
0 |
|
24 |
0 |
0 |
0 |
0 |
|
48 |
0 |
0 |
0 |
0 |
|
72 |
0 |
0 |
0 |
0 |
|
mean |
0 |
0 |
0 |
0 |
|
5 (f) |
1 |
1 |
1 |
1 |
0 |
4 |
1 |
1 |
1 |
0 |
|
24 |
1 |
0 |
0 |
0 |
|
48 |
0 |
0 |
0 |
0 |
|
72 |
0 |
0 |
0 |
0 |
|
mean |
0.33 |
0 |
0 |
0 |
|
6 (f) |
1 |
1 |
1 |
0 |
0 |
4 |
1 |
0 |
0 |
0 |
|
24 |
0 |
0 |
0 |
0 |
|
48 |
0 |
0 |
0 |
0 |
|
72 |
0 |
0 |
0 |
0 |
|
mean |
0 |
0 |
0 |
0 |
|
Only the values from the reading time points 24, 48 and 72 h were used to calculate the mean values.
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 985
- Report date:
- 1985
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 401 (Acute Oral Toxicity)
- GLP compliance:
- no
- Test type:
- standard acute method
- Limit test:
- no
Test material
- Reference substance name:
- 4,4'-[isopropylidenebis(4,1-phenyleneoxy)]dianiline
- EC Number:
- 235-985-8
- EC Name:
- 4,4'-[isopropylidenebis(4,1-phenyleneoxy)]dianiline
- Cas Number:
- 13080-86-9
- Molecular formula:
- C27H26N2O2
- IUPAC Name:
- 4,4'-[isopropylidenebis(4,1-phenyleneoxy)]dianiline
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Albino
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation:
- Weight at study initiation: 200 - 300 g
- Fasting period before study: animals were fasted overnight
- Diet: approprtiate commercial diet, ad libitum
- Water: municipal water, ad libitum
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- VEHICLE
- Concentration in vehicle: 10% (w/v)
- Justification for choice of vehicle: The substance was not suspending in water - Doses:
- 125, 250, 500 and 1000 mg/kg bw (males)
125, 250 and 500 mg/kg bw (females) - No. of animals per sex per dose:
- 5
- Control animals:
- no
- Remarks:
- not required
- Details on study design:
- - Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Day 0, Day 7 and Day 14 (prior to sacrifice)
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathologic evaluation
Results and discussion
Effect levelsopen allclose all
- Key result
- Sex:
- female
- Dose descriptor:
- LD50
- Effect level:
- 308 mg/kg bw
- Based on:
- test mat.
- Remarks on result:
- other: LD50 values are calculated by the moving average method (Thompson 1947) and are based on a 14-day observation period.
- Key result
- Sex:
- male
- Dose descriptor:
- LD50
- Effect level:
- 406 mg/kg bw
- Based on:
- test mat.
- Remarks on result:
- other: LD50 values are calculated by the moving average method (Thompson 1947) and are based on a 14-day observation period.
- Mortality:
- females: 3/5 animals died on Day 5, 1/5 animals on Day 6 and 1/5 animals on Day 8 at a concentration of 500 mg/kg bw; 1/5 animals died on Day 5 at 250 mg/kg bw and no animal died at 125 mg/kg bw.
males: 1/5 animals died on Day 3, 1/5 animals on Day 4, 2/5 animals on Day 5 and 1/5 animals on Day 6 at a concentration of 1000 mg/kg bw; 1/5 animals died on Day 5, 1/5 animals on Day 8 and 1/5 animals on Day 14 at a concentration of 500 mg/kg bw; 1/5 animals died on Day 6 at 250 mg/kg bw and no animal died at 125 mg/kg bw. - Clinical signs:
- females: At a test substance concentration of 500 mg/kg/bw sluggishness, unkempt appearance, red crust on perinasal and periocular fur was observed at Day 4, swollen eyelids and kyphosis at Day 5. At a test substance concentration of 250 mg/kg/bw sluggishness, unkempt appearance, red crust on perinasal and periocular fur was observed at Day 3, emaciation and intermittent tremors in 1 animal at Day 7 and alopecia and unkempt appearance at Day 14. No clinical signs were observed at the lowest test substance concentration.
males: At a test substance concentration of 1000 mg/kg/bw sluggishness and yellow periurogenital discharge was observed at Day 1, unkempt appearance in 2 animals at Day 1, swollen eyelids (eyes partially closed), red perinasal and periocular discharge and kyphosis at Day 3, intermittent tremors and emaciation at Day 4. At a test substance concentration of 500 mg/kg/bw red perinasal crust was observed at Day 2, sluggishness, swollen eyelids, kyphosis and red periocular crust at Day 3, unkempt appearance and emaciation at Day 4, lacrimation in 2 animals at Day 5, intermittent tremors in 2 animals at Day 7 alopecia in 1 animal at Day 5. Recovery of 1 survivor at Day 9. At a test substance concentration of 250 mg/kg/bw red perinasal crust was observed at Day 2, sluggishness and swollen eyelids at Day 3, unkempt appearance and emaciation at Day 4. At a test substance concentration of 125 mg/kg bw unkempt appearance was observed in 2 animals at Day 5. Recovery was observed at Day 7. - Body weight:
- All animals showed normal body weight gains during the observation period.
- Gross pathology:
- females: Lungs mottled light and dark red at a test substance concentration of 500 mg/kg bw. At 250 mg/kg bw, 1/5 females (the one which died later) showed red encrustation of perinasal and periocular fur while in the other 4 animals nothing remarkable was observed. At 125 mg/kg bw no gross pathological abnormalities were observed.
males: Lungs mottled light and dark red at a test substance concentration of 1000 mg/kg bw. At 500 mg/kg bw lungs of 3/5 females (the ones which died later) were dark red and the thoracic and abdominal cavity of 1 animal was filled with brown liquid. In the other 2 animals, nothing remarkable was observed. At 250 mg/kg bw, 1/5 males (the one which died later) showed nothing remarkable, while the cervical lymph nodes of 2/5 animals were enlarged. At 125 mg/kg bw, the spleen of 1/5 animals was enlarged.
Any other information on results incl. tables
Table 1: Mortality and body weight changes
|
Dose |
Dead/ Dosed animals |
Days of death |
Body weight change |
|
Day 7 |
Day 14 |
||||
Male |
1000 |
5/5 |
3, 4, 5, 5, 6 |
- |
- |
500 |
3/5 |
5, 8, 14 |
-38 - 9 (-18) |
-2 - 42 (20) |
|
250 |
1/5 |
6 |
2 - 19 (8) |
61 - 92 (78) |
|
125 |
0/5 |
3, 4, 5, 5, 6 |
30 - 49 (38) |
87 - 120 (111) |
|
Female |
500 |
5/5 |
5, 5, 5, 6, 8 |
173 |
- |
250 |
1/5 |
5 |
2 - 19 (10) |
22 - 58 (38) |
|
125 |
0/5 |
- |
-10 - 33 (5) |
40 - 60 (47) |
|
Applicant's summary and conclusion
- Interpretation of results:
- other: CLP/ EU GHS criteria met, classification required according to Regulation (EC) No 1272/2008
- Conclusions:
- CLP: Acute oral toxicity, Cat. 4, H302
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