Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Acute Toxicity: Oral, rat, LD50 = 4200 mg/kg (RTECS)
Acute Toxicity: Oral, mouse, LD50 = 1300 mg/kg (RTECS)
Acute Toxicity: Oral, LD50 = 4200 mg/kg (rat), LD50 = 1300 (mouse) (Patty´s Industrial Hygiene and Toxicology)
Acute Toxicity: Acute study oral (gavage), rat (Long-Evans), male, similar to OECD 401: LD50 = 4200 mg/kg
Acute Toxicity: Acute study oral (gavage), mouse (Webster), male, similar to OECD 401: LD50 = 1300 mg/kg
Acute Toxicity: Inhalation, rat, 8h exposure, LC50 = 1100 ppm (RTECS)
Acute Toxicity: Inhalation, mouse, 4h exposure, LC50 = 1500 ppm (RTECS)
Acute Toxicity: Inhalation, LC50 = 1100 ppm (rat, 8h exposure), LC50 = 1500 ppm (mouse, 4h exposure) (Patty´s Industrial Hygiene and Toxicology)
Acute Toxicity: Acute inhalation study, whole body, 8h exposure, rat (Long-Evans), male, similar to OECD 403: LC50 = 1100 ppm ≙ 5.226 mg/L
Acute Toxicity: Acute inhalation study, whole body, 4h exposure, mouse (Webster), male, similar to OECD 403: LC50 = 1500 ppm ≙ 7.126 mg/L
Acute Toxicity: Dermal, rat, citation, LD50 > 2000 mg/kg bw
Acute Toxicity: Dermal, rabbit, LD50 = 9650 mg/kg (RTECS)
Acute Toxicity: Dermal, California Albino or New Zealand White rabbit, occlusive, similar to OECD 402, LD50 = 9650 mg/kg

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
other: publication
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Sufficiently documented publication, scientifically reasonable method, testing performed on the registered substance itself.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
not applicable
GLP compliance:
no
Remarks:
conducted prior to GLP implementation
Test type:
standard acute method
Limit test:
no
Species:
mouse
Strain:
other: Webster
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Commercial laboratory in Gilroy, Calif.
- Weight at study initiation: 16 - 22 g
- Housing: 5 - 6 mice per cage
- Diet (e.g. ad libitum): standard laboratory pellets
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 50%
Doses:
graded doses
No. of animals per sex per dose:
five or six
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 10 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, histopathology
Statistics:
LD50 values were calculated by the method of Litchfield and Wilcoxon (Litchfield JT, Wilcoxon F, Simplified Method of Evaluating Dose-Effect Experiments, J Pharmacol & Exper Therap, 96:99, 1949
Sex:
male
Dose descriptor:
LD50
Effect level:
1 300 mg/kg bw
Based on:
test mat.
95% CL:
950 - 1 750
Mortality:
no details given
Clinical signs:
Following intragastric administration, the substance depressed the central nervous system. Incoordination, ataxia, and depressed motor activity preceded frank depression, and the animals were usually comatose at the time of death.
Body weight:
no details given
Gross pathology:
no details given
Other findings:
- Other observations: Some species differences in intragastric toxicity were noted, see respective entry on rats, IPGE was somewhat less toxic to rats than to mice.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The studied was conducted scientifically reasonable with sufficient documentation similar to OECD 401, it was assessed with Klimisch 2. Hence, the results are sufficiently reliable to assess the acute toxicity of isopropyl glycidyl ether in mice. An oral LD50 was determined as 1300 mg/kg, which is between the boundary values of 300 and 2000 mg/kg for classification as acute toxic Cat. IV according to Regulation 1272/2008, hence, the substance should be classified as acute toxic Cat. IV and can be regarded as slightly toxic to mice.
Executive summary:

In an acute oral toxicity study (similar to OECD 401), groups of 5-6 male Webster mice were given a single oral dose of 2,3-epoxypropyl isopropyl ether in propylene glycol at graded doses and observed for 10 days.

Oral LD50Males =  1300 mg/kg bw (95% C.I. 950 - 1750)

 

2,3-epoxypropyl isopropyl etheris of slight Toxicity based on the LD50 in males and should be classified as acute toxic Cat. IV according to Regulation 1272/2008.

 

The substance depressed the central nervous system. Incoordination, ataxia, and depressed motor activity preceded frank depression, and the animals were usually comatose at the time of death.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 300 mg/kg bw
Quality of whole database:
There are two reliable Klimisch 2 studies on the substance itself available, supported by handbook or database entries. Both equivalent studies reveal that the substance maximally needs to be classified as acute toxic Cat. 4, and cover two different species and hence minimise uncertainties resulting from interspecies differences. The tonnage-driven data requirements for a REACh-Registration according to Annex VIII are fully met. The database is hence of high quality.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
other: publication
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Sufficiently documented publication, scientifically reasonable method, testing performed on the registered substance itself.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
not applicable
GLP compliance:
no
Remarks:
conducted prior to GLP implementation
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Long-Evans
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Commercial laboratory in Gilroy, Calif.
- Weight at study initiation: 110 - 140 g
- Housing: 6 rats per cage
- Diet (e.g. ad libitum): standard laboratory pellets
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
not specified
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The motor-driven syringe assembly previously described by Hine and associates (Hine et al., Toxicology and Safe Handling of CBP-55, A. M.A. Arch. Indust. Hyg. 7:118, 1953) delivered measured amounts of the test compound from a 10 ml. Luer-Lok syringe into an evaporator through which metered air moved, at a uniform rate. The air flow was set at approximately 3 to 11 liters per minute, depending on the concentration desired. Nominal concentrations were calculated by the standard gas-concentration formula of Jacobs (Jacobs MB, Analytical Chemistry of Industrial Poisons, Hazards, and Solvents, New York, Interscience Publishers, Inc., 1949: vol. 1.) and were checked by determining the total quantity of material vaporized.
- Exposure chamber volume: 19.5 L
- Temperature, humidity, pressure in air chamber: 30±1°C
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
8 h
Concentrations:
graded concentrations
No. of animals per sex per dose:
six
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 10 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, histopathology
Statistics:
LD50 values were calculated by the method of Litchfield and Wilcoxon (Litchfield JT, Wilcoxon F, Simplified Method of Evaluating Dose-Effect Experiments, J Pharmacol & Exper Therap, 96:99, 1949
Sex:
male
Dose descriptor:
LC50
Effect level:
1 100 ppm
Based on:
test mat.
95% CL:
790 - 1 530
Exp. duration:
8 h
Mortality:
no details given
Clinical signs:
other: Dyspnea, lacrimation, salivation, nasal discharge, and aerophagia were much severer following vapor exposure than intragastric administration (see respective study in oral section), while depression of the central nervous system appeared usually as a ter
Body weight:
no details given
Gross pathology:
The commonest pathologic finding was irritation of the lungs, and pneumonitis was confirmed by microscopic examination.
Discoloration of liver and kidneys was also noted frequently on gross examination, but tissue changes were not consistently confirmed microscopically. In occasional livers focal inflammatory cells were observed, and moderate congestion of the central zones.
Other findings:
IPGE would not be classified as more than "moderately toxic" on single exposure, rather "slightly toxic" or "practically nontoxic" according to the classification of Hodge and Sterner.
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The studied was conducted scientifically reasonable with sufficient documentation similar to OECD 403, it was assessed with Klimisch 2. Hence, the results are sufficiently reliable to assess the acute toxicity of isopropyl glycidyl ether in rats. An inhalatory LC50 was determined as 1100 ppm, which needs to be converted into the unit mg/L as the tested substance was a vapour and classification of vapours according to Regulation 1272/2008 is foreseen in the unit mg/L. Therefore, the formula (ppm * molecular weight) / 24450 L/mol = mg/L is used, resulting in (1100 ppm * 116.1583 g/mol) / 24450 L/mol= 5.226 mg/L. This value is between the boundary values of 2.0 and 10.0 mg/L for classification as acute toxic Cat. III according to Regulation 1272/2008. Hence, the substance should be classified as acute toxic Cat. III and can be regarded as moderately toxic to rats.
Executive summary:

In an acute inhalation toxicity study (similar to OECD 403), groups of 6 male Long-Evans rats were exposed by inhalation route to vapour of 2,3-epoxypropyl isopropyl ether for 8 hours to whole body at graded concentrations. Animals then were observed for 10 days.

 

LC50Males = 1100 (95% C.I. 790 - 1530)

 

2,3-epoxypropyl isopropyl ether is classified as acute toxic Cat.III. The commonest pathologic finding was irritation of the lungs, and pneumonitis was confirmed by microscopic examination.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
5 226 mg/m³
Quality of whole database:
There are two reliable Klimisch 2 studies on the substance itself available, supported by handbook or database entries. Both equivalent studies reveal consistently that the substance needs to be classified as acute toxic Cat. 3, and cover two different species and hence minimise uncertainties resulting from interspecies differences. The tonnage-driven data requirements for a REACh-Registration according to Annex VIII are fully met. The database is hence of high quality.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
other: publication
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Sufficiently documented publication, scientifically reasonable method, testing performed on the registered substance itself.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
not applicable
GLP compliance:
no
Remarks:
conducted prior to GLP implementation
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
other: California Albino or New Zealand White
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: rabbitry at Point Reyes, Calif., or Gilroy laboratory, Calif.
- Weight at study initiation: 2 - 2.5 kg
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: Healthy rabbits were clipped free of hair in a cylindrical swath from the shoulders to the hips 24 hours before use.
- Type of wrap if used: rubber sleeves; the rabbits were then wrapped in toweling to further minimize evaporation

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): graded doses, undiluted
Duration of exposure:
7 h
Doses:
graded doses
No. of animals per sex per dose:
no data
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 10 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, histopathology
Statistics:
LD50 values were calculated by the method of Weil (Weil CS: Tables for Convenient Calculation of Median Effective Dose and Instructions in Their Use, Biometrics 8:249, 1952)
Sex:
male
Dose descriptor:
LD50
Effect level:
9 650 mg/kg bw
Based on:
test mat.
95% CL:
4 300 - 21 600
Mortality:
no details given
Clinical signs:
Signs of pharmacology activity were minimal following percutaneous absorption. When death occurred, it was usually within 17 hours, although occasionally delayed as long as 5 days. Varying degrees of skin irritation were noted.
Body weight:
no details given
Gross pathology:
no details given
Interpretation of results:
GHS criteria not met
Conclusions:
The studied was conducted scientifically reasonable with sufficient documentation similar to OECD 402, it was assessed with Klimisch 2. Hence, the results are sufficiently reliable to assess the acute dermal toxicity of isopropyl glycidyl ether in rats. An dermal LD50 was determined as 9650 mg/kg, which is above the limit value of 2000 mg/kg for classification according to Regulation 1272/2008, hence, the substance does not need to be classified as acute toxic and can be regarded as relatively harmless.
Executive summary:

In an acute dermal toxicity study similar to OECD 402, male California Albino or New Zealand White rabbits were dermally exposed to unchanged Isopropyl glycidyl ether for 7 hours at graded doses.  Animals then were observed for 10 days.

 

Dermal LD50Males = 9650 mg/kg bw (95% C.I. 4300 - 21600)

 

Isopropyl glycidyl ether is of low Toxicity and does need to be classified as acute toxic according to Regulation 1272/2008.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
9 650 mg/kg bw
Quality of whole database:
There is one Klimisch 2 study available, clearly indicating with a dermal LC50 of 9650 mg/kg that Isopropyl glycidyl ether does not need to be classified as acute toxic, which is consistently supported by a read-across estimation (LD50 >2000 mg/kg). The tonnage-driven data requirements for a REACh-Registration according to Annex VIII are fully met. The database is hence of high quality.

Additional information

There are five entries on acute oral toxicity studies available on IPGE (Isopropylglycidether). Most relevant are the two acute studies on rats and mice retrieved from a publication by Hine et al., which are mostly conducted similar to the recent respective OECD guidelines, conducted prior to GLP implementation. The following oral LD50 were determined:

Rat (Long-Evans), male: LD50 = 4200 mg/kg

Mouse (Webster), male: LD50 = 1300 mg/kg

In both studies, following intragastric administration, the substance depressed the central nervous system in rats and mice. Incoordination, ataxia, and depressed motor activity preceded frank depression, and the animals were usually comatose at the time of death.

Although the mode of action appears to be similar in rats and mice, and can hence considered to be similar in humans, too, as no species-specific effect was noted, the effect level differs more than three-fold. Hence, the lower LD50 of 1300 mg/kg should be chosen for further risk assessment out of precautionary reasons. So, a classification as acute toxic cat. IV is triggered from the available studies.

 

Similarly, within the five available entries on acute toxicity studies, the two acute studies on rats and mice retrieved from a publication by Hine et al. are considered to be most relevant:

Rat (Long-Evans), male, whole body, 8h exposure: LC50 = 1100 ppm5.226 mg/L

Mouse (Webster), male, whole body, 4h exposure: LC50 = 1500 ppm7.126 mg/L

In both rats and mice, dyspnea, lacrimation, salivation, nasal discharge, and aerophagia were observed and found to be much severer following vapor exposure than intragastric administration (see respective study in oral section), while depression of the central nervous system appeared usually as a terminal event. In addition, the commonest pathologic finding was irritation of the lungs, and pneumonitis was confirmed by microscopic examination. Discoloration of liver and kidneys was also noted frequently on gross examination, but tissue changes were not consistently confirmed microscopically. In occasional livers focal inflammatory cells were observed, and moderate congestion of the central zones.

Also here, the mode of action appears to be similar in rats and mice, and can hence considered to be similar in humans, too. Both findings are rather similar and reveal consistently the need to classify IPGE as acute toxic Cat. 3. Due to the observed low interspecies differences, no indication is obvious that the results are not relevant for human risk assessment, too.

 

With regard to acute dermal toxicity, all three entries reveal consistently that IPGE is beyond categorisation. Most relevant again is here the study by Hine et al., in which the dermal LD50 in rabbits under occlusive coverage was determined as LD50 = 9650 mg/kg. Signs of pharmacology activity were minimal following percutaneous absorption. When death occurred, it was usually within 17 hours, although occasionally delayed as long as 5 days. Varying degrees of skin irritation were noted. The results does not trigger classification as acute toxic. This is not contradicting to the results determined by the oral or inhalative application route, as is could be easily explained by a hindered absorption through the skin. According to ECHA’s guidance R.7C, if the water solubility is above 10 g/L and the logPow is below 0, the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. The database entries and calculated values for the logPow of IPGE vary from 0.5 – 0.8, and the value of 19 g/L was considered most relevant for water solubility. Hence, it can be reasonably assumed that the dermal absorption of IPGE is hindered, leading to the conclusion that all results on acute toxicity are reasonable and consistent. So, they are sufficiently reliable for further risk assessment.

 

All required routes of application are covered, no data gaps were identified, as all data is considered sufficiently reliable. The relative magnitude of the results derived from the different routes of application are in the expected range when taking into account the sensitivity of the routes and the possible differences in absorption, making the results plausible and sufficient for human risk assessment. IPGE is to be considered slightly toxic. The tonnage-driven data requirements for a REACh-Registration according to Annex VIII are fully met.

Justification for classification or non-classification

From the two most relevant studies on acute oral toxicity, the LD50 of 1300 mg/kg (mice) was chosen over 4200 mg/kg (rats) due to precautionary reasons. This value is between the boundary values of 300 and 2000 mg/kg for classification as acute toxic Cat. IV according to Regulation 1272/2008, hence, the substance should be classified as acute toxic Cat. IV based on the findings via oral application and can be regarded as slightly toxic to mice.

Within the two most relevant inhalation studies in rats and mice, an inhalatory LC50 was determined as 1100 ppm resp. 1500 ppm, which needs to be converted into the unit mg/L as the tested substance was a vapour and classification of vapours according to Regulation 1272/2008 is foreseen in the unit mg/L. Therefore, the formula (ppm * molecular weight) / 24450 L/mol = mg/L is used, resulting in (1100 / 1500 ppm * 116.1583 g/mol) / 24450 L/mol= 5.226 / 7.126 mg/L. These values are between the boundary values of 2.0 and 10.0 mg/L for classification as acute toxic Cat. III according to Regulation 1272/2008. Hence, the substance should be classified as acute toxic Cat. III and can be regarded as moderately toxic to rats and mice.

The available dermal LD50 = 9650 mg/kg in rabbits is above the limit value of 2000 mg/kg according to Regulation 1272/2008, not triggering classification as acute toxic based on findings via the dermal application route.