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Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report date:
2017

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Reference substance name:
Reaction product of tetrahydro-2,5-dimethoxy furan, ethanol and water
EC Number:
947-436-6
Molecular formula:
not applicable for UVCB
IUPAC Name:
Reaction product of tetrahydro-2,5-dimethoxy furan, ethanol and water
Test material form:
liquid

Test animals

Species:
rat
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: Males 56 days; Females 63 days
- Weight at study initiation: Males 292.9-317.3g; Females 206.9-245.5g The body weight range did not exceed 10% of the mean weight for each sex at the time of selection.
- Fasting period before study: no
- Housing: MAKROLON cages type III plus (39 x 23 x 18 cm)
- Diet (e.g. ad libitum): Certified commercial diet (ssniff® R/M-H V1530) provided ad libitum
- Water (e.g. ad libitum): Tap water provided ad libitum
- Acclimation period: 9 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%): 55 ± 15%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The test item formulation was freshly prepared every day. The test item was diluted in water to the appropriate concentrations and administered at a constant volume of 2 mL/kg b.w./day. The control animals received the vehicle only at a constant volume of 2 mL/kg b.w./day. The amount of the test item was adjusted to the animal's current body weight daily.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
GC method: The methanol concentration of the mixture was used as lead substance.
Duration of treatment / exposure:
28 d
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Control
Dose / conc.:
30 mg/kg bw/day (nominal)
Remarks:
low dose
Dose / conc.:
90 mg/kg bw/day (nominal)
Remarks:
intermediate dose
Dose / conc.:
180 mg/kg bw/day (nominal)
Remarks:
high dose, reduced from 270 mg/kg bw/d on day 6 due to mortality
No. of animals per sex per dose:
5+5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
The dose levels were selected based on the results of the 14-day dose-range-finding study in rats.
The animals were treated orally for 14 days with daily dose levels of 100, 300 mg/kg b.w. and for 7 days with a daily dose level of 1000 mg/kg b.w.
Positive control:
No

Examinations

Observations and examinations performed and frequency:
According to guideline requirements.
Statistics:
The test item groups 2 - 4 were compared with the control group 1.
The following statistical methods were used:
- STUDENT's t-test: all numerical functional tests- Multiple t-test based on DUNNETT, C. W. New tables for multiple comparisons with a control Biometrics, 482 - 491 (September 1964): Body weight / food consumption / haematology / clinical biochemistry / relative and absolute organ weights, Numerical parameters of the neurological screening.
- Exact test of R. A. FISHER: Histopathology
These statistical procedures were used for all data.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No changes in behaviour, external appearance, or consistency of faeces were noted at any dose level. Further, all parameters of the detailed clinical observations were in the normal range at all time-points.
Mortality:
mortality observed, treatment-related
Description (incidence):
One of 10 male animals treated with 270 mg Reaction product of DMO-THF, water and ethanol/kg b.w./day by oral administration was found dead in the morning of test day 5.
Hence, the dose level was reduced to 180 mg/kg for both sexes as of test day 6. Four of 10 female animals treated with 270/180 mg Reaction product of DMO-THF, water and ethanol/kg b.w./day were found dead.
Animal no. 52 revealed a considerable body weight loss as of test day 8 by up to 36% compared to the body weight of test day 1. No premortal symptoms were noted for the remaining animals.
All deaths are regarded to be test item-related.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The male animals treated with 270/180 mg Reaction product of DMO-THF, water and ethanol/kg b.w./day revealed a slightly reduced mean body weight by up to 6% during the 28-day treatment period compared to the control group. Four of 10 animals (animal no. 41, 43, 47 and 48) were affected. The body weight gain was reduced accordingly. The mean body weight at necropsy was reduced by 10% compared to the control group. The female animals were not affected (except for the moribund animal no. 52).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The food intake of the male and female animals treated with 270/180 mg Reaction product of DMO-THF, water and ethanol/kg b.w./day was slightly reduced by 7% for the males and by 9% for the females in test week 1 and had normalised in test week 2.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
The visual appraisal of the drinking water consumption did not reveal any test item-related influence in any of the dose groups.
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
The functional observation tests revealed piloerection, an increased respiration rate and an increased startle response, i.e. restlessness, in the male and female rats treated with 270/180 mg Reaction product of DMO-THF,
water and ethanol/kg b.w./day at the end of the treatment period in test week 4.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
A reddened stomach mucosa with ulceration was noted for the deceased male animal (no. 45) treated with 270 mg Reaction product of DMO-THF, water and ethanol/kg b.w./day and a pale stomach for the deceased female animal (no. 57) treated with 270/180 mg Reaction product of DMO-THF, water and ethanol/kg b.w./day which could be associated with the test item in combination with microscopy.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Note: restricted to group 1 (control) and group 4 (high dose) and the kidneys and stomach of group 2 (low dose) and group 3 (high dose)
Histopathology assessment revealed test itemrelated changes in the glandular mucosa of the stomach (erosion/ulcer of the glandular stomach with neutrophilic inflammation in the glandular submucosa) and in the kidneys (tubule degeneration of the cortical tubules) of the male and female animals treated with 270/180 mg Reaction product of DMO-THF, water and ethanol/kg b.w./day.
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Details on results:
Recovery period
All changes noted for the male and female animals previously treated with 270/180 mg Reaction product of DMO-THF, water and ethanol/kg b.w./day had completely subsided at the end of the 18-day recovery period.
No premature deaths occurred and no signs of systemic toxicity were noted. No test itemrelated changes were noted at the neurological screening, for the body weight, body weight gain and body weight at autopsy, the food and drinking water consumption, the haematological and biochemical parameters, at ophthalmological and auditory examinations, at necropsy as well as for the organ weights at the end of the 18-day recovery period.
Histopathology of the remaining recovery animals (5 males and 3 females) did not reveal any test item-related changes after cessation of treatment.

Effect levels

Dose descriptor:
NOAEL
Effect level:
90 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
histopathology: non-neoplastic
mortality

Target system / organ toxicity

Critical effects observed:
yes
Lowest effective dose / conc.:
180 mg/kg bw/day (nominal)
System:
other: see above
Organ:
other: see above
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes

Applicant's summary and conclusion

Conclusions:
Under the present test conditions, the NOAEL was 90 mg/kg b.w./day
Executive summary:

The subacute toxicity of Reaction product of DMO-THF, water and ethanol, given daily by oral administration via gavage, was investigated in CD rats for 28 consecutive days and to assess the reversibility of any effects at the end of an 18-day recovery period. The rats were treated with 30, 90 or 270/180 mg Reaction product of DMO-THF, water and ethanol/kg b.w./day. The control animals received vehicle (tap water).