2,4-diethyl-9H-thioxanthen-9-one

Endpoint summary

Description of key information

- Acute oral toxicity [OECD 401, fixed dose method; GLP, test material: 2-Isopropylthioxanthone (CAS 5495-84-1, EC 226-827-9)]: LD50 in male and female rats >2000 mg/kg bw.

- Acute inhalation toxicity: Taking into account the very low vapour pressures of the substance 2-Isopropylthioxanthone (CAS 5495-84-1, EC 226-827-9) and structurally related registration substance 2,4-diethyl-9H-thioxanthen-9-one (CAS 82799-44-8, EC 280-041-0), exposure via the inhalation route is unlikely and it is therefore considered justified to omit this endpoint information.

- Acute dermal toxicity [OECD 402, fixed dose method; GLP, test material: 2-Isopropylthioxanthone (CAS 5495-84-1, EC 226-827-9)]:

LD50 in male and female rats >2000 mg/kg bw.

- Based on the results of the substance 2-Isopropylthioxanthone (CAS 5495-84-1, EC 226-827-9), the LD50 of the structurally related registration substance 2,4-diethyl-9H-thioxanthen-9-one (CAS 82799-44-8, EC 280-041-0) is considered to be >2000 mg/kg bw in female and male rats (via the oral and dermal route).

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:

23 October 1998 to 11 November 1998

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

no

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

other: Crl:Han Wist(Glx:BRL)BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Females nulliparous and non-pregnant: Yes
- Age at study initiation: Five to seven weeks old
- Weight at study initiation: 113 to 128 g (males) and 107 to 126 g (females)
- Fasting period before study: Overnight fasting prior to dosing which continued until approximately three hours after dosing
- Housing: Up to five rats of the same sex were accommodated in suspended stainless steel mesh cages (with minimum internal dimensions of 55 x 34 x 20 cm). The cages were suspended over cardboard lined trays for collection of excreta. The liners were replaced at least twice weekly.
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19 to 25 °C
- Humidity: 40 to 80 % RH
- Air changes: At least 14 air changes per hour
- Photoperiod: The rooms were illuminated by fluorescent strip-lights for twelve hours daily.

Route of administration:

oral: gavage

Vehicle:

methylcellulose

Details on oral exposure:

VEHICLE
- Amount of vehicle: 20 mL/kg
- Lot/batch no.: T71685
- Purity: 1 % Methyl cellulose

MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg

Doses:

2 000 mg/kg

No. of animals per sex per dose:

Preliminary study: Two females at 2 000 mg/kg
Main study: Five animals per sex at 2 000 mg/kg.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Clinical signs: Treated rats were observed closely for clinical signs of reaction to treatment. Clinical signs were recorded frequently on Day 1 and regularly for the remainder of the study, (the minimum schedule being at least once within half an hour of dosing and four times within the first four hours following administration, twice daily on Days 2, 3 and 4 and once daily from the fifth to last day of the observation period). Individual records of clinical signs were maintained for each treated rat.
- Body weights: Rats were weighed on Day -1 ( day before dosing), on Day 1 and Day 8 and on Day 15 of the main study.
- All rats were killed by intraperitoneal injection of sodium pentobarbitone on Day 15. After exsanguination a full macroscopic necropsy was performed and any lesions recorded. The necropsy procedure included inspection of external surfaces and orifices, all viscera and tissue within the abdominal, thoracic and cranial cavities, free-hand sectioning of the liver and kidneys and examination of representative sections of mucosa} surfaces of the stomach, small and large intestines.

Preliminary study:

A preliminary group of two female fasted rats was subjected to a single oral dose of the test material at 2000 mg/kg. There was no death and no overt clinical signs following treatment. Necropsy on Day 8 revealed no macroscopic changes.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No animal died following a single oral administration of the test material at 2 000 mg/kg.

Clinical signs:

other: No clinical signs of reaction to treatment were seen during the observation period.

Gross pathology:

No macroscopic changes were observed at necropsy on Day 15.

Interpretation of results:

other: Not classified in accordance with EU criteria

Conclusions:

Under the conditions of this study, the oral LD50 value was established to exceed 2 000 mg/kg body weight.

Executive summary:

The acute oral toxicity of the test material 2-Isopropylthioxanthone (CAS 5495-84-1, EC 226-827-9) was investigated in accordance with the standardised guidelines OECD 401 and EU Method B1 under GLP conditions.

The test material was formulated in 1 % methyl cellulose at the limit dose of 2 000 mg/kg. The test formulation was kept stirring during dosing.

A preliminary group of two female fasted rats was subjected to a single oral dose of the test material at 2 000 mg/kg. There was no death and no overt clinical signs following treatment. Necropsy on Day 8 revealed no macroscopic changes. Five male and five females were then subjected to the same limit dose and observed for a period of 14 days.

No animal died following a single oral administration of the test material at 2 000 mg/kg. No clinical signs of reaction to treatment were seen during the observation period. All rats gained weight during the first and second weeks of the observation period and no macroscopic changes were observed at necropsy on Day 15.

Under the conditions of this study, the oral LD50 value was established to exceed 2 000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The study was awarded a reliability score of 1 in accordance with the criteria 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

Study period:

14 July 1987 to 28 July 1987

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:

not specified

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

other: Crl:COBS CD (SD) BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: Seven to ten weeks of age.
- Weight at study initiation: 200 to 221 g
- Housing: Animals were housed individually in metal cages with wire mesh floors.
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature: 21 to 22 °C
- Humidity: 69 % (mean daily relative value)
- Air changes: Approximately 15 per hour.
- Photoperiod: Lighting was controlled by means of a time switch to 12 hours artificial light in each 24 hour period.

Type of coverage:

occlusive

Vehicle:

water

Remarks:

Distilled

Details on dermal exposure:

TEST SITE
- Area of exposure: Dorso-lumbar region. One day prior to treatment hair was removed from the dorso-lumbar region of each rat with electric clippers exposing an area equivalent to 10 % of the total body surface. No shaving or chemical depilation was used.
- % coverage: 10 % of the total body surface
- Type of wrap if used: The test material was applied by spreading it evenly over the prepared skin. The treated area was covered with gauze which was held in place with an impermeable dressing encircled firmly around the trunk.

REMOVAL OF TEST SUBSTANCE
- Washing: At the end of the 24-hour exposure period, the dressings were carefully removed and the treated area of skin decontaminated by washing in warm (30 to 40 °C) water and blotting dry with absorbent paper.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount applied: 2.80 mL/kg
- Concentration: 71.4 % (w/v) in distilled water
- For solids, paste formed: Yes

Duration of exposure:

24 hours

Doses:

2.0 g/kg bodyweight

No. of animals per sex per dose:

Five animals per sex per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed soon after dosing and at frequent intervals for the remainder of Day 1. On subsequent days the animals were observed once in the morning and again at the end of the experimental day. This latter observation was at approximately 16.30 hours on weekdays or 11.30 hours on Saturday and Sunday. Clinical signs were recorded at each observation. The nature, severity, approximate time of onset and duration of each toxic sign were recorded. A separate record was kept of dermal changes other than erythema and oedema.
- Individual bodyweights of rats were recorded on Days 1 (day of dosing), 8 and 15.
- Necropsy of survivors performed: Yes - all animals on the study were killed on Day 15 by cervical dislocation and were subjected to a macroscopic post mortem examination, which consisted of opening the abdominal and thoracic cavities. The macroscopic appearance of abnormal organs when present was recorded.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths following a single dermal dose of the test material at 2.0 g/kg bodyweight.

Clinical signs:

other: There were no clinical signs of systemic reaction to treatment.

Gross pathology:

Terminal autopsy findings were normal.

Other findings:

Sites of application of the test material developed no irritation responses or other dermal changes.

Interpretation of results:

other: Not classified in accordance with EU criteria

Conclusions:

Under the conditions of the study, the LD50 has been determined to be greater than 2.0 g/kg bw.

Executive summary:

A study was conducted to investigate the acute dermal toxicity of the test material in accordance with the standardised guidelines OECD 402 and EU Method B.3.

A group of ten rats (five males and five females) was treated at 2.0 g/kg bodyweight. One day prior to treatment hair was removed from the dorso­lumbar region of each rat with electric clippers exposing an area equivalent to 10 % of the total body surface. The test material was applied by spreading it evenly over the prepared skin. The treated area was then promptly covered with gauze which was held in place with an impermeable dressing encircled firmly around the trunk. The skin was exposed to the test material for 24 hours before the patch was removed and the area washed. The animals were observed for 14 days before they were sacrificed and gross necropsy performed.

Sites of application of the test material developed no irritation responses or other dermal changes. There were no deaths following treatment and no clinical signs of systemic reaction were observed. Anticipated body weight gains were recorded for all animals except one female that had unchanged bodyweight in the second week of the study. Terminal autopsy findings were normal.

Under the conditions of the study, the LD50 has been determined to be greater than 2.0 g/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997).

Additional information

No acute toxicity studies are available for the registration substance 2,4-diethyl-9H-thioxanthen-9-one ("DETX", CAS 82799-44-8, EC 280-041-0) itself.

However, reliable acute oral and dermal toxicity studies of the structurally related substance 2-Isopropylthioxanthone ("ITX", CAS 5495-84-1, EC 226-827-9) can be used to adress the endpoint, which is entirely appropriate to draw conclusions on the acute toxicity potential of the registration substance DETX.

The only difference between the source substance ITX and the target substance DETX can be reduced to slightly differing substituents: ITX possesses one isopropyl group, whereas DETX two ethyl groups.

Acute toxicity: via oral route

The acute oral toxicity of the closely related test material ITX was investigated in accordance with the standardised guidelines OECD 401 and EU Method B1 under GLP conditions. The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997).

The test material was formulated in 1 % methyl cellulose at the limit dose of 2 000 mg/kg. The test formulation was kept stirring during dosing.

A preliminary group of two female fasted rats was subjected to a single oral dose of the test material at 2 000 mg/kg. There was no death and no overt clinical signs following treatment. Necropsy on Day 8 revealed no macroscopic changes. Five male and five females were then subjected to the same limit dose and observed for a period of 14 days.

No animal died following a single oral administration of the test material at 2 000 mg/kg. No clinical signs of reaction to treatment were seen during the observation period. All rats gained weight during the first and second weeks of the observation period and no macroscopic changes were observed at necropsy on Day 15.

Under the conditions of this study, the oral LD50 value was established to exceed 2 000 mg/kg body weight.

In a supporting study, the acute oral toxicity potential of the test material ITX to the rat was investigated in accordance with the standardised guidelines OECD 401 and EU Method B1. The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997).

Five female and five male rats were subjected to a dose of test material by oral gavage at 2.0 g/kg bodyweight. Animals were observed for a period of 14 days following administration before sacrifice when gross necropsy was performed.

There were no deaths following the single dose. Signs of reaction to treatment observed in all rats shortly after dosing were pilo-erection, abnormal body carriage (hunched posture), abnormal gait (waddling), lethargy and pallor of the extremities. Ptosis and decreased respiratory rate were recorded for a single female five hours after treatment. Recovery, as judged by external appearance and behaviour, was advanced by the second observation on Day 2 and complete by Day 4. Slightly low bodyweight gains were recorded for four males and all five females on Day 8 and again for two females on Day 15. The majority of rats achieved anticipated bodyweight gains during the second week of the study.

Under the conditions of this study, the oral LD50 value was established to exceed 2.0 g/kg body weight.

Acute toxicity: via inhalation route

Testing via the inhalation route is not appropriate taking into account the very low vapour pressure of the registration substance DETX (whereby this circumstance applies to the structurally related substance ITX as well)

Acute toxicity: via dermal route

A study was conducted to investigate the acute dermal toxicity of the closely related test material ITX in accordance with the standardised guidelines OECD 402 and EU Method B.3. The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997).

A group of ten rats (five males and five females) was treated at 2.0 g/kg bodyweight. One day prior to treatment hair was removed from the dorso­lumbar region of each rat with electric clippers exposing an area equivalent to 10 % of the total body surface. The test material was applied by spreading it evenly over the prepared skin. The treated area was then promptly covered with gauze which was held in place with an impermeable dressing encircled firmly around the trunk. The skin was exposed to the test material for 24 hours before the patch was removed and the area washed. The animals were observed for 14 days before they were sacrificed and gross necropsy performed.

Sites of application of the test material developed no irritation responses or other dermal changes. There were no deaths following treatment and no clinical signs of systemic reaction were observed. Anticipated body weight gains were recorded for all animals except one female that had unchanged bodyweight in the second week of the study. Terminal autopsy findings were normal.

Under the conditions of the study, the LD50 has been determined to be greater than 2 000 mg/kg bw.

Justification for classification or non-classification

On the basis of the available oral and dermal data of the structurally related substance 2-Isopropylthioxanthone (CAS 5495-84-1, EC 226-827-9), the registration substance 2,4-diethyl-9H-thioxanthen-9-one (CAS 82799-44-8, EC 280-041-0) does not require classification for lethal effects following a single exposure according to Regulation 1272/2008/EC.