2-[2-(3-butoxypropyl)-1,1-dioxo-1,2,4-benzothiadiazin-3-yl]-5'-tert-butyl-2-(5,5-dimethyl-2,4-dioxo-1,3-oxazolidin-3-yl)-2'-[(2-ethylhexyl)thio]acetanilide

Endpoint summary

Description of key information

Oral (OECD 423), rat: LD50 = 5000 mg/kg bw (cut-off limit)
Dermal (OECD 402), rat: LD50 > 2000 mg/kg bw (limit test)

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:

22 Jul - 08 Aug 2003

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: JMAFF Japanese test guidelines

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: Wistar Crl:(WI) BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approximately 11 weeks
- Weight at study initiation: 335 - 384 g (males); 213 - 238 g (females)
- Fasting period before study: overnight prior to dosing until 3-4 h after dosing of the test substance
- Housing: Animals were housed in groups of 3 per sex in Makrolon type IV cages containing purified sawdust as bedding material.
- Diet: Altromin standard pelleted laboratory animal diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.1 - 24.5
- Humidity (%): 47 - 79
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES:
From: 22 Jul 2003 (males)
From: 25 Jul 2003 (females)
To: 05 Aug 2003 (males)
To: 08 Aug 2003 (females)

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Details on oral exposure:

VEHICLE
Specific gravity: 1.036

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION (if unusual): The formulations were prepared (w/w) within 4 h prior to application. Adjustment was made for specific gravity of the vehicle. Homogeneity was accomplished to a visually acceptable level.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The toxicity of the test substance was assessed by stepwise treatment of groups of 3 animals. The first group was treated at a dose level of 2000 mg/kg bw. The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3

Control animals:

other: not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed in periodical intervals on Day 1 and once daily thereafter. Animals were weighed on Day 1 (pre-dose), Day 8 and Day 15.
- Necropsy of survivors performed: yes

Sex:

male/female

Dose descriptor:

LD50

Effect level:

5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: LD50 cut-off according to OECD 423

Mortality:

No mortality occurred during the study period.

Clinical signs:

On Day 1, all animals had a hunched posture. Additionally, all females had uncoordinated movements and piloerection was noted in all males. After Day 1, no clinical signs of toxicity were observed up to the end of the observation period.

Body weight:

No effect on body weight was noted.

Gross pathology:

Necropsy examination revealed no substance-related findings.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

CLP: not classified
DSD: not classified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Quality of whole database:

The study is GLP compliant and has Klimisch score 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:

04 Feb - 18 Feb 2004

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study with acceptable restrictions. An occlusive coverage was used.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

occlusive coverage was used

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

yes

Remarks:

occlusive coverage was used

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: JMAFF Japanese Guidelines

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Wistar Crl:(WI) BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approximately 8 weeks
- Weight at study initiation: 250 - 264 g (males); 181 - 195 g (females)
- Housing: Animals were housed individually in Makrolon type III cages containing purified sawdust as bedding material.
- Diet: Altromin standard pelleted laboratory animal diet, ad libitum
- Water: tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 15.4 - 22.9
- Humidity (%): 29 - 80
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES:
From: 04 Feb 2004
To: 18 Feb 2004

Type of coverage:

occlusive

Vehicle:

propylene glycol

Details on dermal exposure:

TEST SITE
- Area of exposure: approximately 25 cm² for males and 18 cm² for females
- % coverage: 10
- Type of wrap if used: a surgical gauze patch (Surgy 1 D), successively covered with aluminium foil and Coban elastic bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The residual test substance was removed with water.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 mL/kg bw
- Constant volume or concentration used: yes

VEHICLE
- Specific gravity: 1.036

Duration of exposure:

24 h

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: Animals were observed in periodical intervals on Day 1 and once daily thereafter. Animals were weighed on Day 1 (pre-dose), Day 8 and Day 15.
- Necropsy of survivors performed: yes

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred during the study period.

Clinical signs:

Hunched posture and chromodacryorrhoea were noted among all animals between Days 1 and 3. In addition, shallow respiration was shown by one male and one female on Day 2, while uncoordinated movements were shown by one female also on Day 2. White staining, scales, scabs and/or erythema were noted on the treated skin site of all animals during the observation period.

Body weight:

No effect on body weight was noted.

Gross pathology:

Necropsy examination revealed no substance-related findings.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

CLP: not classified
DSD: not classified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The study is GLP compliant and has Klimisch score 2.

Additional information

The acute toxicity of UY-330 was assessed in an oral and a dermal toxicity study.

In the oral toxicity study performed by Hooiveld (2003) according to OECD 423 and GLP, 3 female Wistar rats were treated with 2000 mg/kg bw of the test substance in propylene glycol by oral gavage. As no mortality occurred, another group of 3 male rats was treated with 2000 mg/kg bw of the test substance. Again, there was no mortality.

On the first treatment day, all animals had a hunched posture. During the 14 d-observation period, no other clinical signs and no effects on the body weight were observed in any animal. Macroscopic examinations at necropsy did not reveal any abnormalities.

According to the acute toxic class method described in the OECD guideline 423, if there is no mortality following administration of 2000 mg/kg bw in two separate steps, the LD50 cut-off limit is 5000 mg/kg bw. Therefore, the LD50 is considered to be 5000 mg/kg bw for male and female rats.

A standard acute dermal toxicity study in accordance with OECD 402 and GLP was performed by van Otterdijk (2004). A dilution of the test substance in propylene glycol was applied to the intact skin of 5 male and 5 female Wistar rats at a dose level of 2000 mg/kg bw. Under occlusive conditions, the test substance was held in place for 24 h with an elastic bandage and additionally a piece of Micropore tape in females only. Thereafter, the coverage and the residual test substance were removed and the treated site cleaned with water. 

No mortality occurred during the 14 d- observation period. Between Days 1-3, a hunched posture, chromodacryorrhoea, white staining, scales, scabs and/or erythema on the treated skin sites were noted in all animals. Some other clinical signs were observed in few animals during the observation period, including shallow respiration and uncoordinated movements. No effects on the body weight were observed in any animal. No abnormal findings were noted at necropsy.

The LD50 of the test substance was > 2000 mg/kg bw.

Justification for selection of acute toxicity – oral endpoint
Only one study is available.

Justification for selection of acute toxicity – inhalation endpoint
The acute inhalation toxicity study is not required as no inhalation exposure is expected.

Justification for selection of acute toxicity – dermal endpoint
Only one study is available.

Justification for classification or non-classification

The available data on the acute oral and dermal toxicity of the test substance does not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and is therefore conclusive but not sufficient for classification.