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Description of key information

LD50 dermal, rat > 2000 mg/kg

LD0 oral gavage, rat: 900 mg/kg bw

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
Study period:
From 2019-02-11 to 2019-04-10
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
other: OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
yes only 14 days of exposure (performed as a preliminary study to OECD 422)
Qualifier:
according to guideline
Guideline:
other: EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
yes
Remarks:
yes only 14 days of exposure (performed as a preliminary study to OECD 422)
GLP compliance:
no
Test type:
other: 14-day study
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Toxi-Coop Zrt. 1103 Budapest, Cserkesz u. 90
- Females (if applicable) nulliparous and non-pregnant: no data
- Age at study initiation: 49-54 days (males), 36-41 days (females)
- Weight at study initiation: 216-231 g for males, 132-147 g for females
- Fasting period before study: no data
- Housing: 5 animals of the same sex per cage (Type IV polypropylene/ polycarbonate) with Certified laboratory wood bedding
- Diet: ssniff® SM R/M-Z+H complete diet for rats and mice produced by ssniff Spezialdiäten GmbH, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3 °C
- Humidity: 30 - 70 %
- Air changes: Above 10 air-exchanges/ hour
- Photoperiod: Artificial light, from 6 a.m. to 6 p.m.

IN-LIFE DATES: from February 07, 2019 to February 25, 2019
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
Distilled water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Formulations were prepared not longer than for three days and stored at 5 ± 3 °C until use.

VEHICLE
- Concentration in vehicle: 20, 60 and 180/150 mg/mL
- Amount of vehicle: 5 mL kg/bw
- Lot/batch no. (if required): 181001
- Purity: distilled water
Doses:
0, 100, 300 and 750/900 (900, then reduced to 750 on Day 4) mg/kg bw/day during 14 days
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14-day exposure
- Frequency of observations and weighing:
> clinical sings: once a day, after treatment at approximately the same time
> body weight: on Day 0 (prior to study start) and twice weekly on Days 0, 3, 7, 10
and 13
- Necropsy of survivors performed: yes
- Other examinations performed: fodd consumption, haematology, clinical chemistry (see section 7.5.1 for details)
Key result
Sex:
male/female
Dose descriptor:
LD0
Effect level:
900 mg/kg bw
Based on:
test mat.
Remarks on result:
other:
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 900 mg/kg bw
Based on:
test mat.
Remarks on result:
other: no mortality observed after 14 days of exposure
Mortality:
There was no mortality in the control, 100, 300 or 900/750 mg/kg bw/day groups during the 14-day treatment period (male and female).
Clinical signs:
2,5-Dimethoxytetrahydrofuran caused clinical signs in slight or moderated degree at 900 mg/kg bw/day (decreased activity, squatting position, incoordination and prone position) and at 750mg/kg bw/day (decreased activity incoordination) in male and female animals.
The behavior and physical condition of all animals were normal in male and female animals in the control group and at 100 and 300 mg/kg bw/day during the course of 14-day administration.
At 900 mg/kg bw/day, slight or moderate decreased activity, squatting position, incoordination and prone position were detected in male (5/5) and female (5/5) animals 5-60 minutes after the administration on Days 0, 1 and 2.
After the dose reduction to 750 mg/kg bw/day, decreased activity and incoordination were noted for each animal during the remaining days of treatment period (5/5 male and 5/5 female).
All animals recovered – were normal – on Day 3 (washout day).
Body weight:
Significant body weight loss was detected in male and female animals administered with 900 mg/kg bw/day between Days 0 and 3.
The body weight development was undisturbed in male and female animals after the dose reduction to 750 mg/kg bw/day (between Days 4 and 13).
The body weight and body weight gain of the male and female animals were unaffected at 100 mg/kg bw/day and in female animals at 300 mg/kg bw/day throughout the entire observation period.
In the male animals at 300 mg/kg bw/day, the mean body weight gain was significantly lower than in the control group between Days 0 and 3 resulting in significantly lower mean body weight from Day 3 up to the termination of the study (-5 %, -7 %).
At 900 mg/kg bw/day, the body weight decreased in each male and female animal between Days 0 and 3.
After the dose reduction, the mean body weight gain exceeded the control value reaching statistical significance between Days 3 and 7 (male and female) and between Day 7-10 (female). However, the summarized body weight gain remained significantly lower than in the control group in male animals and was lower – no statistical significance – than in the control group in female animals.
As a consequence, the mean body weight was lower than in the control in male animals from Day 3 up to the end of the study (minus 22 % – minus 13 %) and in female animals on Days 3 and 7 (-16, -7%). The mean body weight of female animals at 900/750 mg/kg bw/day was similar to their control by the end of the treatment period (Day 13).
Gross pathology:
Gross necropsy did not reveal any macroscopic changes, which were related to treatment with test item in male or female animals (100, 300 or 900/750 mg/kg bw/day).
Renal pyelectasia – right side or both sides – was observed in the control group (1/5 male, 1/5 female), at 100 mg/kg bw/day (1/5 male), at 300 mg/kg bw/day (1/5 male and 1/5 female) and at 900/750 mg/kg bw/day (1/5 female).
Pyelectasia is a common finding in this strain of experimental rats. There were no inflammatory or other pathological signs related to this finding and therefore it was not attributed to test item treatment.
Other findings:
Haematology, Clinical biochemistry, Organ weight: see details in section 7.5.1

see section 7.5.1

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Under the condition of the present study 2,5-Dimethoxytetrahydrofuran does not caused mortality after 13 days oral administration at 900/750 mg/kg bw/day to male or female Han:WIST rats, but caused clinical signs, reduction in body weight development and food consumption.
rat oral gavage LD0 = 900 mg/kg bw
Executive summary:

In a subacute toxicity study 2,5-Dimethoxytetrahydrofuran was administered to 5 rats/sex/dose in water by gavage at dose levels of 0, 100, 300 and 900/750  mg/kg bw/day.

Detailed clinical observations were performed daily after the treatment. Body weights were recorded twice weekly in groups of control, 100 and 300 mg/kg bw/day and daily in high dose groups from Day 2. The food consumption was determined weekly to coincide with body weight measurements during the study. Clinical pathology (hematology, blood coagulation and clinical chemistry) and gross pathology examinations were conducted one day after the last treatment (on Day 14). Selected organs were weighed.

There was no mortality in control, 100, 300 or 900/750 mg/kg bw/day groups.

Test item related clinical signs were observed in slight or moderated degree at 900 mg/kg bw/day (decreased activity, squatting position, incoordination and prone position on Days 0, 1, 2) and at 750mg/kg bw/day (decreased activity incoordination, from Day 4 to Day 13) in male and female animals.

Significant body weight loss was detected in male and female animals administered with 900 mg/kg bw/day between Days 0 and 3. The body weight development was undisturbed in male and female animals after the dose reduction to 750 mg/kg bw/day – between Days 4 and 13.

The mean daily food consumption was reduced in male and female animals at 900/750 mg/kg bw/day during the first week of the study in full compliance with the body weight changes.

Necropsy examinations did not reveal any macroscopic changes, which were related to treatment with test item in male or female animals (100, 300 or 900/750 mg/kg bw/day).

The LD0 in rat by oral gavage is 900 mg/kg bw in this study.

No LD50 value can be calculated but as some adverse effects are observed at 900 mg/kg bw, 2,5-Dimethoxytetrahydrofuran is considered as classified as Acute Tox category 4 by oral route.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating dose
Value:
900 mg/kg bw
Quality of whole database:
Reliable OECD 407 study with a Klimisch rating of 2, useful for C&L classification.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

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
Study period:
From 2018-01-30 to 2018-03-26
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Toxi-Coop Zrt. 1103 Budapest, Cserkesz u. 90.
- Age at study initiation: 8 weeks old in range-finding study and 9 weeks old in
main study
- Weight at study initiation: in range-finding study (at starting): 211 - 219 g; in main study
(at starting): 212 - 216 g
- Fasting period before study: not specified
- Housing: during acclimatization (and after exposition of main study): 3 animals/cage
During the exposition: animals were housed individually. Cage type: Type III polypropylene/polycarbonate; (378x217x180 mm)
- Historical data: not specified
- Diet and water (e.g. ad libitum): Animals received ssniff® SM R/M-Z+H complete diet for rats and mice produced by ssniff Spezialdiäten GmbH, D-59494 Soest Germany and tap water from municipal supply, as for human consumption from bottle ad libitum.
- Acclimation period: 5 days in first step, 7 days in second step, 9 days in third step and 12 days in fourth step.
- Microbiological status when known : not specified
- Method of randomisation in assigning animals to test and control groups: not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): above 10 air exchanges/hour by central air-condition system.
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 a.m. to 6.00 p.m.

IN-LIFE DATES: From: February 08, 2018 To: March 07, 2018
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: back of the animals
- % coverage: approximately 10 % area of the total body surface
- Type of wrap if used: Sterile gauze pads were placed on the skin of rats. These gauzes were kept in contact with the skin by a patch with adhesive hypoallergenic plaster. The entire trunk of the animal was wrapped with semi occlusive plastic wrap for 24 hours.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): At the end of the exposure period, residual test item was removed, using water at body temperature.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw (main test)

VEHICLE not specified/not used
Duration of exposure:
24 hours
Doses:
At first, a range-finding study was performed using one animal. The initial dose was 200 mg/kg bw. The animal did not die, so further one animal was treated with 1000 mg/kg bw dose. The animal of second step did not die, so further one animal was treated with 2000 mg/kg bw dose. The animal of third step did not die, so further two animals were treated with same dose (2000 mg/kg bw). No animal died in the fourth step, too, so the test was finished, the stopping criteria of Annex 2 of OECD Guideline No. 402 (presented in Appendix VII-VIII) was met.
A period of at least 48 hours was allowed between the testing of each step in range-finding study and before main study.
No. of animals per sex per dose:
(range-finding study): 1 animal/dose
(main study): 1+2 animals
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Inspection for signs of morbidity and mortality were made twice daily at the beginning and end of the working day. Careful clinical observations were made at the following intervals: 30 minutes, 2h, 4h and 6 h after the treatment and once each day for 14 days thereafter for systemic toxic signs. Individual observations included skin and fur, eyes and mucous membranes, and also respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern as well. Particular attention was directed to the observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma as signs of animals being in the moribund state.The body weight was recorded on day 0 (shortly before the treatment), on day 7 and on day 15 with a precision of 1 g.
- Necropsy of survivors performed: yes At the end of the observation period all rats were sacrificed under isofluran anaesthesia (on Day 15).
- Other examinations performed: clinical signs, skin reactions, body weight, after examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs was observed, and any abnormality was recorded with details of its location, colour, shape and size.
Skin reactions: The treatment site was observed at 1, 24, 48 and 72 h after removal of test item using the Draize criteria. The skin of each animal in the main study was observed for the development of erythema and oedema and was rated.
Preliminary study:
Mortality:
No mortality occurred after the 24-hour dermal exposure to 2,5-Dimethoxytetrahydrofuran in female rats during the range-finding study. The initial dose was 200 mg/kg bw. The other doses were as 1000 mg/kg bw and 2000 mg/kg bw, respectively.
Clinical symptoms:
No behavioural changes or signs of systemic toxicity were noted during the study in all animals. No dermal irritation symptom was observed on the treatment site in all animals.
Body weights:
The body weight of all animals corresponded to their species and age throughout the study.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Remarks on result:
other: No death occurred after a single 2000 mg/kg bw dermal dose
Mortality:
There was no mortality in main study.
Clinical signs:
No behavioural changes or signs of systemic toxicity were noted during the study in all animals.
No dermal irritation symptom was observed on the treatment site in all animals.
Body weight:
The body weight of all animals corresponded to their species and age throughout the study.
Gross pathology:
All animals survived until the scheduled necropsy on Day 15.
Moderate hydrometra was found in female No.: 9548 and slight hydrometra was detected in animal No.: 9553 of 2000 mg/kg bw dose. The hydrometra is a physiological finding and connected to the cycle of the animal.
No pathological changes were found related to the effect of the test item during the macroscopic examination of animals.
Interpretation of results:
GHS criteria not met
Conclusions:
No death was observed in 2000 mg/kg bw dose in main study. No systemic or local clinical symptoms were observed on the day of the treatment and during the 14-day observation period, the general state and behaviour of experimental animals were normal.
The body weight development was undisturbed in all animals.
No pathological changes were found related to the effect of the test item during the macroscopic examination of the animals.
Under the experimental conditions applied, the GHS category of the test item 2,5-Dimethoxytetrahydrofuran is 5/Unclassified in female Crl:WI rats.
Executive summary:

The objective of the study was to assess the toxicity of test item 2,5-Dimethoxytetrahydrofuran when administered in a single dermal dose to rats, according to OECD 402 guideline and following GLP. The main study was performed on the basis of result of range-finding study. The doses were as follows in the range-finding study: 200, 1000 and 2000 mg/kg bw. There was no death in the range-finding study, so the dose was 2000 mg/kg bw in main study. The test item was applied in original form and left in contact with the skin for 24 hours, followed by a 14-day observation period. No death was observed in 2000 mg/kg bw dose in main study. No systemic or local clinical symptoms were observed on the day of the treatment and during the 14-day observation period, the general state and behaviour of experimental animals were normal.

The body weight development was undisturbed in all animals.

No pathological changes were found related to the effect of the test item during the macroscopic examination of the animals.

Under the experimental conditions applied, the GHS category of the test item 2,5-Dimethoxytetrahydrofuran is 5/Unclassified in female Crl:WI rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Reliable OECD 402 study done under GLP, with a Klimisch rating of 1.

Additional information

The acute toxicity of 2,5-Dimethoxytetrahydrofuran was tested in rats using the dermal route of administration. The key study is quoted as reliability 1 according to Klimisch criteria (OECD studies and performed in accordance with GLP).

No acute toxicity study by oral route is available, but a 14 -day repeated dose toxicity study is useful for the C&L assessment. It is quoted as reliability 2 according to Klimisch criteria (performed as preliminary study to OECD 422 assay)

Acute toxicity - dermal:

The objective of the study was to assess the toxicity of test item 2,5-Dimethoxytetrahydrofuran when administered in a single dermal dose to rats, according to OECD 402 guideline and following GLP. The main study was performed on the basis of result of range-finding study. The doses were as follows in the range-finding study: 200, 1000 and 2000 mg/kg bw. There was no death in the range-finding study, so the dose was 2000 mg/kg bw in main study. The test item was applied in original form and left in contact with the skin for 24 hours, followed by a 14-day observation period. No death was observed in 2000 mg/kg bw dose in main study. No systemic or local clinical symptoms were observed on the day of the treatment and during the 14-day observation period, the general state and behaviour of experimental animals were normal.

The body weight development was undisturbed in all animals.

No pathological changes were found related to the effect of the test item during the macroscopic examination of the animals.

LD50 dermal, rat > 2000 mg/kg

Acute toxicity - oral:

In a subacute toxicity study 2,5-Dimethoxytetrahydrofuran was administered to 5 rats/sex/dose in water by gavage at dose levels of 0, 100, 300 and 900/750  mg/kg bw/day.

Detailed clinical observations were performed daily after the treatment. Body weights were recorded twice weekly in groups of control, 100 and 300 mg/kg bw/day and daily in high dose groups from Day 2. The food consumption was determined weekly to coincide with body weight measurements during the study. Clinical pathology (hematology, blood coagulation and clinical chemistry) and gross pathology examinations were conducted one day after the last treatment (on Day 14). Selected organs were weighed.

There was no mortality in control, 100, 300 or 900/750 mg/kg bw/day groups.

Test item related clinical signs were observed in slight or moderated degree at 900 mg/kg bw/day (decreased activity, squatting position, incoordination and prone position on Days 0, 1, 2) and at 750mg/kg bw/day (decreased activity incoordination, from Day 4 to Day 13) in male and female animals.

Significant body weight loss was detected in male and female animals administered with 900 mg/kg bw/day between Days 0 and 3. The body weight development was undisturbed in male and female animals after the dose reduction to 750 mg/kg bw/day – between Days 4 and 13.

The mean daily food consumption was reduced in male and female animals at 900/750 mg/kg bw/day during the first week of the study in full compliance with the body weight changes.

Necropsy examinations did not reveal any macroscopic changes, which were related to treatment with test item in male or female animals (100, 300 or 900/750 mg/kg bw/day).

The LD0 in rat by oral gavage is 900 mg/kg bw in this study.

Justification for classification or non-classification

2,5-Dimethoxytetrahydrofuran does not induce mortality in the rat following a single exposure by dermal route up to a limit dose/concentration and thus should not to be classified for acute toxicity via the dermal route as defined by the criteria of the Annex I of the CLP regulation (1272/2008) or UN/GHS classification criteria.

By oral route, 2,5-Dimethoxytetrahydrofuran does not caused mortality after 13 days oral administration at 900/750 mg/kg bw/day to male or female Han:WIST rats, but caused clinical signs, reduction in body weight development and food consumption.

rat oral gavage LD0 = 900 mg/kg bw

No LD50 value can be calculated but as some adverse effects are observed at 900 mg/kg bw, 2,5-Dimethoxytetrahydrofuran is considered as classified as Acute Tox category 4 by oral route.

Acute exposure does not induce important systemic effect and thus 2,5-Dimethoxytetrahydrofuran should also not be classified as STOT SE according to UN/EU GHS classficiation criteria.