2,4-dimethyl-4-phenyltetrahydrofuran

Endpoint summary

Description of key information

Oral

Oral LD50 = 3980 mg/kg bw (eq. to OECD 401, K, Rel.2, Standard acute Method)

Oral LD50 < 4960 mg/kg bw (eq. to OECD 401, S, Rel.4, Standard acute Method)

Inhalation

Waiver (exposure considerations)

Dermal

Waiver (study scientifically not necessary)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

No guideline available in the report as the test has been performed prior to the OECD guideline. However it conforms to the OECD 401 guideline.

Principles of method if other than guideline:

No guideline available in the report as the test has been performed prior to the OECD guideline. However it conforms to the OECD 401 guideline.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

Name: Rhubafuran
Received on September 9, 1980
Stored in refrigerator until use
Appearance: Light-yellow liquid with a pungent odour

Species:

rat

Strain:

Wistar

Remarks:

Cpb:WU

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS (Cpb:WU; Wistar random)
- Source: Central Institute for the Breeding of Laboratory Animals TNO, Zeist, The Netherlands.
- Age at study initiation: young adult
- Weight at study initiation: 92 to 168g for males and 94 to 170g for females.
- Fasting period before study: overnight before dosing
- Housing: in stainless-steel cages with grid-bottom and front
- Diet (e.g. ad libitum): Stock diet.
- Water (e.g. ad libitum): Tap water ad libitum.
- Acclimation period: not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 °C +/- 1°C, well-ventilated

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Remarks:

Concentration in vehicle: 50 % (v/v)

Doses:

2381, 2877, 3422, 4117 and 4960 mg test material/kg bw diluted in a solution of propylene glycol (50% v/v).

No. of animals per sex per dose:

5 animals per sex per dose

Control animals:

no

Details on study design:

After treatment, the rats received stock diet and tap water ad libitum. They were observed for signs of intoxication during a 14-day period after which autopsies were carried out on the survivors.
The LD50 was calculated according to the method of Weil (Biometrics 8 (1952), 249-263).
Each dose was expressed in milliliter per kg in the study.
Considering the relative density of the substance (0.992 g/cm3), the dose level was converted in miligramme per kg.

Preliminary study:

The dose selection was performed based on a previous study (TNO, 1981b, Tentative determination of the acute oral toxicity of Rhubafurane in rats).
The undiluted test material was administered by gavage to ten males and ten females in one single dose of 4960 mg test material/kg bw.
Out of 10 males and 10 females, 7 males and 7 females succumbed within a 6 hours to 5 days period after treatment. The LD50 is determined to be lower than 4960 mg test material/kg bw.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

3 980 mg/kg bw

Based on:

test mat.

Mortality:

Death occurred between 6 hours and 5 days after treatment.
See the table of results below.

Clinical signs:

other: Within a few hours after dosing the rats showed sedation and signs of ataxia. Later on encrustations around eyes and nostrils, signs of emaciation and coma were frequently observed. Survivors recovered gradually and looked quite healthy again at the end o

Gross pathology:

Macroscopic examination of the survivors at autopsy did not reveal any treatment-related gross alterations.

Table 7.2.1/01. Dose applied and mortality results

Dose	Mortality
Test material	Number		%
(mg/kg)	males	females
2381	0/5	0/5	0
2877	1/5	1/5	20
3422	1/5	2/5	30
4117	2/5	4/5	60
4960	4/5	3/5	70

The LD50 of the test substance to male/female Wistar rats was found to be 3980 mg/kg bw.

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

Under the test conditions of this study, the oral LD50 of the test substance to male/female Wistar rats was estimated to be equal to 3980 mg/kg bw.
Therefore, the test material is classified Category 5 (H303: May be harmful if swallowed) according to the GHS, as the LD50 value is comprised between 2000 and 5000 mg/kg bw, and is not classified according to the Regulation (EC) No. 1272/2008 (CLP).

Executive summary:

In an acute oral toxicity study equivalent to the OECD test guideline No. 401, five males and five females Wistar (Cpb:WU) rats per dose were given the following dose level as a solution in propylene glycol (50% v/v): 2381, 2877, 3422, 4117 and 4960 mg test material/kg bw.

Mortality and clinical signs were monitored during the study, and all surviving animals were subjected to gross necropsy after a 14-day observation period.

 

Death occurred between 6 hours and 5 days after treatment. Within a few hours after dosing the rats showed sedation and signs of ataxia. Later on encrustations around eyes and nostrils, signs of emaciation and coma were frequently observed. Survivors recovered gradually and looked quite healthy again at the end of the observation period. Macroscopic examination of the survivors at autopsy did not reveal any treatment-related gross alterations.

 

Oral LD50 Males/Females = 3980 mg/kg bw (4.02 mL/kg bw)

The LD50 of the test substance to male/female Wistar rats was found to be 4.02 ml/kg bw, with a 95% confidence limits between 3.34 to 4.85.
Considering the relative density of the substance, the oral LD50 of the test substance to male/female Wistar rats was estimated to be equal to 3980 mg/kg bw.

 

Therefore, the test material is classified Category 5 (H303: May be harmful if swallowed) according to the GHS, as the LD50 value is comprised between 2000 and 5000 mg/kg bw, and is not classified according to the Regulation (EC) No. 1272/2008 (CLP).

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1981

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

No guideline available in the report as the test has been performed prior to the OECD guideline. However it conforms to the OECD 401 guideline.

Principles of method if other than guideline:

No guideline available in the report as the test has been performed prior to the OECD guideline. However it conforms to the OECD 401 guideline.

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

Name: Rhubafurane
Received on September 9, 1980
Stored in refrigerator until use
Appearance: Light-yellow liquid with a pungent odour

Species:

rat

Strain:

Wistar

Remarks:

Cpb:WU

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS (Cpb:WU; Wistar random)
- Source: Central Institute for the Breeding of Laboratory Animals TNO, Zeist, The Netherlands.
- Age at study initiation: young adult
- Weight at study initiation: 108 to 168g for males and 94 to 118g for females.
- Fasting period before study: overnight before dosing
- Housing: in creen-bottomed stainless-steel cages
- Diet (e.g. ad libitum): Stock diet.
- Water (e.g. ad libitum): Tap water ad libitum.
- Acclimation period: not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 °C +/- 1°C, well-ventilated

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

4960 mg test material/kg bw

No. of animals per sex per dose:

10 males, 10 females

Control animals:

no

Details on study design:

After treatment, the rats received stock diet and tap water ad libitum. They were observed for signs of intoxication during a 14-day period after which autopsies were carried out on the survivors.
Each dose was expressed in milliliter per kg in the study.
Considering the relative density of the substance (0.992 g/cm3), the dose level was converted in miligramme per kg.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

< 4 960 mg/kg bw

Based on:

test mat.

Mortality:

Death occurred between 6 hours and 5 days after treatment. Out of ten males and ten females, 7 males and 7 females succumbed.

Clinical signs:

other: Within a few hours after dosing the rats showed sedation and signs of ataxia. Later on encrustations around eyes and nostrils, signs of emaciation and coma were frequently observed. After five days, survivors recovered gradually and looked quite healthy a

Gross pathology:

Macroscopic examination of the survivors at autopsy did not reveal any treatment-related gross alterations.

The LD50 of the test substance to male/female Wistar rats was found to be lower than 4960 mg/kg bw.

Interpretation of results:

study cannot be used for classification

Conclusions:

The LD50 of the test substance to male/female Wistar rats was found to be lower than 4960 mg/kg bw.

Executive summary:

In an acute oral toxicity study equivalent to the OECD test guideline No. 401, ten males and ten females Wistar (Cpb:WU) rats received a single undiluted oral dose of 4960 mg test material/kg bw.

Mortality and clinical signs were monitored during the study, and all surviving animals were subjected to gross necropsy after a 14-day observation period.

 

Death occurred between 6 hours and 5 days after treatment. Out of ten males and ten females, 7 males and 7 females succumbed. Within a few hours after dosing the rats showed sedation and signs of ataxia. Later on encrustations around eyes and nostrils, signs of emaciation and coma were frequently observed. After five days, survivors recovered gradually and looked quite healthy again at the end of the observation period. Macroscopic examination of the survivors at autopsy did not reveal any treatment-related gross alterations.

 

Oral LD50 Males/Females 4960 mg/kg bw (< 5 mL/kg bw)

The LD50 of the test substance to male/female Wistar rats was found to be < 5 mL/kg bw. Considering the relative density of the substance, the oral LD50 of the test substance to male/female Wistar rats was estimated to be lower than 4960 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

3 980 mg/kg bw

Quality of whole database:

Two studies are available to address the acute oral toxicity endpoint. Both were conducted in a method similar to OECD 401 and both pre-date GLP. The key study investigated a range of test material concentrations and it was possible to deduce a substance classfication from the study findings; it was therefore assigned a reliability score of 2 in accordance with Klimisch (1997). The supporting study was conducted as a limit test; it was not possible to determine a substance classification from the study findings and hence it was assigned a reliability score of 4 and regarded a range finder for the key study. Overall the quality of the database if high.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

ORAL

A key study was identified (TNO, 1981a, rel. 2), on the basis that it gives a definitive LD50, which can be used for classification and labelling purposes.

The acute oral toxicity of the test substance was examined in a gavage study using male/female Wistar rats. The study was performed in a method similar to OECD guideline 401. The study pre-dates GLP. The study was assigned a reliability score of 2, in accordance with the scoring system of Klimisch et al (1997).

At 3.45 mL/kg bw, 3/10 animals were found dead (1 male and 2 females).

At 4.15 ml/kg bw, 6/10 animals were found dead (2 males and 4 females).

At 5 ml/kg bw, 8/10 animals were found dead (4 males and 3 females).

Therefore the LD50 of the test substance for males/females Wistar rats was estimated to be 3980 mg/kg bw.

 

A supporting study was identified (TNO, 1981b, rel. 4), not enabling substance classification.

The acute oral toxicity of the test substance was examined in a gavage limit-test study using male/female Wistar rats. The study was performed in a method similar to OECD guideline 401. The study pre-dates GLP.

During the study the rats were all given a single dose of 4960 mg/kg bw.

7/10 male rats and 7/10 female rats died during the 14 day observation period. The LD50 of the test substance to male/female Wistar rats was therefore < 4960 mg/kg bw.

 

DERMAL

Study scientifically not necessary 

The study does not need to be conducted because the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route and no systemic effects have been observed in in vivo studies with dermal exposure (e.g. skin irritation, skin sensitisation).

 

INHALATION

Exposure considerations

The study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size.

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008.

Self classification:

Acute toxicity (Oral)

With respect to the acute oral toxicity data that are available for the test substance, no classification is required for acute oral toxicity, in accordance with Regulation (EC) No. 1272/2008.

However, based on the available study, the test material is classified Category 5 (H303: May be harmful if swallowed) according to the GHS, as the LD50 value is comprised between 2000 and 5000 mg/kg bw.

Acute toxicity (Dermal)

No data available - waiver

Acute toxicity (Inhalation)

No data available - waiver

Specific target organ toxicity: single exposure (Oral)

The classification criteria according to the CLP and to the GHS as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value (oral).

Specific target organ toxicity: single exposure (Dermal)

No data available - waiver

Specific target organ toxicity: single exposure (Inhalation)

No data available - waiver

Aspiration hazard

The substance is not a hydrocarbon and no effects were observed on lungs in oral studies, therefore the criteria for aspiration toxicity according to the CLP and to the GHS are not met.