Registration Dossier

Administrative data

Description of key information

Acute toxicity of GE 100 is moderate via oral route and low via dermal route. Acute toxicity by inhalation can be ruled out. 

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: well documented GLP-guideline study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Remarks:
- only minor deviation (relative humidity sometimes outside of the target ranges specified in the protocol). This minor deviation was not considered to comprise the validity or integrity of the study.
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
Remarks:
- only minor deviation (relative humidity sometimes outside of the target ranges specified in the protocol). This minor deviation was not considered to comprise the validity or integrity of the study.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS - Sprague-Dawley ICO: OFA-SD (IOPS Caw)
- Source: Iffa Credo, L'Arbresle, France
- Age at study initiation: on the day of treatment, the animals were approximately 6 weeks old
- Weight at study initiation: mean body weight +/- standard deviation of 191 +/- 6 g for the males and 144 +/- 7 g for the females.
- Fasting period before study: overnight (approximately 18 hours, but had free access to water. Food was given back approximately 4 hours after administration of the test substance
- Housing: The animals were housed in polycarbonate cages (48 cm * 27 cm * 20 cm). Each cage contained four to seven animals of the same sex during the acclimatization period and five rats of the same sex during the treatment period. Each cage contained dust-free sawdust. Bacterial and chemical analyses of the sawdust, including the detection of possible contaminants (pesticides, heavy metals), are performed regularly by external laboratories.
- Diet (e.g. ad libitum): All animals had free access to A04C pelleted diet (UAR, Villemoisson-sur-Orge, France), except as noted above for fasting purposes. Each batch of food was analysed by the supplier for composition and contaminant levels.
- Water (e.g. ad libitum): Drinking water filtered by a FG Millipore membrane (0.22 micron) was provided at libitum. Bacteriological and chemical analyses of the water and diet, including the detection of possible contaminantes (pesticided, heavy metals and nitrosamines), are performed regularly by external laboratories.
No contaminants are known to be present in the diet, drinking water or bedding material at levels which may be expected to interfere with or prejudice the outcome of the study.
- Acclimation period: at least 5 days
- Identification. the animals were identified individually by earmarks of earmotches

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 2°C
- Humidity (%): 30 - 70 %
- Air changes (per hr): approximately 12 cycles/hours of filtered, non-recycled air.
- Photoperiod (hrs dark / hrs light): 12 h/ 12 h

The temperature and relative humidity were under continuous control and recording. The records were checked daily and retained. In addition to these daily checks, the housing conditions and corresponding instrumentation and equipment are verified and calibrated at regular intervals.
Route of administration:
oral: gavage
Vehicle:
other: unchanged for 2000 mg/kg bw, corn oil in the dose-levels 1415 mg/kg and 1000 mg/kg
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 141,5 mg/mL or 100 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: commonly used and well established
- Lot/batch no. (if required): 86H0059

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg
Doses:
2000 (undiluted), 1415 (diluted in corn oil), and 1000 mg/kg (diluted in corn oil)
No. of animals per sex per dose:
2000mg/kg dose-level: 5 males and females
1415mg/kg dose-level: 5 females
1000mg7Kg dose-level: 5 females
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
The animals were observed frequently during the hours following administration of the test substance, for detection of possible treatment-related clinical signs. Thereafter, observation of the animals was made at least once a day until day 15. Type, time of onset and duration of clinical signs were recorded for each animal individually. Time of death was recorded individually, in terms of the number of hours or days after dosing.
Body weight - the animals were weighed individually just before administration of the test substance on day 1 and then on days 8 to 15. Individual weights of animals found dead during the study were measured at necropsy when survival exceeded 24 hours and if no signs of "cannibalism" were present. The body weight gain of the treated animals was compared to that of CIT control animals wi9th the same initial body weight.
- Necropsy of survivors performed: yes
The animals found dead during the study were subjected to a macroscopic examination as soon as possible. On day 15, all surviving animals were killed by carbon dioxide asphyxiation and a macroscopic examination was performed.
After opening the thoracic and abdominal cavities, a macroscopic examination of the main organs (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organs with obvious abnormalities) was performed. In case of macroscopic lesions, organ samples were taken and preserved in 10 % buffered formalin. No microscopic examination was performed.
- Other examinations performed: clinical signs, body weight,organ weights
Statistics:
Evaluation of the toxicity of the test substance following a single oral administration in rats should include the relationship, in any, between the animals' exposure to the test substance and the incidence and severity of all abnormalities including behavioural and clinical abnormalities, macroscopic lesions, body weight changes,mortality and any other toxic effects.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 2 000 mg/kg bw
Based on:
act. ingr.
Mortality:
no animals died in the 1000 and 1415 mg/kg dose groups. 3 of 5 males and 2 of 5 females died in the 2000 mg/kg dose group.
Clinical signs:
At the 2000 mg/kg dose-level, hypoactivity or sedtion and piloerection were observed in all animals from day 1 up to day 3 at the latest; coma was also observed prior to death in one female. Recovery was complete in the surviving animals on day 2. At the 1415 mg/kg dose-level, hypoactivity and piloerection were noted in 3/5 females on day 1. At the 1000 mg/kg dose-level, hypoactivity was noted in all females on day 1.
Body weight:
The body weight gain of the surviving animals was not affected by treatment with the test substance.
Gross pathology:
macroscopic examinations of the main organs of the animlas revealed no apparent abnormalities
Table 1:Individual clinical signs and mortality
Dose Time Animals Mortality Clinical signs
(mg/kg)   Males Females    
1000 30 min   02-03 No Hypoactivity
01-04 -05 No None
1h-2h-4h 01-02-03-04-05 No Hypoactivity
D2 to D 15 01-02-03-04-05 No None
1415 30 min - 1 h   01-02-03-04-05 No None
2h 01-02-05 No Hypoactivity, piloerection
03-04 No None
4h 01-02-03-04-05 No None
D 2 to D 15 01-02-03-04-05 No None
2000 30 min - 1 h 01-02-03-04-05 01-02-03-04-05 No None
2h 01-02-03-04-05 01-02-03-04-05 No Sedation, piloerection
4h 02 Yes
01 No Piloerection, coma
01-03-04-05 02-03-04-05 No Hypoactivity, piloerection
6h 01 No Piloerection, coma
01-03-04-05 02-03-04-05 No Hypoactivity, piloerection
D2 (morning) 01 Yes
03-04 No Hypoactivity, piloerection
01 -05 02-03-04-05 No None
D2 (afternoon) 03-04 No Hypoactivity, piloerection
01-05 02-03-04-05 No None
D3 (morning) 03 03 Yes
04 No Hypoactivity
01-05 02-04-05 No None
D3 (afternoon) 04 No Hypoactivity
01-05 02-04-05 No None
D4 (morning) 04 Yes
01-05 02-04-05 No None
D > 4 (afternoon) to D 15 01-05 02-04-05 No None
min:minutes
h  :hour
D  :day

Table 2: Individual and mean body weight and weekly body weight change of treated rats (g) 
Dose Volume Sex Animals Days
mg/kg ml/kg 1 (1) 8 (1) 15 At death
1000 10 Female 01 131 38 169 21 190 -
02 136 35 171 23 194 -
03 149 48 197 41 238 -
04 136 42 178 43 221 -
05 141 29 170 22 192 -
M 139 38 177 30 207 -
SD 7 7 12 11 21 -
1415 10 Female 01 152 36 188 22 210 -
02 147 45 192 22 214 -
03 149 50 199 26 225 -
04 146 39 185 28 213 -
05 147 39 186 24 210 -
M 148 42 190 24 214 -
SD 2 6 6 3 6 -
2000 1.67 Male 01 183 59 242 66 308 -
02 188 -
03 192 174
04 200 -
05 194 72 266 60 326 -
M 191 66 254 63 317
SD 6 9 17 4 13
2000 1.67 Female 0! 156 -
02 149 42 191 27 218 -
03 148 147
04 140 35 175 21 196 -
05 140 31 171 25 196 -
M 347 36 179 24 203
SD 7 6 11 3 13  
(1)  -Body weight gain
M   -Mean
SD  -Standard Deviation
 - = not applicable
Animals found dead during the study not mentioned

Table 3: Individual macroscopic examinations at necropsy
Dose Time Animals Macroscopic abnormalities
mg/kg Males Females
1000 D15   01-02-03-04-05 None
1415 D15   01-02-03-04-05 None
2000 D1 02   No apparent abnormalities
D2 01 Advanced autolysis
D3 03 03 Advanced autolysis
D4 04 Cannibalized animal
D15 01-05 02-04-05 No apparent abnormalities
D: day
Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: other: EU-GHS
Conclusions:
LD50 is near 2000 mg/kg bw. C&L is required.
Executive summary:

The test substance was administered via oral gavage to groups of five male and/or female fasted Sprague-Dawley rats. In the first instance, the test substance was administered undiluted, at the dose of 2000 mg/kg (dose volume 1.67 ml/kg, taking into consideration that its specific gravity was 1.2. As 50 % mortality occurred in this limit test, the test substance was then prepared in corn oil and administered to other animals at lower doses (1415 mg/kg and 1000 mg/kg in corn oil (dose volume 10 ml/kg) to 5 females each). Clinical signs, mortality and body weight gain were checked for a period of up to 14 days following the single administration of the test substance. All animals were subjected to necropsy. At the 2000 mg/kg dose-level 3/5 males and 2/5 females died between days 1 and 4. Hypoactivity or sedation and piloerection were observed in all animals from day 1 up to day 3 at the latest, coma was observed prior to death in one female. Recovery was complete in the surviving animals on day 2. At the 1415 mg/kg dose-level, no mortality was observed. Hypoactivity and piloerection were noted in 3/5 females on day 1. At the 1000 mg/kg dose-level, no mortality was observed. Hypoactivity was noted in all females on day 1. The body weight gain of the surviving animals was not affected by treatment with the test substance. No apparent abnormalities were observed in all the animals at necropsy. In conclusion and under the experimental conditions, the oral LD50 of the test substance is near 2000 mg/kg. In accordance with ethic and scientific recommendations concerning the LD50, a more precise determination was not conducted. According to the classification criteria laid down in Commission Directive 93/21/EEC, concerning the potential toxicity by the oral route, the test substance should be assigned the symbol Xn, the indication of danger "Harmful" an the risk phrase R 22 " Harmful if swallowed".

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
Numerous studies have been perfomed with structurally similar chemicals (epoxides).

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: well documented GLP-guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS - Sprqgue-Dawley ICO:OFA-SD (IOPS Caw)
- reason for this choice: rodent species are generally accepted by regulatory authorities for this type of study
- Source: Iffa Credo, L'Arbresle, France
- Age at study initiation: on the day of treatment, the animals were approximately 8 weeks old
- Weight at study initiation: mean body weight */- standard deviation of 267 +/- 6 g forthe males and 233 +/- 8 g for females.
- Fasting period before study:
- Housing:
- Diet (e.g. ad libitum): All tha animals had free access to A04C pelleted diet. Each batch of food was analysed by the supplier for composition and contaminant levels.
- Water (e.g. ad libitum): Drinking water filtered by a FG Millipore membrane (0.22 micron) was provided ad libitum.
Bacteriological and chemical analyses of the water and diet, including the detection of possible contaminants pesticides, heavy metals and nitrosamines, are performed regularly by external laboratories.
No contaminants are known to be present in the diet, drinking water or bedding material at levels which may be expected to interfere with or prejudice the outcome of the study
- Acclimation period: at least 5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 2 °C
- Humidity (%):30 - 70 %
- Air changes (per hr): 12 cycles / hours of filtered, non-recylced air
- Photoperiod (hrs dark / hrs light): 12 h / 12 h
The temperature and relative humidity were under continuous control and recording. The records were checked daily and retained. In addition to these daily checks, the housing conditions and corresponding instrumentation and equipment are verified and calibrated at regular intervals. Duringthe acclimatization period, four to seven animals of the same sex were housed in polycarbonate cages (48 cm * 27 cm * 20 cm). During the treatment period, the animals were housed individually in polycarbonate cages (35,5 cm * 23.5 cm * 19.3 cm). Each acge contained dust-free sawdust. Bacteriological and chemical analyses ofthe sawdust, including the detection of possible contaminants (pesticides, heavy metals) are performed regularly by external laboratories.

Identification: the animals were identified individually by earmarks or earnotches
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure:
- % coverage:
- Type of wrap if used:

REMOVAL OF TEST SUBSTANCE
- Washing (if done):
- Time after start of exposure:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution):
- Constant volume or concentration used: yes/no
- For solids, paste formed: yes/no
Duration of exposure:
single 24 hour exposure
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 males / 5 females
Control animals:
yes, concurrent no treatment
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed frequently during the hours following administration of the test substance, for detection of possible treatment-related clinical signs. Thereafter, observations of the animals was made at least once a day until day 15. Type, time of onset and duration of clinical signs were recorded for each animal individually. Time of death was recorded individually, in terms of the number of hours or days after dosing.
The animals were weighed individually, just before administration of the test substance on day 1 and then on days 8 and 15. The body weight gain of the treated animals was compared to that of CIT control animals with the same initial body weight.
- Necropsy of survivors performed: yes
On day 15, all animals were killed by carbon dioxide asphyxiation and a macroscopic examination was performed. After opening the thoracic and abdominal cavities, a macroscopic examination of the main organs (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organs with obvious abnormalities was performed. In case of macroscopic lesions, organ samples were taken and preserved in 10% buffered formalin. No microscopic examination was performed.
- Other examinations performed: clinical signs, body weight
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Remarks on result:
other: No mortality occurred
Mortality:
No death occurred during the study
Clinical signs:
No clinical signs and no cutaneous reactions were observed during the study
Body weight:
One female did not gain weight during the first week of the study and another female lost weight during the second week of the study. The body weight gain of the other animals was not affected by treatment with the test substance.
Gross pathology:
Macroscopic examinations of the main organs of the animals revealed no apparent abnormalities.

Table 1: Individual clinical signs and mortality
Dose Time Animals Mortality Clinical signs
(mg/kg) Males Females
2000 30 min 01-02-03-04-05 01-02-03-04-05 No None
lh-2h-5h 
D 2 to D 15.
min:minutes
h  :hour
Table2:Cutaneous reactions
Dose Time Animals Cutaneous reactions
mg/kg Males Females
2000 D 2 to D15 01-02-03-04-05 01-02-03-04-05 None
D: day

Table 3: Individual and mean body weight and weekly body weight change of treated rats (g)
Dose Volume Sex Animals Days
mg/kg ml/kg 1 (1) 8 (8) 15
2000 1.67 Male 01 270 37 307 35 342
02 261 62 323 45 368
03 264 29 293 39 332
04 264 26 290 44 334
05 277 32 309 35 344
M 267 37 304 40 344
SD 6 14 13 5 14
2000 1.67 Female 01 239 0 239 25 264
02 221 26 247 23 270
03 241 31 272 -19 253
04 230 25 255 21 276
05 235 14 249 19 268
M 233 19 252 14 266
SD 8 12 12 I8 9
(1)  - Body weight gain
M   - Mean
SD  - Standard Deviation

Table 4: Individual macroscopic examinations at necropsy
Dose Time Animals Macroscopic abnormalities
mg/kg  Males Females
2000 D15 01-02-03-04-05 01-02-03-04-05 None
D: day
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the experimental conditions tests, the dermal LD50 ofthe test substance is higher than 2000 mg/kg in rats.
Executive summary:

The test substance (targert substance GE-100) was applied to the skin of one group of ten Sprague-Dawles rats( five males and five females). The application was performed with the undiluted test substance at the dose of 2000 mg/kg, taking into consideration that its specific gravity was 1.2 . The test site was then covered by a semi-occlusive dressing for 24 hours. Clinical signs, mortality and body weight gain were checked for a period of 14 days following the single application ofthe test substance. No death occurred at 2000 mg/kg. No clinical signs were observed during the study. One female did not gained weight during the first week of the study and another female lost weight during the second week of the study. The body weight gain of the other animals was not affected by treatment with the test substance. No cutaneous reactions were observed. No apparent abnormalities were observed at necropsy. In conclusion, under the experimental conditions, the dermal LD50 of the test substance is higher than 2000 mg/kg in rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Additional information

Acute toxicity - oral:

The test substance (target substance GE-100) was administered via oral gavage to groups of five male and/or female fasted Sprague-Dawley rats (Manciaux, 1999). In the first instance, the test substance was administered undiluted, at the dose of 2000 mg/kg (dose volume 1.67 mL/kg, taking into consideration that its specific gravity was 1.2. As 50 % mortality occurred in this limit test, the test substance was then prepared in corn oil and administered to other animals at lower doses (1415 mg/kg and 1000 mg/kg in corn oil (dose volume 10 mL/kg) to 5 females each). Clinical signs, mortality and body weight gain were checked for a period of up to 14 days following the single administration of the test substance. All animals were subjected to necropsy. At the 2000 mg/kg dose-level 3/5 males and 2/5 females died between days 1 and 4. Hypoactivity or sedation and piloerection were observed in all animals from day 1 up to day 3 at the latest, coma was observed prior to death in one female. Recovery was complete in the surviving animals on day 2. At the 1415 mg/kg dose-level, no mortality was observed. Hypoactivity and piloerection were noted in 3/5 females on day 1. At the 1000 mg/kg dose-level, no mortality was observed. Hypoactivity was noted in all females on day 1. The body weight gain of the surviving animals was not affected by treatment with the test substance. No apparent abnormalities were observed in all the animals at necropsy. In conclusion and under the experimental conditions, the oral LD50 of the test substance is near 2000 mg/kg.

The Handbook of Filler, Extenders, and Diluents also gives some information about 1,2,3 -propanetriol, glycidyl ethers (Ash, 2007). There is stated that the substance was administered to rats (route of exposure is not specified) and a LD50 value of 5000 mg/kg bw was established. No more details are given.

Data on Read Across substances:

Data on Polyglycidyl Ether of Substituted Glycerin (EPON 562)

The "Patty´s Industial Hygiene and Toxicology" contains information about Polyglycidyl Ether of Substituted Glycerin (EPON 562) (Hine et al., 1981). It is mentioned, that the substance, when administered orally to rats via intragastric administration at a dose of 5000 mg/kg bw, caused only depression and slight dyspnoea as ante mortem events of significance. In conclusion, systemic toxicity is low, the compound is practically nontoxic by ingestion and also percutaneous absorption. If death occurs, it is mainly due to depression of the respiratory centre and secondary shock. An LD50 value of >5000 mg/kg bw is given.

In mice, the substance caused after intragastric administration only depression and slight dyspnoea as ante mortem events of significance. If death occurs, it is mainly due to depression of the respiratory centre and secondary shock. An LD50 value of >1870 mg/kg bw is given(Hine et al., 1981).

In addition, data on its toxicity in rabbits is given. Rabbits showed after intragastric oral administration of the test substance the same signs as mentioned above and an LD50 value of >4010 mg/kg bw is given (Hine et al., 1981).

The acute toxicity of some epoxy resins was investigated by Hine et al. (1958). EPON 562 (Polyglycidyl Ether of Substituted Glycerine) was one of the tested epoxy resins. The test material was given intragastrically to rats (male Long-Evans), mice (male Swiss-Webster) and rabbits (male Albino) as a single administration). It was diluted with propylene glycol to ease the administration. Because of the large volume of the highest intragastric dose for rats, the suspension was given in two aliquots, three hours apart, to fasted animals. The animals were observed for the following 10 days, and those that died were subjected to necropsy. At the end of the observation period, the survivors were killed for necropsy, and sections of their tissues were preserved in 10% formalin for histologic examination. EPON 562 was more toxic than the other EPON resins. It produced deaths and clinical signs in animals. The toxicity in general decreased with the other resins with increasing molecular weight. The pharmacologic effects, even in lethal doses, were not outstanding. There was moderate depression, slight dyspnea, and in surviving animals loss of weight and diarrhoea. Also, animals that died within 48 hours had a blood-tinged nasal discharge. All compounds were considerably more toxic when administered intraperitoneally than when administered intragastrically, EPON 562 being approximately 5 to 10 times more toxic than the other EPON resins. The wide range in lethal doses which was observed after intragastric administration was not apparent, however, after intraperitoneal administration. The insolubility of the aromatic type of resins and their failure to penetrate the gastroenteric tract, made them less toxic than when administered intraperitoneally by a factor of 10. Gross pathology was nonspecific, and the chief effect was that of local irritation. There was no noticeable species variation among the rat, mouse, and rabbit. Central nervous depression was noted with all of the agents. An excitement period of a few minutes usually preceded the convulsive seizures. Neither gross nor microscopic examination indicated any significant lesions other than those associated with irritation, and there was no evidence of degenerative changes in any of the organs examined. According to the author, EPON 562 would be classified as "slightly toxic following peroral administration". The LD50 values for EPON 562 were: 5000 mg/kg bw (rats), 1870 mg/kg bw (mice) and 4010 mg/kg bw (rabbits).

In conclusion, EPON 562 was of a low order of toxicity.

Data on glycidol, allyl glycidyl-, n-butyl glycidyl-, isopropyl-, phenyl glycidyl ethers and diglycidyl ether

The toxicity of glycidol and five related ethers - allyl glycidyl ether, n-butyl glycidyl ether, diglycidyl ether, isopropyl glycidyl ether and phenyl glycidyl ether - was evaluated experimentally in male rats and mice (Hine, 1956). Animals were given graded doses of the seven compounds intragastrically by means of a ball-point needly and syringe. Glycidyl and diglycidyl ether (DGE) were administrered 10 % in propylene glycol; allyl glycidyl ether (AGE) and isopropyl glycidyl ether (IGE), 50 %; n-butyl glycidyl ether (BGE), 5 %, and phenyl glycidyl ether (PGE), undiluted. In all acute experiments the animals were held for a 10 day observation period after treatment, during which mortality records were kept and weight changes noted. Representative survivors were then killed for necropsy - mice and rats by decapitation under light ether anaesthesia and rabbits by air injection into an ear vein. Suitable tissues were taken for histologic examination from all animals killed and from those that died during laboratory hours. The predominant signs of toxicologic activity varied according to the route of administration: On intragastric administration, depression of the central nervous system was the most common effect. Incoordination, ataxia and depressed motor activity preceded frank depression was noted, and the animals were usually comatose at the time of death, in the case of BGE some agitation and excitement preceded the final depression. In animals which received glycidol and PGE and survived, a reversal of the depressant effect was noted, with increased degree of activity of the central nervous system. Hypersensitivity to sound, vibration of the facial muscles, and involuntary tremors were seen, especially with glycidol. Some of the rats which died of the latter compound exhibited terminal intermittent epileptiforme convulsions. Dyspnoea appeared in all animals given the compounds intragastrically, to some extent, and lacrimation was noted with glycidol and AGE. Some species differences in intragastric toxicity were noted. IGE and PGE were somewhat less toxic to rats than to mice. AGE was considerably less toxic to rats. The difference between the most toxic and the least toxic compounds was tenfold in mice and greater than this in rats. The commonest pathologic finding was irritation of the lungs, and pneumonitis was confirmed by microscopic examination. In the case of glycidol an inexplicable pulmonary emphysema was also detected. Discolouration of liver and kidney 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, following AGE, BGE, and IGE administration. On intraperitoneal administration, the obtained LD50 values of 1.14 and 0.70 g/kg for rats and mice, respectively, indicate only a slight increase in toxicity by this route, suggesting ready absorption from the gastroenteric tract after oral exposure.

While the compounds varied somewhat in toxicity according to the route of administration, none of the compounds would be classified as more than moderately toxic on single exposure; most of them were slightly toxic or practically nontoxic.

Similar to other common industrial chemicals, such as ammonia, acid gases, and acrolein, which possess good warning properties, the compounds offer relatively slight hazard from breathing of the vapours. Percutaneous absorption does not appear to offer any serious hazard in industrial use because of the low toxicity by this route. All the compounds produce skin irritation by repeated contact, and dermatitis may occur in humans exposed cutaneously. Some typical case histories exemplifying industrial exposure, are reported. The oral LD50 values were given for glycidol (LD50 rats: 850 mg/kg bw, LD50 mice: 450 mg/kg bw), for allyl glycidyl ether (LD50 rats: 1600 mg/kg bw, LD50 mice: 390 mg/kg bw ), for n-butyl glycidyl ether (LD50 rats: 2260 mg/kg bw, LD50 mice: 1530 mg/kg bw), for diglycidyl ether (LD50 rats: 450 mg/kg bw, LD50 mice: 170 mg/kg bw), for isopropyl glycidyl ether (LD50 rats: 4200 mg/kg bw, LD50 mice: 1300 mg/kg bw) and for phenylglycidyl ether (LD50 rats: 3850 mg/kg bw, LD50 mice: 1400 mg/kg bw).

Acute toxicity - inhalation:

Data on Read across substances:

Data on Polyglycidyl Ether of Substituted Glycerin (EPON 562)

The "Patty´s Industrial Hygiene and Toxicology" contains information about 1,2,3 -propanetriol, glycidyl ethers (Hine et al., 1981). There is mentioned, that the substance, when administered via inhalation (vapour) for 8 hours to rats, no mortality and no signs of toxicity occurred. In addition, there is mentioned, that the substance, when administered via inhalation (vapour) for 8 hours to mice, no mortality occurred and the only signs of toxicity were a slight eye irritation.

The acute toxicity of epoxy resins was investigated by Hine et al., (1958). The effect of inhalation of EPON 562 was tested in rats (male Long Evans) and mice (male Swiss Webster) by an eight-hour exposure. Air was saturated with EPON 562 at 20±2°C and at 30±1°C, by passage through the liquids in two fritted glass bubblers connected in series. The animals were observed for the following 10 days, and those that died were subjected to necropsy. At the end of the observation period, the survivors were killed for necropsy, and sections of their tissues were preserved in 10% formalin for histologic examination. The compound caused no deaths when rats were exposed for eight hours to saturated vapours. The toxicity of the derivative was slightly less than that of the parent compound. Gross pathology was nonspecific, and the chief effect was that of local irritation. There was no noticeable species variation among the rat and mouse.

In conlusion, the investigation of the toxicology of certain epoxy resins, a new type of condensation plastic, indicated that the epoxy resins are of a low order of toxicity.

Data on glycidol, allyl glycidyl-, n-butyl glycidyl-, isopropyl-, phenyl glycidyl ethers and diglycidyl ether

The toxicity of glycidol and five related ethers - allyl glycidyl ether, n-butyl glycidyl ether, diglycidyl ether, isopropyl glycidyl ether and phenyl glycidyl ether - was evaluated experimentally in male rats and mice (Hine et al., 1956). In vapour experiments graded concentrations of the compounds were used when death was produced with exposures to concentrated vapour. The term "saturated vapour" is not used, since it is the experience that the theoretical concentration at saturation is frequently not obtained. The concentrated vapours approached theoretical saturation, however, except with DGE, where, owing to a small volume of sample, only about 200 ppm were obtained. For the four hour period, groups of five or six mice (20-28 g) were exposed to graded concentrations of the vapours of glycidol, AGE, and IGE at 30 +/- 1 °C and to DGE at room temperature (25 +/- 1 °C) in a glass chamber of 19.5 litres capacity. The motor driven syringe assembly previously described by Hine et al. (1956) associates delivered measured amounts of the test compound from a 10 mL Luer-Lok syringe into an evaporator through which metered air flow was set at approximately 3 to 11 litres per minute, depending on the concentration desired. Nominal concentrations were calculated by the standard gas-concentration formula of Jacobs and were checked by determining the total quantity of material vapourised. Similar groups were exposed to concentrated vapours of PGE, and DGE. High concentration was obtained by bubbling air through a fritted glass disc immersed in the compound, which was held in a glass container. The rate of air flow was set at approximately 5 litres per minute. For the eight- hour period, groups of six rats (110-140 g) were exposed to graded concentrations of glycidol, AGE, BGE, and IGE, with temperatures and apparatus as described above. Groups of six rats were also exposed for eight hours to concentrated vapours of DGE, and PGE, using temperatures and apparatus as described above.

In all acute experiments the animals were held for a 10 day observation period after treatment, during which mortality records were kept and weight changes noted. Representative survivors were then killed for necropsy - mice and rats by decapitation under light ether anaesthesia. Suitable tissues were taken for histologic examination from all animals killed and from those that died during laboratory hours. The predominant signs of toxicological activity were hypoxia, aerophagia, dyspnoea, lacrimation, salivation and irritation of the pulmonary tract. Depression of the central nervous system appeared usually as a terminal event. Depression appeared early only with AGE and BGE. Delirium was again noted with BGE. Signs of frank stimulation were seen with glycidol but not with PGE, which was not toxic at the highest vapour concentration attainable (100 ppm). Corneal opacity resulted from eight-hour exposures to glycidol, AGE, and IGE. Death was usually the result of acute pulmonary oedema. Diglycidyl ether was by far the most toxic of the compounds to mice, with an LC50 of 30 ppm. However, it was completely nontoxic to rats at the highest level tested (200 ppm). Conversely, BGE was more toxic to rats than to mice. LC50 values for rats exposed for eight hours to glycidol, AGE, and IGE were much more uniform, with only about a two-fold difference at greatest, and there was no especial species difference. The commonest pathologic finding was irritation of the lungs, and pneumonitis was confirmed by microscopic examination. In the case of glycidol inexplicable pulmonary emphysema was also detected. Discolouration of liver and kidney 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, following AGE, BGE, and IGE administration.

While the compounds varied somewhat in toxicity according to the route of administration, none of the compounds would be classified as more than moderately toxic on single exposure; most of them were slightly toxic or practically nontoxic.

Similar to other common industrial chemicals, such as ammonia, acid gases, and acrolein, which possess good warning properties, the compounds offer relatively slight hazard from breathing of the vapours. The LC50 values were given for glycidol (LC50 rats: 580 ppm, LC50 mice: 450 ppm), for allyl glycidyl ether (LC50 rats: 670 ppm, LC50 mice: 270 ppm), for n-butyl glycidyl ether (LC50 rats: 1030 ppm, LC50 mice: >3500 ppm), for diglycidyl ether (LC50 rats: >200 ppm, LC50 mice: 30 ppm), for isopropyl glycidyl ether (LC50 rats: 1100 ppm, LC50 mice: 1500 ppm) and for phenylglycidyl ether (LC50 rats: >100 ppm, LC50 mice: >100 ppm).

Male Sprague Dawley rats were exposed for 4 hours to a vapour-aerosol mixture of phenylglycidyl ether (PGE), (Terrill, 1977). The test atmosphere was generated by syringe-driving the unheated liquid into a tube furnace. The furnace tube (2 in. i.d. x 24 in. length, stainless steel) was constructed in such a way that the wall temperature of the delivery tube and the purge nitrogen stream (10 litres/min) were the same temperature, 310°C. Nitrogen was required because of the design of the PGE industrial process. The nitrogen-PGE atmosphere was delivered directly to the exposure chamber. Chamber temperature was maintained below 32°C by cooling with ice packs and by dilution of concentrated PGE vapours with a room-temperature oxygen/air mixture. After the exposure the animals were observed for a 14 -day period, and the surviving animals were weighted. However, no histopathological examinations or clinical chemistry was performed. The only significant finding was patchy, bilateral, hair loss in both male and female rats exposed at the two highest levels. Loss of weight and severe irritation of the scrotum were observed in surviving rats during their 14 day recovery period. An approximate lethal concentration of 323 ppm was determined, which corresponds to an LC50 value of 1.98 mg/L.

Acute toxicity - dermal:

The test substance (target substance GE-100) was applied to the skin of one group of ten Sprague-Dawley rats( five males and five females). The application was performed with the undiluted test substance at the dose of 2000 mg/kg, taking into consideration that its specific gravity was 1.2 . The test site was then covered by a semi-occlusive dressing for 24 hours. Clinical signs, mortality and body weight gain were checked for a period of 14 days following the single application ofthe test substance. No death occurred at 2000 mg/kg. No clinical signs were observed during the study. One female did not gained weight during the first week of the study and another female lost weight during the second week of the study. The body weight gain of the other animals was not affected by treatment with the test substance. No cutaneous reactions were observed. No apparent abnormalities were observed at necropsy. In conclusion, under the experimental conditions, the dermal LD50 of the test substance is higher than 2000 mg/kg in rats.

Data on Read across substances:

Data on Polyglycidyl Ether of Substituted Glycerin (EPON 562)

The "Patty´s Industrial Hygiene and Toxicology" contains information about 1,2,3 -propanetriol, glycidyl ethers (Hine et al., 1981). It is mentioned, that the substance, when administered dermally to rabbits, an LD50 of > 14.4 mL/kg bw could be determined.

In conclusion, systemic toxicity is low; the compound is practically nontoxic by ingestion and also percutaneous absorption. If death occurs, it is mainly due to depression of the respiratory centre and secondary shock.

Moreover the substance was reported to cause no deaths, when administered at a dose of 12 g/kg bw percutaneous for 2 hours. However, severe local irritation was noted in the animals treated this way.

The acute toxicity of the epoxy resin EPON 562 was investigated by Hine et al.(1958). Since it appeared possible that EPON 562, one of the most fluid resins, might be absorbed through the skin, 12 g/kg was applied to the clipped backs of rabbits (male Albino) under a rubber sleeve. The rabbits were wrapped in toweling for several hours, then released, examined, and returned to their cages for further observation. The animals were observed for the following 10 days, and those that died were subjected to necropsy. At the end of the observation period, the survivors were killed for necropsy, and sections of their tissues were preserved in 10% formalin for histologic examination. The cutaneous application of EPON 562 caused no deaths in rabbits, even at the high dose used, although their skins showed large areas of subcutaneous haemorrhage and necrosis.

In conlusion the investigation of the toxicology of certain epoxy resins, a new type of condensation plastic, indicated that the epoxy resins are of a low order of toxicity.

Data on glycidol, allyl glycidyl-, n-butyl glycidyl-, isopropyl-, phenyl glycidyl ethers and diglycidyl ether

The toxicity of glycidol and five related ethers - allyl glycidyl ether (DGE), n-butyl glycidyl ether, diglycidyl ether, isopropyl glycidyl ether and phenyl glycidyl ether (PGE) - was evaluated experimentally in male California Albino or New Zealand White rabbits (Hine et al., 1956). Healthy rabbits (2.0 to 2.5 kg) were clipped free of hair in a cylindrical swath from the shoulders to the hips 24 hours before use. The undiluted compounds, in graded doses, were introduced under rubber sleeves; the rabbits were then wrapped in towelling to further minimise evaporation and held in a multiple rabbit holder for seven hours. In all acute experiments the animals were held for a 10 day observation period after treatment, during which mortality records were kept and weight changes noted. Representative survivors were then killed for necropsy by air injection into an ear vein. Suitable tissues were taken for histologic examination from all animals killed and from those that died during laboratory hours. Surprisingly, signs of pharmacology activity were minimal following percutaneous absorption (comparing to those after intragastrical administration, see above). Depression was noted only with DGE and PGE. When death occurred, it was usually within 17 hours, although occasionally delayed as long as 5 days. Varying degrees of skin irritation were noted, most pronounced with DGE. While the compounds varied somewhat in toxicity according to the route of administration, none of the compounds would be classified as more than moderately toxic on single exposure; most of them were slightly toxic or practically nontoxic.

Similar to other common industrial chemicals, such as ammonia, acid gases, and acrolein, which possess good warning properties, the compounds offer relatively slight hazard from breathing of the vapours. Percutaneous absorption does not appear to offer any serious hazard in industrial use because of the low toxicity by this route. All the compounds produce skin irritation on repeated contact, and dermatitis may occur in personnel exposed cutaneously. Some typical case histories exemplifying industrial exposure are reported. The dermal LD50 values were given for glycidol (LD50 rabbits: 1980 mg/kg bw), for allyl glycidyl ether (LD50 rabbits: 2550 mg/kg bw), for n-butyl glycidyl ether (LD50 rabbits: 4930 mg/kg bw), for diglycidyl ether (LD50 rabbits: 1500 mg/kg bw), for isopropyl glycidyl ether (LD50 rabbits: 9650 mg/kg bw) and for phenylglycidyl ether (LD50 rats: 2990 mg/kg bw).


Justification for selection of acute toxicity – oral endpoint
The most reliable study available conducted with the target substance.

Justification for classification or non-classification

Acute oral toxicity:

Due to the deaths and effects seen at 2000 mg/kg bw in treated animals, the test material meets the criteria for classification and will require labelling for oral toxicity as Cat 4 (warning, H 302: harmful if swallowed) in accordance with European regulation (EC) No. 1272/2008.

Acute inhalation toxicity:

In accordance with European regulation (EC) No. 1272/2008, the target substance does not need to be classified and labelled for acute toxicity by inhalation since there is no respiration hazard (very low vapour pressure).

Acute dermal toxicity:

The test material does not meet the criteria for classification and will not require labelling for dermal toxicity in accordance with European regulation (EC) No. 1272/2008.