Diphenyl carbonate

Endpoint summary

Description of key information

ORAL

LD50 1500 mg/kg bw , rat (male/female), OECD 401, FitzGerald (1990)

DERMAL

LD50 >2000 mg/kg bw, rat (male/female), OECD 402, Krötlinger (1999)

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Wilmington, MA
- Age at study initiation: 32-68 days
- Weight at study initiation: 100-225 grams
- Fasting period before study: over night
- Housing: individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 8 days

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: no data
DOSAGE PREPARATION (if unusual): Test substance was ground to a find powder and suspended in corn oil (heated to 45°C). The suspension was cooled to 37°C for dosing.

Doses:

750, 1500 and 3000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: twice daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

The method of Litchfield and Wilcoxon could not be employed due to a limitation in this procedure that requires at least two response values that are not 0 or 100 %.

Preliminary study:

Limit study: 5/sex; dose: 5000 mg/kg bw; mortality: 7 of 10 animals died
Range Finding study: 1/sex/dose; doses: 500, 1000, 1500, 2000, 4000 mg/kg bw

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 500 mg/kg bw

Mortality:

3000 mg/kg: all animals died by the end of day 1
1500 mg/kg: two out of the ten animals (1m/1f) died by 4 h and 3 died (1m/2f) by day 1 of the study. Five animals survived the 14 day observation period
750 mg/kg: all animals survived at this dose level

Clinical signs:

other: 3000 mg/kg:  the one animal that survived until day 1 showed signs of clonic convulsions 1500 mg/kg:  the five surviving animals and three of the animals that died experienced clonic convulsions 750 mg/kg: none of the surviving animals exhibited any cli

Gross pathology:

no unusual lesions were noted in any of the animals

Interpretation of results:

other: Acute category 4 according to EU criteria

Conclusions:

The LD50 of the test substance has been determined to be 1500 mg/kg bw based upon the observed 50 % mortality at this dose.

Executive summary:

The acute oral toxicity of the test material was investigated in a study which was conducted in accordance with the standardised guideline OECD 401, under GLP conditions.

During the study Sprague-Dawley male and female rats (five animals per sex per dose) were dosed with the test material in corn oil via gavage at 750, 1500 and 3000 mg/kw bw and observed over a 14 day period.

Under the conditions of this study, the acute oral LD50 of Diphenyl carbonate in rats was determined to be 1500 mg/kg bw, with clonic convulsions the main clinical sign appearing at doses near to or exceeding the LD50 value.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 500 mg/kg bw

Quality of whole database:

The quality of the whole database is considered to be good. The key study was performed in accordance with a standardised guideline under GLP conditions. There are a further six supporting studies available, all with limited documentation, and thus all awarded a reliability score of 2 in accordance with the criteria for assessing data quality as set forth by Klimisch et al. (1997).

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

modified according to the acute toxic class method

GLP compliance:

yes

Remarks:

Deviation from GLP: No analytical investigations on stability and  homogeneity were perfomed.

Test type:

other: acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Winkelmann, Borchen, Germany
- Age at study initiation: 8-12 weeks
- Weight at study initiation: mean 273 g for males and 216 g for females
- Fasting period before study: none
- Housing: individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

Type of coverage:

occlusive

Vehicle:

water

Details on dermal exposure:

For a better contact to the skin, the test substance was moistened with  water, applied to the prepared skin area and fixed with non-irritant skin plaster (occlusive conditions) for 24 hours.

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

Deviation from OECD 402: the number of animals and the procedure of dose  finding was done according to OECD guideline 423 (Acute Oral Toxicity -  Acute Toxic Class Method) due to animal welfare reasons.

Statistics:

none: limit test

Preliminary study:

none

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

none

Clinical signs:

other: none

Gross pathology:

no noticable gross pathological findings

Other findings:

no local effects

Interpretation of results:

other: Not classified according to EU criteria

Conclusions:

Under the conditions of this study, the acute dermal LD50 in rats was determined to be greater than 2000 mg/kg bw.

Executive summary:

The acute dermal toxicity of the substance was investigated in accordance with the standardised guideline OECD 402 modified according to the acute toxic class method under GLP conditions.  

During the study three male and three female Wistar rats were exposed to the test material moistened with water at a limit dose of 2000 mg/kg in an occlusive fashion for 24 hours.

Under the conditions of this study, the acute dermal LD50 in rats was determined to be greater than 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The quality of the whole database is considered to be good. The key study and one supporting study were performed in accordance with a standardised guideline under GLP conditions. There is a further supporting study available, with limited documentation, awarded a reliability score of 2 in accordance with the criteria for assessing data quality as set forth by Klimisch et al. (1997).

Additional information

Oral

This endpoint is addressed with seven studies; one key study and six supporting studies. The key study was awarded a reliability score of 1 and the supporting studies were all awarded a reliability score of 2 in accordance with the criteria for assessing data quality as set forth by Klimisch et al. (1997) due in part to limited documentation.

 

The key study (FitzGerald, 1990) is a GLP compliant study performed in accordance with the standardised guideline OECD 401.

Sprague-Dawley male and female rats (five animals per sex per dose) were dosed with the test material in corn oil via gavage at 750, 1500 and 3000 mg/kw bw and observed over a 14 day period. Under the conditions of this study, the acute oral LD50 of Diphenyl carbonate in rats was determined to be 1500 mg/kg bw, with clonic convulsions the main clinical sign appearing at doses near to or exceeding the LD50 value.

 

In the first supporting study (Kimmerle, 1967) (rat), fifteen animals were used per sex per dose, with male animals being dosed at 500, 1000 and 2500 mg/kg bw and female animals being dosed at 1000 and 2500 mg/kg bw. The vehicle used for the administration of the test material was water and Cremophor EL. The test material was administered at concentrations of 5, 10 and 25 % at the 500, 1000 and 2500 mg/kg dose levels, respectively. Animals were observed for seven days.

Under the conditions of this study, the acute oral toxicity in both male and female rats was determined to be >2500 mg/kg bw.

 

In the second supporting study (Kimmerle, 1967) (mouse), male animals were dosed at 250, 500 and 1000 mg/kg bw with the test material in water and Cremophor EL (15 animals per dose). Animals were then observed over a seven day period.

Under the conditions of this study, the LD50 was determined to be >1000 mg/kg bw.

 

In the third supporting study (Kimmerle, 1967) (dog), animals were dosed at 250, 500 and 1000 mg/kg bw with the test material in water and Cremophor EL (one or two animals per dose level) and observed over a seven day period.

Under the conditions of this study, the LD50 was determined to be>1000 mg/kg bw.

 

In the fourth supporting study (Kimmerle, 1963) (rat), male animals were exposed to the test material at dose levels of 100, 250, 500, 1000 and 2500 mg/kg bw in DMSO with 10 animals per dose.

Under the conditions of this study, the LD50 was determined to be >2500 mg/kg.

 

In the fifth supporting study (Kimmerle, 1963) (guinea pig), females were exposed to the test material at dose levels of 500 and 1000 mg/kg bw in water and Cremophor EL (five animals per dose level). Animals were then observed over a seven day period.

Under the conditions of this study, the LD50 was determined to be>1000 mg/kg bw.

 

In the final supporting study (Kimmerle, 1967) (rabbit), animals were dosed at either 500 or 1000 mg/kg bw test material with water and Cremophor EL (three rabbits per dose level). Animals were then observed over a seven day period.

Under the conditions of this study, the LD50 was determined to be>1000 mg/kg bw.

 

Inhalation

In accordance with Section 8.5.2 of Column 2 of REACH Annex VIII, it is considered justified to omit acute toxicity testing by the inhalation route on the grounds that exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and the possibility of exposure to aerosols, particles or droplets of an inhalable size.

 

Dermal

This endpoint is addressed with three studies; one key study and two supporting studies.

 

The key study (Krötlinger, 1999) was performed in accordance with the standardised guideline OECD 402 modified according to the acute toxic class method under GLP conditions. The study was awarded a reliability score of 1 in accordance with the criteria for assessing data quality as set forth by Klimisch et al. (1997). 

Three male and three female Wistar rats were exposed to the test material moistened with water at a limit dose of 2000 mg/kg in an occlusive fashion for 24 hours.

Under the conditions of this study, the acute dermal LD50 in rats was determined to be greater than 2000 mg/kg bw.

 

In the first supporting study (Desai, 1990a) the acute dermal toxicity potential of diphenyl carbonate was determined in study that was performed in accordance with the standardised guideline OECD 402 under GLP conditions. The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997).

Male and female New Zealand White rabbits (5/sex/dose) were exposed to the test material moistened with water at a limit dose of 2000 mg/kg in an occlusive fashion for 24 hours. Animals were observed immediately following dosing and three times during the first two hours after application. Animals were observed twice daily for 14 days for clinical manifestations and mortality.

Under the conditions of this study, the acute dermal LD50 was determined to be greater than 2000 mg/kg bw.

 

In the second supporting study (Kimmerle, 1967), the acute dermal toxicity potential of diphenyl carbonate to rats was determined in study that was awarded a reliability score of 2 in accordance with the criteria set forth by Klimisch et al. (1997) as there is limited documentation.

Male rats were exposed to the test material at a dose of 500 mg/kg (prepared as a 10 % emulsion). The test material was not removed and the animals were observed for 7 days.

Under the conditions of the study, the acute dermal LD50 in male rats was determined to be greater than 500 mg/kg bw.

 

Other Routes

There are two studies available to address the acute toxicity of diphenyl carbonate via the intraperitoneal route.  Both were awarded a reliability score of 2 in accordance with the criteria for assessing data quality as set forth by Klimisch et al. (1997) as there is limited documentation.

 

The first study (Kimmerle, 1963) was performed using ten (presumably male) rats per dose. The animals were dosed at 0.005, 0.01, 0.025, 0.05, 0.1, 0.25, 0.5 and 1 g/kg bw in DMSO. Animals were observed for 7 days.

Under the conditions of this study, the LD50 was determined to be 200 mg/kg.

 

The second study ( Kimmerle, 1967) was performed in male rats. Fifteen animals per dose were treated at 100, 250, 500, 750, 1000, 1500, 2000 and 2500 mg/kg bw using water and Cremophor EL as the vehicle. Clinical symptoms observed included convulsions and bad condition starting 10 to 20 minutes and up to 3 days after dosing. Deaths occurred in the first 24 hours after dosing.

Under the conditions of the study, the LD50 was determined to be 1005 mg/kg.

Justification for selection of acute toxicity – oral endpoint

Although there are a number of studies available to address this endpoint, the key study was selected on the basis that it was conducted in a standard species and was awarded a reliability score of 1 in accordance with the criteria for assessing data quality as set forth by Klimisch et al. (1997). The remaining studies were judged to be more appropriate as supporting data.  

Justification for selection of acute toxicity – dermal endpoint

There are a number of studies available to address this endpoint; the key study was selected on the basis that it was conducted in the species most commonly used to address this endpoint (rat) and was awarded a reliability score of 1 in accordance with the criteria for assessing data quality as set forth by Klimisch et al. (1997). The remaining studies were judged to be more appropriate as supporting data.  

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does not require classification with respect to acute toxicity via the dermal route.

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance requires classification with respect to acute toxicity via the oral route as Category 4 (H302: Harmful if swallowed).