Pregna-1,4-diene-3,20-dione, 9-bromo-6-fluoro-11-hydroxy-16-methyl-21-[(1-oxopentyl)oxy]-, (6.alpha.,11.beta.,16.alpha.)-

Endpoint summary

Description of key information

The acute oral toxicity (LD50) of bromhydrin-valerate in rats is 3100 mg/kg bw based on an acute rat study with the read-across substance diflucortolone-21-valerate (Geretzki and Richter, 1973).

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

not applicable

Remarks:

pre-guideline study

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Tierzüchter Dr. Hagemann (not further specified)
- Age at study initiation: no data
- Weight at study initiation: 84 -117 g
- Fasting period before study: approx. 20 hours
- Housing: conventional (1 animal per cage) macrolon cages type II
- Diet (ad libitum): Altromin R
- Water (ad libitum): tap water
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5 - 24.0
- Humidity (%): 50 - 63
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

Route of administration:

oral: gavage

Vehicle:

other: 0.9 g NaCl + 0.5 g CMC + 0.085 g Myrj ad 100 ml aqua dest.

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 10 g in 100 mL
- Amount of vehicle (if gavage): 2, 2.5, 3, 3.5, 4 mL/kg


MAXIMUM DOSE VOLUME APPLIED: 4.0mL/kg

Doses:

2000, 2500, 3000, 3500 and 4000 mg/kg bw

No. of animals per sex per dose:

5/sex/dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 39 days
- Kind of observations: clinical signs, mortality
- Necropsy of survivors performed: yes

Statistics:

Probit analysis

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

3 100 mg/kg bw

Based on:

test mat.

95% CL:

>= 2 700 - <= 3 800

Mortality:

Mortality was observed at 2000 mg/kg bw and above in both sexes. Animals died between 5 and 22 days after application (details see Table 1).

Clinical signs:

other: After single oral administration animals of all dose levels showed emaciation from day 5 to day 39 of the observation period. At 2000 mg/kg bw and above ungroomed coat and apathy was observed. At 2500 mg/kg bw and above sporadic increased girth of abdomen

Gross pathology:

At necropsy perforating ulcers in the cutaneous stomach mucosa were observed in sacrificed animals at the end of the observation period (from 2500 mg/kg bw). In animals found dead perforating ulcers in the cutaneous stomach mucosa and splenic athropy (from 2000 mg/kg bw), hyperemia in the gastrointestinal tract and necrobiosis in the liver (from 2500 mg/kg bw) as well as petechial bleedings in the glandular stomach mucosa and anaemic renal infarction (from 3000 mg/kg bw) were recorded.

Table 1: Number of dead animals per dose group after single oral application of difluocortolon-valerinat (ZK 22612) to rats:

Dose [mg/kg]	No of dead males/ No of treated males	No of dead females/ No of treated females	No of dead animals (total 39 days after admin.) / No of treated animals
2000	3/5	2/5	5/10
2500	1/5	3/5	4/10
3000	3/5	4/5	7/10
3500	4/5	1/5	5/10
4000	2/5	4/5	6/10

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

In the present study conducted according to OECD test guideline 401, 25 female and 25 male Wistar rats were orally administered single doses of Difluocortolon-valerianat in 0.9 g NaCl + 0.5 g CMC + 0.085 g Myrj ad 100 mL Aqua dest. at concentrations of 2000, 2500, 3000, 3500 and 4000 mg/kg bw. The animals were observed for 39 days and subsequently sacrified if no premature mortality occurred. The LD50 value was obtained from Probit analysis. The LD50 is 3100 mg/kg bw.

Executive summary:

After single oral administration of the test item difluocortolon-valerianat (diflucortolone-21-valerate) in doses of 2000, 2500, 3000, 3500 and 4000 mg/kg bw to male and female Wistar rats (5/sex/group) and during an observation period of 39 days clinical signs (emaciation, ungroomed coat, apathy, sporadic increased girth of abdomen, individual anaemic animals) were observed starting at 2000 mg/kg bw. Mortality was observed at 2000 mg/kg bw and above in both sexes. Animals died between 5 and 22 days after application. At necropsy perforating ulcers in the cutaneous stomach mucosa were observed in sacrificed animals at the end of the observation period (from 2500 mg/kg bw). In animals found dead perforating ulcers in the cutaneous stomach mucosa and splenic athropy (from 2000 mg/kg bw), hyperemia in the gastrointestinal tract and necrobiosis in the liver (from 2500 mg/kg bw) as well as petechial bleedings in the glandular stomach mucosa and anaemic renal infarction (from 3000 mg/kg bw) were recorded. The acute oral toxicity (LD50) of diflucortolone-21-valerate was determined to be 3100 mg/kg bw for male and female Wistar rats using probit analysis.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

JUSTIFICATION FOR READ-ACROSS FROM SUPPORTING SUBSTANCE (STRUCTURAL ANALOGUE OR SURROGATE)
For bromhydrin-valerate (CAS No. 54605-02-6) no acute toxicity data are available. Therefore, acute oral toxicity data of diflucortolone-21-valerate (CAS No. 59198-70-8) were used since these data are regarded as representative. In diflucortolone-21-valerate the bromine atom in position 9 of the target molecule (bromhydrin-valerate) is replaced by a fluorine atom. No other changes in the molecule occured. No relevant toxicological effects are expected by the change of a halogen atom (Br) versus another (F). A search for structure-analogue substances using the QSAR OECD Toolbox 3.4 recommended diflucortolone-21-valerate as one out of 8 category substances for a read-across approach (for additional information see QSAR OECD Toolbox Report on Bromhydrin-valerat in "Attached justification"). Please refer also to the justification for read-across attached in chapter 13 of this IUCLID file.

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

3 100 mg/kg bw

Based on:

test mat.

95% CL:

>= 2 700 - <= 3 800

Mortality:

Mortality was observed at 2000 mg/kg bw and above in both sexes. Animals died between 5 and 22 days after application (details see Table 1).

Clinical signs:

other: After single oral administration animals of all dose levels showed emaciation from day 5 to day 39 of the observation period. At 2000 mg/kg bw and above ungroomed coat and apathy was observed. At 2500 mg/kg bw and above sporadic increased girth of abdomen

Gross pathology:

At necropsy perforating ulcers in the cutaneous stomach mucosa were observed in sacrificed animals at the end of the observation period (from 2500 mg/kg bw). In animals found dead perforating ulcers in the cutaneous stomach mucosa and splenic athropy (from 2000 mg/kg bw), hyperemia in the gastrointestinal tract and necrobiosis in the liver (from 2500 mg/kg bw) as well as petechial bleedings in the glandular stomach mucosa and anaemic renal infarction (from 3000 mg/kg bw) were recorded.

Table 1: Number of dead animals per dose group after single oral application of difluocortolon-valerinat (ZK 22612) to rats:

Dose [mg/kg]	No of dead males/ No of treated males	No of dead females/ No of treated females	No of dead animals (total 39 days after admin.) / No of treated animals
2000	3/5	2/5	5/10
2500	1/5	3/5	4/10
3000	3/5	4/5	7/10
3500	4/5	1/5	5/10
4000	2/5	4/5	6/10

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

In the present study conducted according to OECD test guideline 401, 25 female and 25 male Wistar rats were orally administered single doses of Difluocortolon-valerianat in 0.9 g NaCl + 0.5 g CMC + 0.085 g Myrj ad 100 mL Aqua dest. at concentrations of 2000, 2500, 3000, 3500 and 4000 mg/kg bw. The animals were observed for 39 days and subsequently sacrified if no premature mortality occurred. The LD50 value was obtained from Probit analysis. The LD50 is 3100 mg/kg bw.

Executive summary:

After single oral administration of the test item difluocortolon-valerianat (diflucortolone-21-valerate) in doses of 2000, 2500, 3000, 3500 and 4000 mg/kg bw to male and female Wistar rats (5/sex/group) and during an observation period of 39 days clinical signs (emaciation, ungroomed coat, apathy, sporadic increased girth of abdomen, individual anaemic animals) were observed starting at 2000 mg/kg bw. Mortality was observed at 2000 mg/kg bw and above in both sexes. Animals died between 5 and 22 days after application. At necropsy perforating ulcers in the cutaneous stomach mucosa were observed in sacrificed animals at the end of the observation period (from 2500 mg/kg bw). In animals found dead perforating ulcers in the cutaneous stomach mucosa and splenic athropy (from 2000 mg/kg bw), hyperemia in the gastrointestinal tract and necrobiosis in the liver (from 2500 mg/kg bw) as well as petechial bleedings in the glandular stomach mucosa and anaemic renal infarction (from 3000 mg/kg bw) were recorded. The acute oral toxicity (LD50) of diflucortolone-21-valerate was determined to be 3100 mg/kg bw for male and female Wistar rats using probit analysis.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 100 mg/kg bw

Quality of whole database:

The study is of sufficient quality (Klimisch score = 2)

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

For bromhydrin-valerate (CAS No. 54605-02-6) no acute toxicity data are available. Therefore, acute oral toxicity data of diflucortolone-21-valerate (CAS No. 59198-70-8) were used since these data are regarded as representative. In diflucortolone-21-valerate the bromine atom in position 9 of the target molecule (bromhydrin-valerate) is replaced by a fluorine atom. No other changes in the molecule occured. No relevant toxicological effects are expected by the change of a halogen atom (Br) versus another (F). A search for structure-analogue substances using the QSAR OECD Toolbox 3.4 recommended diflucortolone-21-valerate as one out of 8 category substances for a read-across approach (for additional information see QSAR OECD Toolbox Report on Bromhydrin-valerat in "Attached justification"). Please refer also to the justification for read-across attached in chapter 13 of this IUCLID file.

 

After single oral administration of the test item difluocortolon-valerianat (diflucortolone-21-valerate) in doses of 2000, 2500, 3000, 3500 and 4000 mg/kg bw to male and female Wistar rats (5/sex/group) and during an observation period of 39 days clinical signs (emaciation, ungroomed coat, apathy, sporadic increased girth of abdomen, individual anaemic animals) were observed starting at 2000 mg/kg bw. Mortality was observed at 2000 mg/kg bw and above in both sexes. Animals died between 5 and 22 days after application. At necropsy perforating ulcers in the cutaneous stomach mucosa were observed in sacrificed animals at the end of the observation period (from 2500 mg/kg bw). In animals found dead perforating ulcers in the cutaneous stomach mucosa and splenic athropy (from 2000 mg/kg bw), hyperemia in the gastrointestinal tract and necrobiosis in the liver (from 2500 mg/kg bw) as well as petechial bleedings in the glandular stomach mucosa and anaemic renal infarction (from 3000 mg/kg bw) were recorded. The acute oral toxicity (LD50) of diflucortolone-21-valerate was determined to be 3100 mg/kg bw for male and female Wistar rats using probit analysis.

Justification for classification or non-classification

No classification is required for acute oral toxicity according to Regulation (EC) No. 1272/2008 (CLP).