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Administrative data

Description of key information

1) Repeated dose toxicity: oral - Pattys - page 2237-2240
2) Repeated dose toxicity: oral - Hine, 1958 - rats

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well-documented publication, which meets basic scientific principles
Reason / purpose:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
The test material was fed for 26 weeks in three concentrations (0.04, 0.2 and 1%) each to male Long-Evans rats. The rats (85 to 161 gm.) were randomized into 4 groups (3 test groups and one control group) of 10 rats each. The rats were observed daily and weighed weekly. Animals that died were subjected to necropsy when feasible. At the end of 26 weeks, the animals were killed and inspected for gross abnormalities and suitable tissues were taken for microscopic examination.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Long-Evans
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 85 - 161 g
Route of administration:
oral: feed
Vehicle:
other: mixed into a standard green feed
Details on oral exposure:
DIET PREPARATION
- Mixing appropriate amounts with (Type of food):
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
no details given
Duration of treatment / exposure:
continuously in diet
Frequency of treatment:
26 weeks
Remarks:
Doses / Concentrations:
0.04 %
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0.2 %
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
1 %
Basis:
nominal in diet
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Observations and examinations performed and frequency:
The rats were observed daily and weighed weekly.
Sacrifice and pathology:
Animals that died were subjected to necropsy when feasible. At the end of 26 weeks, the survivors were weighed and decapitated under light ether anesthesia. After careful gross inspection, suitable tissues were taken for microscopic examination. These included brain, thyroid, thymus, lung, heart, stomach, intestine, pancreas, liver, kidney, testis, and urinary bladder. Organ body weight ratios of the liver and kidneys were compared by means of the "Student" t-test, and a similar comparison was made of the percentage weight gains.
Other examinations:
no other examinations performed
Statistics:
Organ body weight ratios of the liver and kidneys were compared by means of the "Student" f-test, and a similar comparison was made of the percentage weight gains.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Significant depression of body weight gain
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
significant increase in kidney weights in groups fed 0.04% and 1.0% (P=<0.05 and 0.01, respectively).
Gross pathological findings:
no effects observed
Description (incidence and severity):
No significant lesions grossly or microscopically were seen in the tissues examined after any of the treatments.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No significant lesions grossly or microscopically were seen in the tissues examined after any of the treatments.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No significant lesions grossly or microscopically were seen in the tissues examined after any of the treatments.
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: retardation of body weight gain and significantly increased liver and kidney ratios in the animals of the highest dose group.
Critical effects observed:
not specified
Table 2 - Results of Twenty-Six-Week Feeding of Uncured Resins to Rats
    Organ/Body Weight Ratios Significant Weight
EPON % Fed Mortality
Ratio Xdver Kidney Lesions Gain
562 0.04 0/10 0 + 0 0
 0.2  1/10 0 0 0 0
1.0 0/10 + + 0
Note: + — significantly greater than control.
— = significantly less than control.
0 = not significantly different from control.

The toxicity of even the uncured EPONs is of extremely low order. With the exception of the experimental resin, diglycidyl resor-cinol, and EPON 562, both of which would be classified as "slightly toxic following peroral administration," the resins are either "practically nontoxic" or "relatively harmless" by this route of administration.

Conclusions:
No information is available concerning methods used, guidelines followed. However, as the data comes from a peer-reviewed handbook, the information is considered to be of the high quality (reliability Klimisch 2). Based on the study results, NOAEL is the dose based on 0.2% of test material in diet.
Executive summary:

The test material (EPON 562) was fed for 26 weeks in three concentrations (0.04, 0.2 and 1%) each to male Long-Evans rats. The test material was mixed into the standard green feed and held in stock containers from which the feed jars were filled twice a week. The rats (85 to 161 g) were randomized into 4 groups (3 test groups and one control group) of 10 rats each. The rats were observed daily and weighed weekly. Animals that died were subjected to necropsy when feasible. At the end of 26 weeks, the animals were killed and inspected for gross abnormalities and suitable tissues were taken for microscopic examination. These included brain, thyroid, thymus, lung, heart, stomach, intestine, pancreas, liver, kidney, testis, and urinary bladder. Organ body weight ratios of the liver and kidneys were compared by means of the "Student" f-test, and a similar comparison was made of the percentage weight gains. One animal fed 0.2% died but the mortality was considered to be unrelated to treatment. Rats fed 1% EPON 562 showed significant retardation of body weight gain. Liver and kidney weight ratios of animlas from this dose group were significantly greater than controls.There was a significant increase in kidney/body weight ratios in groups fed 0.04% and 1% test material (P=<0.05 and 0.01, respectively). However, the kidney/body weight ratios of animals fed 0.2% were unaffected (no dose response). No significant lesions grossly or microscopically were seen in the tissues examined. According to the authors, EPON 562 was assigned as slightly toxic following peroral administration. Based on this study results, NOAEL is the dose based on 0.2% of test material in diet.

To convert the concentration in % into a dose in mg/kg bw, default values for body weights of rats and their food intake per day were used (Table R. 8-17, ECHA guidance R.8). In the feeding study, rats body weight ranged from 85-161 g. Taking body weight of 0.35 g for females (as worst case) and the corresponding food intake of 17.5g/day, if extrapolating linearly, the food intake of rats which body weight is 85 g (the low limit of the range body weights determined in the study) would be 41.3 g. This is in good agreement with default value of 50 mg food/kg bw /day for female rats defined in the ECHA guidance document. Thus, 0.2% corresponds to100 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
The test result originates from an old publication which is well documented and meets basic scientific principles.There are a lot of data on structurally similar epoxides, therefore the overal database quality is high.

Additional information

There are no repeated dose toxicity studies available for the target substance 1,2,3-Propanetriol, glycidyl ethers (GE-100). Therefore, data on structurally similar analogues (epoxy resins) have been used to assess toxicity potential of GE-100 at repeated exposures.

Toxicity after repeated oral administration:

Data on Polyglycidyl Ether of Substituted Glycerin (EPON 562)

The test material Polyglycidyl ether of substituted glycerine (EPON 562) was fed for 26 weeks in three concentrations (0.04, 0.2 and 1%) each to male Long-Evans rats (Hine et al., 1958).The test material was mixed into the standard green feed and held in stock containers from which the feed jars were filled twice a week.The rats (85 to 161 g) were randomized into 4 groups (3 test groups and one control group) of 10 rats each. The rats were observed daily and weighed weekly. Animals that died were subjected to necropsy when feasible. At the end of 26 weeks, the animals were killed and inspected for gross abnormalities and suitable tissues were taken for microscopic examination. These included brain, thyroid, thymus, lung, heart, stomach, intestine, pancreas, liver, kidney, testis, and urinary bladder. Organ body weight ratios of the liver and kidneys were compared by means of the "Student" f-test, and a similar comparison was made of the percentage weight gains. One animal fed 0.2% died but the mortality was considered to be unrelated to treatment. Rats fed 1% EPON 562 showed significant retardation of body weight gain. Liver and kidney weight ratios of animals from this dose group were significantly greater than controls.There was a significant increase in kidney/body weight ratios in groups fed 0.04% and 1% test material (P 0.05 and 0.01, respectively). However, the kidney/body weight ratios of animals fed 0.2% were unaffected (no dose response). No significant lesions grossly or microscopically were seen in the tissues examined. According to the authors, EPON 562 was assigned as slightly toxic following peroral administration. Based on this study results, NOAEL is the dose based on 0.2% of test material in diet. 0.2 % corresponds to 100 mg/kg bw (conversion is presented in the section 7 of IUCLID file or section 5.11.2 of this CSR).

The "Patty´s Industrial Hygiene and Toxicology" also contains information about EPON 562 (Hine et al., 1981). There a study is mentioned, where the uncured resin was fed in the diet of rats for 26 weeks at a level of 0.04, 0.2 and 1 percent. No mortalities and no significant pathology occurred at any of the levels tested. At the highest level were, however, retardations of weight gains.

Toxicity after repeated inhalation administration:

Data on Polyglycidyl Ether of Substituted Glycerin (EPON 562)

The repeated toxicity of the read-across substance polyglycidyl ether of substituted glycerine (EPON 562) was investigated by Hine et al. (1958). The effect of inhalation of the EPON 562 was tested on rats (male Long Evans). Groups of 10 male rats were exposed five days a week for seven hours, for a total of 50 exposures, to air saturated with the vapour of EPON 562. Similarly, a group of 10 control rats was exposed to uncontaminated air. The animals were exposed in cylindrical steel chambers of 210-liter capacity at 20±1C. Air was substantially saturated with EPON 562 by passage through two fritted glass bubblers connected in series. The airflow rate was held constant at 15 litres per minute. A preliminary saturation period of about an hour insured greater than 95% saturation of the air prior to the exposure of animals. No analytical check was made of the concentration, since it was too low to permit accuracy of determination in either case. The rats were observed for signs of intoxication during and after each exposure. Individual weights were recorded weekly, and mean weight changes were graphed in the form of growth curves. At the end of the experimental period, the rats were decapitated under light ether anaesthesia, exsanguinated, and examined for gross changes. Representative tissues were taken for histologic study, and the organ/body weight ratios were determined on liver, lungs, and kidneys for statistical analysis. The series of 50 exposures to the saturated vapours of EPON 562 was singularly free of untoward effects. Aside from a very slight incrustation of the eyelids of some animals, with red-brown exudate, none of the rats showed any signs of toxicity or irritation attributable to the exposure. Two rats in the control group died between the third and fourth weeks. At necropsy of these animals, bronchopneumonia was found. No significant gross or microscopic lesions were found in the surviving animals. Analysis of variance showed no significant difference in mean weight gains or in organ/body weight ratios (P 0.05).

The Patty´s Industrial Hygiene and Toxicology contains information about repeated inhalation exposure to Polyglycidyl ether of substituted glycerine (EPON 562, Hine et al., 1981). There is mentioned, that the substance was administered torats (groups of 10 male rats), exposed for 7 hours a day, 5 days a week, for a total of 50 exposures to air saturated with the vapours of EPON resin 562. Aside from a slight encrustation of the eyelids in some animals, none of the rats showed any signs of toxicity or irritation attributable to the exposure. In addition, no effects on body weight gain and haematology were found.

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

The toxicity of glycidol and three related ethers - allyl glycidyl ether, isopropyl glycidyl ether and phenyl glycidyl ether - was evaluated experimentally in male rats (Hine et al., 1956). Repeated vapour exposures were carried out at four concentrations of allyl glycidyl ether (260, 400, 600 and 900 ppm), at 400 ppm of glycidol and isopropyl glycidyl ether, and at 100 ppm (approximate saturation) of phenyl glycidyl ether. Groups of 10 rats were given daily seven-hour exposures (except week-ends) to the test materials. Since high mortalities occurred in the animals exposed to 600 and 900 ppm of AGE, exposures to these concentrations were terminated (after 25 exposures). In a second experiment, the animals were exposed to only 260 ppm of AGE. Both control groups were exposed to uncontaminated air. The exposures were made in chambers of 200 litres capacity, and the air flow ranged from 11.7 to 22.0 litres per minute (3.5 to 6.6 air changes per hour). The constant-metering device delivered the liquids in measured amounts to the evaporator, where they were vaporized in the air entering the chamber. The measured amounts of test compounds were obtained by motor-driven syringe from a 10 mL Luer-Lok syringe into an evaporator through which metered air moved at a uniform rate. Nominal concentrations were calculated by the standard gas-concentration formula of Jacobs and were checked by determining the total quantity of material vaporized. The air in the chamber was allowed to equilibrate to a theoretical 95% to 99% of the desired concentration before the animals were introduced. Vapour concentrations were monitored by frequent analysis of air drawn from a sampling port and absorbed in a magnesium chloride and hydrochloric acid solution.

The rats were carefully observed at intervals during the exposure and were weighed weekly. At the end of the experimental period all survivors were decapitated under light ether anaesthesia, and blood was collected for haemoglobin determination (Sahli method). At necropsy the animals were carefully examined for gross pathologic changes, and the lungs, livers, and kidneys of all animals were freed of connective tissues and excess moisture and weighed for determination of organ/body weight ratios. Sections of these tissues were retained for histologic examination, and also tissues from alternate animals, as follows: brain, thyroid, thymus, heart, stomach, intestine, pancreas, adrenal, testis, and bladder. Organ/body weight ratios, percentage weight gain, and haemoglobin concentrations of the experimental animals were compared with those of the controls by the "Students" t-test.

On repeated vapour exposure glycidol, AGE, and IGE were not lethal at 400 ppm; PGE was not lethal at 100 ppm (near saturation). Mortality occurred in animals treated with 600 and 900 ppm AGE. At 600 and 900 ppm AGE and 400 ppm IGE pronounced irritation of the eyes and the respiratory tract were seen. Body weight gain was reduced in animals treated with 200 ppm GE, all concentrations of AGE and 400 ppm IGE. Only AGE and IGE caused any evidence of systemic toxicity at 400 ppm (ocular irritation and respiratory distress, at higher doses uni- or bilateral corneal opacity). IGE was not tested at other concentrations; however, AGE produced systemic toxicity, manifested by decreased weight gain at 260 ppm and high mortality at 600 and 900 ppm. There were no significant organ/body weight ratios, except for kidneys of animals exposed to AGE at 400 ppm. The increased stress on this organ may have appeared also at the higher concentrations, but the survival of only a few animals prevented statistical comparison. The increased kidney weight found for 400 ppm AGE is not readily explainable. Haemoglobin-concentration (in animals treated with 400 ppm AGE, 400 ppm IGE and 100 ppm PGE) appeared with all compounds except AGE (at 400 ppm even reduced Hb concentration), but there was no evidence of effect on red blood cell production in the bone marrow or extramedullary haemopoetic centres. Pneumonitis and haemorrhagic lungs were common microscopic findings in both experimental animals and controls.

Toxicity after repeated dermal administration:

Data on Polyglycidyl Ether of Substituted Glycerine (EPON 562)

The effect of multiple dermal application of EPON 562 was studied in Albino rabbits (Hine et al., 1958). Acetone was used as a negative control solution. These tests were set up according to the Latin square method: four to five spots on each animal's back were depilated, and a different compound applied to each. The compounds was diluted with acetone if it was not practical to apply them undiluted, and the amounts applied were adjusted to give approximately the same final quantity of each compound. The materials remained on the skin for both one-hour and seven-hour periods, in most cases, after which they were removed with acetone. Readings were made just prior to application. The degree of irritation was scored directly after the test material removal. The irritation reactions were scored according to the method of Draize (the maximum score for erythema and oedema is 8). Applications were made daily except week ends for a total of 20 days, or until death or eschar formation made further application impractical. The rabbits were weighed weekly, and after the final application, representative animals were killed to determine the systemic effects. Suitable tissues were taken for histologic study. Repeated application of EPON 562 caused definite signs of skin irritation. The applications which were left in place for seven hours did not produce a significantly greater score than the one-hour applications. Final mean scores with EPON 562 approached the maximum degree of irritation (7.6). In the group of animals that were exposed during 8 day to the test material, two of the four treated animlas died six days after the eighth (last) application. These animals showed dyspnoea, rales, and nasal discharge, and signs of bronchopneumonia were found in all at necropsy. According to the authors, the death of these animlas was primarily due to disability produced by the extreme irritation, rather than to any systemic effect of the resin.

The "Patty´s Industrial Hygiene and Toxicology" also contains information about 1,2,3 -propanetriol, glycidyl ethers (Hine et al., 1981). A study is mentioned, in which the uncured resin was administered to rabbits in 20 applications of 0.2 g total dose of the resin, which was allowed to remain for 1 or 7 hours. Draize score gave high scores of 8 in both cases, with a final mean of 7.6 to 7.8, indicating the compounds to be highly irritating on repeated exposures. In addition, another study is mentioned, where the uncured resin was administered to rabbits at 1 g cutaneously on five successive days. The animals developed severe subcutaneous haemorrhage and skin necrosis. 2 of 4 rabbits died. Moreover, there is a reference to a study, where the test substance was administered to rabbits at 1, 2 and 4 g subcutaneously for 20 days. The animals developed depression of bone marrow nucleated cell count only at the highest dose administered.

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

Glycidol and the five glycidyl ethers (diglycidyl ether, allyl-, n-butyl-, isopropyl-, and phenyl glycidyl ethers) were applied repeatedly to the backs of rabbits (Hine et al., 1956). The method employed in these tests was based on the method of Draize. The fur was closely clipped from the backs of albino rabbits at least 20 hours before the tests started. When it was necessary to clip regrowth of fur during the experiment, a period of at least 15 hours was allowed for healing of possible injury before further applications were made. Six rabbits were used for the series. The compounds were placed on the backs in a geometrically even pattern, and the locations were changed on successive rabbits. All applications consisted of 0.2 mL of undiluted test material, applied with a syringe and spread with a glass rod over an area approximately 1 cm. in diameter. The material was removed at the end of one hour by wiping with soft laboratory tissues followed by tissues moistened with acetone. Daily applications were made, excepting week ends, until the degree of eschar formation at the site made further applications undesirable, or the animals showed signs of systemic toxicity.

Three of six animals died after the seventh application, and the experiment was discontinued at that time. Maximum irritation had already occurred with three of the compounds, and the changes with the other changes had stabilized. None of the animals gained weight, and the weight of those that died, decreased significantly prior to death. Signs of systemic toxicity appeared 48 hours before death, and the surviving animals were below normal in appearance. In order of decreasing skin irritation the compounds were DGE (6.5), glycidol (5.7), PGE (5.2), AGE (3.8), BGE (3.3) and IGE (2.2). The compounds could be divided into two general groups: the three producing the greatest amount of irritation were significantly different from the other three. In all cases the erythema was greater than the oedema, and it usually appeared earlier. There was a steady progression in degree of irritation, with only a few instances of lessening irritation on subsequent applications. Maximum irritation appeared as early as the fourth day with glycidol, AGE, and PGE. Applications were discontinued in some rabbits after the fifth because of maximum escharotic effect.

On necropsy the skin treated with DGE and glycidol appeared to show somewhat more localised effect than the other compounds, but the penetration was greater.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
One study is available.

Justification for classification or non-classification

No systemic toxicity to organs was observed in the chronic feeding toxicity study in rats conducted with the nearest analogue polyglycidyl ether of substituted glycerine (Hine et al., 1958). No significant lesions grossly or microscopically were seen in the tissues examined. Excluding the increased kidney/body weight ratios seen in the lowest dose group, which were not dose-dependent, no further target organs were affected. The read-across substance did not cause other relevant significant toxicological effects after repeated oral, dermal or inhalation exposures. The effects seen in the inhalation studies were rather local effects of irritation to respiratory tract. Therefore, it does not meet the criteria for classification and will not require labelling for STOT-RE, according to the European regulation (EC) No. 1272/2008..