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Administrative data

Description of key information

Among the existing valid studies following three studies were found to show the highest toxicity after oral, dermal and inhalativ application of isophorone: The acute toxicity in laboratory animals is low  to moderate with an oral LD50 (rat) of 1500 mg/kg bw (Günzel and Richter, Schering AG, 1968), a dermal LD50 (rabbit) of 1200 mg/kg bw (Dutertre-Catella, 1976) and an inhalative LC50 (rat, aerosol) of 7000 mg/m3 air (Esso Research, 1965).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment
Principles of method if other than guideline:
Method: Acute oral toxicity study in rats - single administration
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Breeder Voss
Sex:
male/female
Details on test animals and environmental conditions:
Study performed with animals of relatively low body weight:  Weight at study initiation: 80-115 g.
Route of administration:
oral: unspecified
Vehicle:
other: Emulsion 0.5 g carboxymethyl cellulose in 100 ml dist. water
Doses:
Doses: 0.5; 1.0; 1.25; 1.50; 1.75; 2.0; 2.5 g/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Post dose observation period: 13 days;
EXAMINATIONS:  gross examination of: coat of fur, skin, eye and conjunctiva, nose,  mouth, ear, anus, preputial opening, vulva, subcutaneous 
connective  tissue, abdominal cavity, pelvic cavity, peritoneum, esophagus, stomach,  small intestine, large intestine, mesenteric lymph nodes, liver,  
pancreas, spleen, kidneys, urinary bladder, seminal vesicle, prostate,  testicles, epididymis, ovary, uterus, vagina, thoracic cavity, pleura,  heart, lungs,trachea, thymus gland, cerebrum, middle ear, application  sites
Statistics:
STATISTICAL METHODS: Probit analysis
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 500 mg/kg bw
Remarks on result:
other: LD50 confidence limits: 1400-1800 mg/kg
Mortality:
MORTALITY: 
- Time of death: 1 hour to 3 days after dosing
- Number of deaths at each dose:  500 mg/kg:  0/10; 1000 mg/kg:  1/10; 1250 mg/kg: 1/10; 1500 mg/kg:  5/10; 1750 mg/kg:  7/10; 2000 mg/kg: 10/10; 2500 mg/kg:  8/10;
LD50 confidence limits: 1400-1800 mg/kg
Clinical signs:
> 1,000 mg/kg: general apathy, lateral position, irregular respiration
Body weight:
no data
Gross pathology:
NECROPSY FINDINGS:  Results of animals that died: - increased secretion in stomach and small intestine , - thickening and hermorrhagic erosions of 
proventiculus lining, - urine retention, - hyperemia of liver, - pulmonary emphysema, edema or hyperemia and - splenic enlargement
Other findings:
no data

no remarks



Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: other: EC Directive 67/548/EEC
Conclusions:
The LD50 value of isophorone in female and male rats was estimated to be 1500 mg/kg bw. Clinical signs like general apathy, lateral position and
irregular respiration occured at doses > 1000 mg/kg bw. The test animals died 1 hour to 3 days after feeding.
Executive summary:

The acute oral toxicity to rats was evaluated by standard acute method. The test item was administered to five female and five male rats orally. The animals were observed for mortality and any sub-lethal effects for 13 days after dosing. Isophorone was orally of moderate acute toxicity: The LD50 value in rats was estimated to be 1500 mg/kg bw. Clinical signs like general apathy, lateral position and irregular respiration occured at doses > 1000 mg/kg bw. Increased secretion in stomach and small intensine, thickening and hermorrhagic erosions of proventiculus lining, urine retention, hyperemia of liver, pulmonary emphysema, edema or hyperemia and splenic enlargement were found at necrospy.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 500 mg/kg bw
Quality of whole database:
The study is well documented, meets generally accepted scientific principles, and is acceptable for assessment. Klimisch score 2 (reliable with restrictions)

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1964-12-02 - 1965-01-15
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment
Principles of method if other than guideline:
Method: Acute Inhalation Toxicity: Whole body exposure; described in reference
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ORGANISMS: 
- Weight at study initiation: 200-225 grams
- Number of animals: 10
- Controls: yes
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
- Type of exposure: inhalation, aerosol

Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
4 h
Concentrations:
- Concentrations: 5; 7; 10; 17.8 mg/l
No. of animals per sex per dose:
10 males
Control animals:
yes
Details on study design:
EXAMINATIONS: 
- Observations for deaths and toxic signs: 30 min intervals
- post observation: 14 days, daily
- gross pathology: at end of post observation period: all surviving animals
Statistics:
no data
Sex:
male
Dose descriptor:
LC50
Effect level:
7 mg/L air
Exp. duration:
4 h
Remarks on result:
other: aerosol
Mortality:
- Number of deaths at each dose, time of death:     
5000 mg/m3: 4 hours = 0; 14 days = 1 death     
7000 mg/m3: 4 hours = 0; 14 days = 4 deaths
>= 10000 mg/m3: 4 hours = 10 deaths
LD50 confidence intervals: 5700-8600 mg/m3; slope function 1.27
Clinical signs:
other: 5000 mg/m3: none; higher doses: ataxia and coma, dyspnea, piloerection, depression,  decreased activity
Body weight:
no data
Gross pathology:
>= 10000 mg/m3:
- pulmonary congestion
Other findings:
no other findings

no remarks



 

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: other: EC Directive 67/548/EEC
Conclusions:
Under the conditions of this study, the acute toxicity of isophorone after inhalative exposure in male rats is very low : the LC50 value was determined to be 7 mg/l.
Executive summary:

Groups of 10 male rats were exposed to isophorone for 4 hours by whole body exposure. The observation period was 2 weeks. At a concentration of 5000 mg/m3 one animal died after the observation period of 14 days. At a concentration of 7000 mg/m3 40 % of the rats died . At very high concentrations of 10000 and 17800 mg/m3 all animals died within 4 hours. Clinical signs were ataxia and coma, dyspnea, piloerection, depression and decreased activity at doses >= 5000 mg/m3. At necropsy of the high exposure concentrations, congestion of the lungs were observed.

The LC50 value was determined to be 7 mg/l. Therefore, under the conditions of this study the acute toxicity of isophorone after inhalative exposure in rats is very low.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
7 000 mg/m³
Quality of whole database:
The study is well documented, meets generally accepted scientific principles, and is acceptable for assessment. Klimisch score 2 (reliable with restrictions)

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1975 - 1976-06-24
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Principles of method if other than guideline:
Method: based on Draize, modified method
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
TEST ORGANISMS: 
- Weight at study initiation: ca. 2.5 kg
- Controls: yes
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
ADMINISTRATION: 
- Occlusion: yes
- Vehicle: none
- Doses: 9.2; 13.85; 23; 23; 32.3 g   
absorbed: see Results
- Removal of test substance: after 24 hours, unresorbed quantity  determined
Duration of exposure:
24 hours
Doses:
600 mg/kg, 750 mg/kg, 1700 mg/kg, 2500 mg/kg and 2850 mg/kg
No. of animals per sex per dose:
6
Control animals:
yes
Details on study design:
EXAMINATIONS: mortality, clinical signs, skin reaction, 
14 days postexposure observation, autopsy
Statistics:
no data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 200 mg/kg bw
Mortality:
- Number of deaths and time at each dose: 
9.2 g dose(0.6 +/- 0.4 g/kg absorbed): none
13.85 g dose (0.75 +/- 0.5 g/kg): 2 after 6 and 12 hours, resp.
23 g dose (1.7 +/- 0.9 g/kg): 3 after 3, 4, and 5 hours, resp.
23 g dose (2.85 +/- 1.3 g/kg): 3 after 4, 6, and 48 hours, resp.
32.3 g dose (2.5 +/- 1 g/kg): 6 after 2.5, 4x4, 5 hours, resp.
Clinical signs:
CLINICAL SIGNS: accelerated breathing, prostration, narcosis, death (mostly within 6 hours) or recovery. The intensity of the erythema varied  
between animals. Recovery of the skin was not always complete within the  postexposure period. Doses at which clinical signs appeared are not  
defined.
Body weight:
no data
Gross pathology:
no data
Other findings:
- POTENTIAL TARGET ORGANS: none identified (except skin)
- SEX-SPECIFIC DIFFERENCES: none identified

no remarks


Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: other: EC Directive 67/548/EEC
Conclusions:
Under the conditions of this study, the acute toxicity of isophorone after dermal application to male and female rabbits is moderate: the LD50 value
was determined to be 1200 mg/kg bw.
Executive summary:

The acute dermal toxicity was evaluated by standard acute method. A single application of test item to the intact skin of six female and six male rabbits was made at dosage levels of 600 mg/kg bw to 2850 mg/kg bw for 24 hours.The animals were observed for mortality and any sub-lethal effects for 14 days after application. Isophorone was dermally of moderate acute toxicity. The LD50 value in rabbits was estimated to be 1200 mg/kg bw. Clinical signs were accelerated breathing, prostration and narcosis.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 200 mg/kg bw
Quality of whole database:
Test procedure of the study is in accordance with generally accepted scientific standards and described in sufficient detail. Klimisch score 1 (reliable without restriction).

Additional information

Oral

LD50 values of isophorone in rats were 1500 mg/kg bw (Günzel and Richter, Schering AG, 1968), 2100 mg/kg bw (Dutertre-Catella, 1976) and 3450 mg/kg (Esso Research, 1964). The LD50 in mice is 2200 mg/kg bw (Dutertre-Catella, 1976). Clinical signs like general apathy, depression, wearness (leading to coma) ptosis, lacrimation and laboured respiration occured at doses of >= 1450 mg/kg bw (Günzel and Richter, 1968; Dutertre-Catella, 1976; Esso Redearch 1965). At doses of >= 5000 mg/kg bw congestion of lungs, kidneys and pancreas (Esso Research, 1964) and liver lesions (Dutertre-Catella, 1976) were found at necropsy.

Inhalation

In acute inhalation studies isophorone showed very low acute toxicity with LC50 values sometimes exceeding the maximum tested concentrations (LC0 > 3500 mg/m3 and LC50 = 7000 mg/m3; both aerosol) in rats, mice and guinea pigs (Esso Reserach 1964; Esso Research, 1965). Mortality was observed in another study with rats but not guinea pigs at concentrations > 10570 mg/m3 (Smyth and Seaton, 1940). Clincal signs were nose and eye irritation, accelerated, laboured respiration, intestinal peristalsis and coma at dose

>= 5000 mg/m3 (Smyth and Seaton, 1940; Esso Research, 1965). At necropsy of the high exposure concentrations, congestion of the lungs and occasionally observed liver and stomach congestion was found (Esso Research 1965; Smyth and Seaton, 1940).

Dermal

In rats, the LD50 after dermal application was 1700 mg/kg bw (Günzel and Richter, Schering AG, 1968). For rabbits the LD50 values were 1200 mg/kg bw (Dutertre-Catella, 1976) and > 3160 mg/kg bw (Esso Research, 1964). Clinical signs were general apathy, later on occasionally coma, cachexia, tremor, lacrimation (Günzel and Richter, 1968) and depression, accelerated/laboured respiration, sprawling, prostration and narcosis at doses of 3160 mg/kg bw at least. At necropsy uniform thickening of the cutaneous stomach mucosa and pulmonary emphysema, edema or hyperemia was observed.


Justification for selection of acute toxicity – oral endpoint
Among the excisting valid studies the selected study was found to show the highest toxicity after oral application of isophorone.

Justification for selection of acute toxicity – inhalation endpoint
Among the excisting valid studies the selected study was found to show the highest toxicity after inhalative application of isophorone.

Justification for selection of acute toxicity – dermal endpoint
Among the excisting valid studies the selected study was found to show the highest toxicity after dermal application of isophorone.

Justification for classification or non-classification

According to the criteria of CLP Regulation 1272/2008 isophorone is classified as harmful in contact with skin and harmful if swallowed.

Based on the result of the acute inhalation studies (Esso Research, 1965; Esso Research; 1964) isophorone has a low acute toxicity if inhaled. Therefore, the test substance must not be classified.