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Toxicological information

Repeated dose toxicity: oral

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Administrative data

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
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
The Toxicology of Epoxy Resins
Author:
Hine, C.H., Kodama, J.K., Anderson, H.H., Simonson, D.W., Wellington, J.S.
Year:
1958
Bibliographic source:
AMA archive s of industrial health / American Medical Association, 17, p. 129-144

Materials and methods

Test guideline
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

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Long-Evans
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 85 - 161 g

Administration / exposure

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
Doses / concentrationsopen allclose all
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

Examinations

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.

Results and discussion

Results of examinations

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.

Effect levels

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.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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.