Registration Dossier

Administrative data

Description of key information

Acute oral toxicity: weight of evidence approach including the following studies:

- Sanders (2000): LD50 (male/female rat) between 500 and 1000 mg a.i./kg bw (OECD TG 423, K1)

- Goldschmidt GmbH (1976): LD50 (male rat) between 1500 and 2250 mg a.i./kg bw (similar OECD TG 401, K2)

- Sterner and Chibanguza (1978): LD50 (male/female rat) ca. 2184 mg a.i./kg bw (similar OECD TG 401, K2)

- Thompson (1980): LD50 (male) > 1750 mg a.i./kg bw and LD50 (female) < 1750 mg a.i./kg bw (similar OECD TG 401, K2)

Acute dermal toxicity:

Sanders (2000): dermal LD50 > 2000 mg a.i./kg bw (OECD 402, K1)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
From October 20, 1999 to November 24, 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP study performed according to OECD TG 423. Dose levels follow guideline as it was in 2000.
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
Dose levels deviating from current guideline. Compliant with guideline as it was in 2000
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent, UK
- Age at study initiation: eight to twelve weeks old
- Weight at study initiation: males weighed 228 to 236 g, and the females 201 to 236 g
- Fasting period before study: overnight immediately before dosing
- Housing: in groups of three by sex in solid-floor polypropylene cages furnished with wood flakes
- Diet (e.g. ad libitum): ad libitum with the exception of an overnight fast immediately before dosing and for approximately three to four hours after dosing
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25 ºC
- Humidity (%): 30 - 70 %
- Air changes (per hr): The rate of air exchange was approximately fifteen changes per hour
- Photoperiod (hrs dark / hrs light): cycles of twelve hours continuous light and twelve hours darkness.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 217.4 mg/ml and 21.8 mg/ml
- Amount of vehicle (if gavage): 10 ml

DOSAGE PREPARATION: The test material solutions were prepared using a correction factor based on the purity of the test substance to ensure that the animals received 2000 and 200 mg/kg of the pure test material

MAXIMUM DOSE VOLUME APPLIED: 10 mL

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Using all available information, 2174 mg/kg bodyweight was selected as the starting dose. (This dose level was selected using a correction factor based on the purity of the supplied test material, to ensure that the animals received a dose equivalent to 2000 mg/kg bodyweight of pure test material).
Doses:
2174 mg/kg (equivalent to 2000 mg pure test material/kg) and 218 mg/kg (equivalent to 200 mg pure test material/kg)
No. of animals per sex per dose:
2000 mg/kg: a group of 3 female rats.
200 mg/kg: 6 rats, one group of 3 females and one group of 3 males
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Individual bodyweights were recorded prior to dosing and seven and fourteen days after treatment or at death
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs and body weight.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
>= 500 - <= 1 000 mg/kg bw
Based on:
act. ingr.
Remarks on result:
other: According to classification scheme in report
Mortality:
Two animals treated with 2174 mg/kg were found dead one or two days after dosing. There were no deaths noted at a dose level of 218 mg/kg.
Clinical signs:
Clinical signs in animals treated with 2174 mg/kg were hunched posture, diarrhoea and increased salivation with incidents of pallor of the extremities, emaciation, lethargy, pilo-erection, decreased respiratory rate, laboured respiration, red/brown staining around snout and tiptoe gait. All animals treated with 218 mg/kg appeared normal throughout the study.
Body weight:
All surviving animals showed expected gains in bodyweight over the study period.
Gross pathology:
Necropsy results of animals died during the study (treated with 2174 mg/kg) were haemorrhagic lungs, dark liver, dark kidneys, haemorragic gastric mucosa, sloughing and/or haemorrhage of the non-glandular epithelium of the stomach and haemorrhagic small and large intestines. No abnormalities were noted at necropsy of animals that were killed at the end of the study.

Individual Clinical Observations

Dose level mg/kg

Animal Nº

and Sex

Effects Noted After Dosing (Hours)

Effects Noted During Period After Dosing (Days)

 

2174

 

 

1/2

1

2

4

1

2

3

4

5

6

7

18

9

10

11

12

13

14

1-0

Female

H

H

HD

HD

HPD

Ss

HP

H

H

 

 

 

 

 

 

 

 

 

 

1-1

Female

HS

HS

 

HSD

HSD

X

 

 

 

 

 

 

 

 

 

 

 

 

 

1-2

Female

HS

HS  

HSD

HSD

H

P

Em

Ss

Rd

RL

Wt

E

X

 

 

 

 

 

 

 

 

 

 

 

 

D: diarrhea                                                               E: pallor of extremities

Em: emaciation                                                         H: hunched posture

L: lethargy                                                               P: pilo-erection

Rd: decreased respiratory rate                                RL: labored respiration

S: increased salivation                                              Ss: red/brown stainig around snout

Wt: tiptoe gait                                                          X: animal death

 

No clinical observations were noted at the dose of 218 mg/kg.

 

Body weights

Only the animals that died during the study showed a loss of weight

 

Dose Level mg/kg

Animal Nº and sex

Body weight (g) at day

Body weight (g) at

2174

 

0

7

14

Death

1-0 Female

204

243

246

 

1-0 Female

201

 

 

175

1-0 Female

207

 

 

170

 

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Mortalities were noted in animals treated at 2174 mg/kg b.w. No mortalities were noted in animals treated with 218 mg/kg b.w. The acute oral LD50 of the test substance in Sprague-Dawley rats was estimated as being in the range of 500 and 1000 mg/kg of pure test substance, according to the criteria in the guideline.
Executive summary:

The Acute Oral toxicity 'Acute Toxic Class method' study was performed in Sprague-Dawley CD strain rats. A stepwise procedure was used; a group of 3 females was treated with a dose of 2174 mg/kg (equivalent to 2000 mg of pure test material/kg) and 2 groups (3 females and 3 males) were treated with a dose of 218 mg/kg (equivalent to 200 mg of pure test material /kg). The test substance was administered as a solution in distilled water. An oral single dose of 10 ml/kg was given by gavage.

Clinical observations were made at 0.5, 1, 2, and 4 hours after dosing and subsequently once daily for up to 14 days. Individual body weights were recorded prior to dosing and 7 and 14 days after treatment or at death. All animals including those that died during the study were subjected to gross pathological observations. Two animals treated with 2174 mg/kg died. No mortalities were noted in animals treated with 218 mg/kg. The acute oral LD50 of the test substance in Sprague-Dawley rats was estimated as being in the range of 500 - 1000 mg/kg of pure test substance.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Well-documented non-GLP study performed according to a method similar to OECD TG 401.
Qualifier:
according to
Guideline:
other: Appraisal of the safety of chemicals in foods, drugs and cosmetics; by the Staff of the Division of Pharmacology, FDA, 1959
Deviations:
not specified
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Winkelmann, Paderborn, Germany
- Age at study initiation: no data
- Weight at study initiation: 160-205 g
- Fasting period before study: 16h prior to dosage
- Housing: in groups of 5 rats in plastic cages (42x26x14 cm) on wood chips bedding.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 45-55
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Substance was administered in a 100% concentration at dosage levels of 3.98, 5.00, 6.30 and 7.94 ml/kg bw.

Doses:
3.98, 5.00, 6.30 and 7.94 ml/kg.
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 and weighing: animals were observed closely for gross signs of systemic toxicity and mortality at frequent intervals during the day of dosage, and at least once daily thereafter.
- Necropsy of survivors performed: yes
Statistics:
Mortality data by Probit-analysis
Sex:
male/female
Dose descriptor:
LD50
Effect level:
6.24 mL/kg bw
Based on:
test mat.
95% CL:
5.84 - 6.65
Mortality:
After 14 days: 0/10 died at 3.98 ml/kg; 2/10 animals died at 5 ml/kg; 6/10 died at 6.30 ml/kg; 8/10 died at 7.94 ml/kg.
Clinical signs:
All animals at all levels exhibited decreased motor activity, coordination disturbance, abnormal body posture, abnormal gait, diarrhea and piloerection beginning approx. 20 min after dosage. At the two highest dose levels animals showed decreased grip- and limbtone. These symptoms partly persisted for 24h. At the 48h observation and later, all surviving animals appeared normal.
Body weight:
No effects.
Gross pathology:
Animals that died during the study showed slight redness of the gastro-intestinal mucous membrane and the intestine was filled with liquid.
Surviving animals did not show adverse effects.
Interpretation of results:
not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The oral rat LD50 derived after acute exposure and a 14-day recovery period, was 6.24 ml/kg bw. Assuming a relative density of 1, the oral LD50 equals 6240 mg/kg bw. When correcting for the active content (i.e. 35%) the LD50 is 2184 mg/kg bw , which is above the classification limits of the CLP Regulation.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
August-October 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Well-documented non-GLP study performed similar to OECD TG 401.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan
- Age at study initiation: approx. 7 weeks
- Weight at study initiation: 222-278 g; average males: 260 g; average females: 245 g
- Fasting period before study: 17h prior to dosage (only food withheld)
- Housing: group housed
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
no data

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Dose volume: 5.05 ml/kg bw
Doses:
5000 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 and weighing: animals were observed for pharmacotoxic signs and mortality at 1, 2.5, and 4h after compound administration and daily thereafter. Animals were weighed just before administration and at 7 and 14 days.
- Necropsy of survivors performed: only on animals that died during the study
Statistics:
Not applicable
Sex:
female
Dose descriptor:
LD50
Effect level:
< 5 000 mg/kg bw
Based on:
test mat.
Sex:
male
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
Males: 2 of 5 died on day 2 and 3.
Females: all animals died on day 1 or 2.
Clinical signs:
Males: On day 4 and thereafter all animals appeared normal. On day 3 and before, the following signs were noted: diarrhea (3/5), hypoactive (5/5), ataxia (3/5), urine stained abdomen (5/5), decreased limb tone (1/4), impaired righting reflex (1/4)
Females: 4 animals showed diarrhea before death, the remaining animal on day 1 showed ataxia, hypoactivity, decreased limb tone, bradypnea and urine stained abdomen.
Body weight:
No effects
Gross pathology:
Males that died during study: one animal only showed severe cannibalization; the other animal showed light to dark-red mottled lungs and gastrointestinal tract with little content and distented with gas.
Females that died during study: one female showed small red areas on thymus and slightly dark lungs. The other females showed distended stomach and empty colon. One female also showed multiple dark red areas on the lung.
Interpretation of results:
study cannot be used for classification
Conclusions:
The oral rat LD50 in males was found to be >5000 mg/kg bw; while the LD50 in females was <5000 mg/kg bw. When correcting for the active content (i.e. 35%) the male LD50 is >1750 mg/kg bw and the female LD50 is <1750 mg/kg bw.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
October-December 1976.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Non-GLP study performed similar to OECD TG 401.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
not specified
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Holtzman
- Age at study initiation: approx. 7 weeks
- Weight at study initiation: average group weights: 146, 177 and 191 g
- Fasting period before study: no data
- Housing: individually in screen bottom cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
no data
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Substance administered as such.
Doses:
5000, 7500 and 10000 mg/kg bw
No. of animals per sex per dose:
6
Control animals:
no
Details on study design:
Observations were made at hourly intervals for 5h after dosing and twice daily thereafter.
Surviving animals were sacrified. Gross post mortem examinations were performed on all animals and gross tissue alterations noted.
Statistics:
No data
Sex:
male
Dose descriptor:
LD50
Effect level:
> 5 000 - < 7 500 mg/kg bw
Based on:
test mat.
Mortality:
5000 mg/kg: 0/6 died
7500 mg/kg: 4/6 died on day 1 or 2
10000 mg/kg: all animals died on day 1 or 2
Clinical signs:
No data
Body weight:
No data
Gross pathology:
No data
Other findings:
No data
Interpretation of results:
not classified
Conclusions:
The male rat oral LD50 was estimated as being between 5000 and 7500 mg/kg bw. When correcting for the active content (i.e. 30%): the LD50 is between 1500 and 2250 mg/kg bw.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
1 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
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
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:
From October 20, 1999 to November 3, 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
OECD guideline 402 and EU guideline B.3. GLP study.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK)
- Age at study initiation: eight to twelve weeks old
- Weight at study initiation: males 206 to 232 g, and the females 214 to 225 g.
- Housing: in suspended polypropylene cages furnished with wood flakes. The animals were housed individually during the 24-hour exposure period and in groups of five, by sex, for the remainder of the study
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25 ºC
- Humidity (%): 30-70 %
- Air changes (per hr): approximately fifteen changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light and twelve hours darkness
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: approximating to 10% of the total body surface area.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with cotton wool moistened with distilled water to remove any residual test material.
- Time after start of exposure: After the 24-hour contact period

TEST MATERIAL
- Concentration (if solution): 2174 mg/kg (equivalent to 2000 mg/kg bodyweight of pure test material).
Duration of exposure:
24-hours
Doses:
2174 mg/kg (equivalent to 2000 mg/kg bodyweight of pure test material).
No. of animals per sex per dose:
Ten animals (five males and five females)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days. Individual bodyweights were recorded prior to application of the test material on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 174 mg/kg bw
Based on:
test mat.
Remarks on result:
other: The dose 2174 mg/kg is equivalent to 2000 mg/kg bodyweight of pure test material
Mortality:
There were no deaths.
Clinical signs:
No signs of systemic toxicity were noted during the study. Very slight to well-defined erythema was noted at the treatment sites of all animals one and two days after dosing and very slight oedema was noted at the treatment sites of eight animals one day after dosing. On the treated site of some animals a slight brown discoloration of the epidermis (in four animals) bleeding (in one animal), desquamation (in four animals) and crust formation (in five female animals) was noted.
Body weight:
All animals showed expected gain in bodyweight during the study except for one female animal which showed bodyweight loss during the first week and expected gain in bodyweight during the second week.
Gross pathology:
No abnormalities were noted at necropsy.

Table 1: Individual bodyweight and weekly changes

 

Doselevel

mg/kg

Animal Number and Sex

Bodyweight

(g) atDay

Bodyweight Gain (g)

During Week

 

 

0

7

14

1

2

2174

1-0 Male

206

238

286

32

48

1-1 Male

228

285

336

57

51

1-2 Male

232

280

345

48

65

1-3Male

220

257

312

37

55

1-4 Male

215

201

322

46

61

2-0 Female

214

215

234

1

19

2-1 Female

220

225

236

5

11

2-2 Female

225

220

245

-5

25

2-3 Female

224

235

265

11

30

2-4 Female

225

226

250

1

24

 

 

Interpretation of results:
not classified
Conclusions:
The acute dermal median lethal dose (LD50) of the test substance in the Sprague-Dawley rat was found to be greater than 2174 mg/kg bodyweight (equivalent to 2000 mg/kg bodyweight of pure test material). The test substance is not to be classified as acute dermal toxicant according to CLP Regulation.
Executive summary:

The Acute Dermal Toxicity assay for the test substance was performed in Sprague-Dawley rats. One female group and one male group, of 5 animals each one, were treated with a single dose of 2174 mg/kg bodyweight, equivalent to 2000 mg/kg bodyweight of pure test material (Limit test). The test material was applied uniformly to an area of shorn skin (approximating to 10% of the total body surface area). A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage. After the 24-hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with distilled water. Clinical observation was conducted at 1/2,1, 2 and 4 hours after dosing and subsequently once daily for fourteen days. Body weight was controlled before the administration, on day 0 and on days 7 and 14 after the administration. All animals were subjected to gross necropsy. No test substance related effects were noted from clinical observations or post-mortem examination. The acute dermal median lethal dose (LD50) of the test substance in the Sprague-Dawley rat was found to be greater than 2174 mg/kg bodyweight (equivalent to 2000 mg/kg bodyweight of pure test material).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Additional information

For acute oral toxicity, a weight of evidence approach is used to define an LD50 value. The Sanders (2000) study estimated an LD50 value as being between 500 and 1000 mg/kg bw, according to OECD 423 guideline methodology in 2000 (K1). Three additional studies are available, performed according to a method similar to OECD guideline 401 (K2). The Sterner and Chibanguza (1978) study showed an LD50 of ca. 2184 mg/kg bw, estimated using an assumed density of 1 g/ml. The 1976 study (Goldschmidt GmbH) only used male rats and estimated an LD50 value as being between 1500 and 2250 mg/kg bw. The Thompson (1980) study showed a male LD50 of >1750 mg/kg bw and a female LD50 of <1750 mg/kg bw (corrected for the active content (i.e. 35%)).

Based on all the available data on the acute oral toxicity of this substance, an LD50 value of 1000 mg/kg bw is proposed.

Acute dermal toxicity is covered by the key study by Sanders (2000, K1), revealing a dermal LD50 > 2000 mg/kg bw.

Acute inhalation toxicity is waived as the other routes of exposure have been covered, and inhalation exposure is not likely during use as the substance is marketed as a dilution in water.

Justification for classification or non-classification

In view of the assumed oral LD50 value of 1000 mg a.i./kg bw, the substance should be classified for acute oral toxicity as category 4 (H302)according to the CLP Regulation.

In view of the dermal LD50 value of >2000 mg a.i./kg bw, the substance should not be classified for acute dermal toxicity according to the CLP Regulation.