Registration Dossier

Administrative data

Description of key information

Studies for acute oral and acute dermal toxicity are available, performed according to OECD and GLP guidelines.

- The oral LD50 value of Ditetrahydrofurylpropane in Wistar rats was established to be between 300 and 2000 mg/kg body weight;

- The dermal LD50 of Ditetrahydrofurylpropane in Wistar rats was established to exceed 2000 mg/kg body weight.

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:
20 May - 11 June, 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: approx. 8 weeks old
- Weight at study initiation: First group 2000 mg/kg: 153-159 g
- Fasting period before study: Food was withheld overnight (for a maximum of 20 hours) prior to dosing until 3-4 hours after administration of the test substance.
- Housing: Group housing of 3 animals per cage in labeled Macrolon cages (MIV type) containing sterilized sawdust as bedding material and paper as cage-enrichment.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days before start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.3 – 21.3°C
- Humidity (%): 32 - 80%; Cleaning procedures in the room might have caused the temporary fluctuations above the optimal maximum level of 70% for relative humidity. Based on laboratory historical data, these fluctuations were considered not to have affected the study integrity.
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg (2 mL/kg) body weight and 300 mg/kg (0.3 mL/kg) body weight.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: according to the guideline
Doses:
2000 mg/kg and 300 mg/kg

No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality and viability: twice daily. Body weights: Days 1 (pre-administration), 8 and 15 and at death (if found dead after Day 1).
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15.
Statistics:
Not applicable, the method used is not intended to allow the calculation of a precise LD50 value
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
300 - 2 000 mg/kg bw
Based on:
test mat.
Mortality:
At 2000 mg/kg: first group 1/3, second group 2/3
At 300 mg/kg: first group 0/3, second group 0/3
The decedents and moribund animals were found between days 1 and 2.
Clinical signs:
2000 mg/kg: Lethargy, uncoordinated movements, flat and hunched posture, quick and slow breathing, shallow and labored respiration, piloerection, salivation, hypothermia, ptosis, scabs ear right.
300 mg/kg: Hunched posture, piloerection, quick breathing.
The surviving animals had recovered from the symptoms between Days 3 and 7.
Body weight:
The mean body weight gain shown by the surviving animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain. The incidence of slight body weight loss or reduced body weight gain in individual animals was considered not indicative of toxicity, based on the absence of any corroborative findings in these animals.
Gross pathology:
No test substance related abnormalities were found at macroscopic post mortem examination of the animals.
Incidental findings included cannibalism (missing ears) of one non-surviving animal.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The oral LD50 value of Ditetrahydrofurylpropane in Wistar rats was established to be within the range of 300-2000 mg/kg body weight. According to the OECD 423 test guideline the LD50 cut-off value was considered to be 2000 mg/kg body weight.
Executive summary:

In an acute oral toxicity study performed according to test guidelines OECD 423, Ditetrahydrofurylpropane was initially administered by oral gavage to three female Wistar rats at 2000 mg/kg body weight. In a stepwise procedure additional groups of females were dosed at 2000, and 300 mg/kg body weight. All animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed on the day of death or after terminal sacrifice (Day 15). Three (of the six) females dosed at 2000 mg/kg bw were found dead or sacrificed moribund between Days 1 and 2. No mortality occurred at 300 mg/kg bw. The surviving animals had recovered from the clinical symptoms between Days 3 and 7. The mean body weight gain shown by the surviving animals over the study period was considered to be normal. No substance related abnormalities were found at macroscopic post mortem examination of the animals. The oral LD50 value of Ditetrahydrofurylpropane in Wistar rats was established to be within the range of 300-2000 mg/kg body weight. According to the OECD 423 test guideline the LD50 cut-off value was considered to be 2000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
300 mg/kg bw
Quality of whole database:
One reliable study available (Klimisch 1).

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:
27 June - 11 July, 2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
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
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 8 weeks old
- Weight at study initiation: males 257-287 g; females 181-198 g
- Fasting period before study: not applicable
- Housing: Individually housed in labeled Macrolon cages (MIII type) containing sterilized sawdust as bedding material and paper as cage-enrichment.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days before start of treatment under laboratory conditions.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.4 - 22.7°C
- Humidity (%): 39 - 86%; Cleaning procedures in the room might have caused the temporary fluctuations above the optimal maximum level of 70% for relative humidity. Based on laboratory historical data, these fluctuations were considered not to have affected the study integrity.
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: approx. 10% of the total body surface, i.e. approx. 25 cm² for males and 18 cm² for females.
- % coverage: approx. 10%
- Type of wrap if used: The test substance was held in contact with the skin with a dressing, consisting of a surgical gauze patch (Surgy 1D)*, successively covered with aluminum foil and Coban elastic bandage*. A piece of Micropore tape* was additionally used for fixation of the bandages in females only.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the skin was cleaned of residual test substance using tap water.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg (2 ml/kg) body weight.
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality/viability twice daily; body weights on day 1 (pre-administration, 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15.

Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.

Clinical signs:
Hunched posture, piloerection, chromodacryorrhoea, ptosis, and/or lethargy were noted in four males and 2 females on Days 1 and/or 2.

Body weight:
The changes noted in body weight gain in males and females were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity.

Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.

Interpretation of results:
GHS criteria not met
Conclusions:
The dermal LD50 value of Ditetrahydrofurylpropane in Wistar rats was established to exceed 2000 mg/kg body weight.
Executive summary:

In an acute dermal toxicity study performed according to OECD 402 test guidelines, Ditetrahydrofurylpropane was administered to five Wistar rats of each sex by a single dermal application at 2000 mg/kg body weight for 24 hours. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15). No mortality occurred. Hunched posture, piloerection, chromodacryorrhoea, ptosis, and/or lethargy were noted in four males and 2 females on Days 1 and/or 2. The body weight gain during the observation period was within the range expected for rats used in this type of study. No abnormalities were found at macroscopic post mortem examination of the animals. The dermal LD50 value of Ditetrahydrofurylpropane in Wistar rats was established to exceed 2000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
One reliable study available (Klimisch 1).

Additional information

Oral:

In an acute oral toxicity study performed according to test guidelines OECD 423, Ditetrahydrofurylpropane was initially administered by oral gavage to three female Wistar rats at 2000 mg/kg body weight. In a stepwise procedure additional groups of females were dosed at 2000, and 300 mg/kg body weight. All animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed on the day of death or after terminal sacrifice (Day 15). Three (of the six) females dosed at 2000 mg/kg bw were found dead or sacrificed moribund between Days 1 and 2. No mortality occurred at 300 mg/kg bw. The surviving animals had recovered from the clinical symptoms between Days 3 and 7. The mean body weight gain shown by the surviving animals over the study period was considered to be normal. No substance related abnormalities were found at macroscopic post mortem examination of the animals. The oral LD50 value of Ditetrahydrofurylpropane in Wistar rats was established to be within the range of 300-2000 mg/kg body weight. According to the OECD 423 test guideline the LD50 cut-off value was considered to be 2000 mg/kg body weight. Therefore, the oral LD50 was set to be between 300 and 2000 mg/kg bw.

Dermal:

In an acute dermal toxicity study performed according to OECD 402 test guidelines, Ditetrahydrofurylpropane was administered to five Wistar rats of each sex by a single dermal application at 2000 mg/kg body weight for 24 hours. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15). No mortality occurred. Hunched posture, piloerection, chromodacryorrhoea, ptosis, and/or lethargy were noted in four males and 2 females on Days 1 and/or 2. The body weight gain during the observation period was within the range expected for rats used in this type of study. No abnormalities were found at macroscopic post mortem examination of the animals. The dermal LD50 value of Ditetrahydrofurylpropane in Wistar rats was established to exceed 2000 mg/kg body weight.

Justification for classification or non-classification

Based on the available data the substance is classified for Acute toxicity Category 4, H302 according to CLP Regulation (EC) 1272/2008. According to the same regulation, no classification for Acute dermal toxicity is required.