Registration Dossier

Administrative data

Description of key information

Acute oral toxicity and an acute dermal toxicity studies are available on the target and read across substances

The LD50 were >2000 mg/kg bw in both sets of studies.

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:
key study
Reliability:
1 (reliable without restriction)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
GLP compliance:
not specified
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Initial testing with 5 females and 5 females will be performed at a dose of 5000 mg/kg. If mortality does not exceed 50% at this dose level, no further dose levels will be tested, If mortality os produced, additional dose levels will be performed in order to obtain the LD50 value. All animals will be dosed by oral gavage with the rest material
No. of animals per sex per dose:
5/sex/dose
Control animals:
no
Details on study design:
All animals will be individaully housed in stainless stell cages and offered food and water ad libitum. All test animals will be fasted overnight prior to dosing. Following dosing, all test animals will be oserved daily for 14 days following dosing for any toxic or deleterious effects, The weight of each animal will be determined prior to dising, at death, or at the end of the 14 day observation period.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no mortalities observed during the study
Clinical signs:
There were no clinical signs of toxicity observed during the study
Gross pathology:
No gross changes observed
Interpretation of results:
GHS criteria not met
Conclusions:
The Acute oral LD50 was found to be > 2000 mg/kg
Executive summary:

Based on the results of this study, the LD50 of the test material is considered to be greater than 2000 mg/kg and does not meet the GHS classification criteria for acute toxicity.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 23 September 2002 to 10 October 2002
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline-conform study under GLP without deviations
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
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: Harlan UK. Ltd., Bicester, Oxon, England
- Age at study initiation: 5-7 weeks
- Weight at study initiation: 85-108g
- Fasting period before study: Access to food only was prevented overnight prior to and approximately four hours after dosing
- Housing: In groups of three rats of the same sex in metal cages with wire mesh floors
- Diet (e.g. ad libitum): standard laboratory rodent diet ad libitum
- Water (e.g. ad libitum): drinking water at libitum
- Acclimation period: minimum period of five days prior to the start of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%): relative humidity 40 - 70%.
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): controlled by means of a time switch to provide 12 hours of artificial light (0600 - 1800 hours GMT) in each 24-hour period

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 100 mg/mL
- Amount of vehicle (if gavage): 20 mL/kg body weight
- Justification for choice of vehicle: soluble in water


MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg body weight

DOSAGE PREPARATION (if unusual): not applicable

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: according to the guideline, start with 2000mg/kg if no of low toxicity is expected
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations twice daily, Weighing on day 1 (prior to dosing), 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: mortality clinical signs, body weight, macroscopic examination
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Sex:
male/female
Dose descriptor:
LD0
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths following a single oral gavage dose of DV6850 to a group of six rats (three males and three females) at a dose level of 2000 mg/kg bodyweight.
Clinical signs:
No clinical signs of reaction to treatment were observed in any animal throughout the duration of the study.
Body weight:
All animals were considered to have achieved satisfactory bodyweight gains throughout the study.
Gross pathology:
No abnormalities were revealed at the macroscopic examination at study termination on Day 15.

Individual and group mean bodyweights (g)

Dose
(rng)kg)

Sex

Animal
Number

Bodyweight (g) at Day

1*

8

15

2000

Male

GG4

103

153

187

GG5

108

161

200

GG6

104

166

218

Mean

105

160

202

Female

GGI

86

128

145

GG2

92

138

164

GG3

85

132

159

Mean

88

133

156

* Prior to dosing

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute lethal oral dose to rats of DV6850 was demonstrated to be greater than 2000 mg/kg bodyweight in accordance with OECD Guideline No. 423. DV6850 is in accordance with DSD (Directive 67/548/EEC) or CLP Regulation (EC) No 1272/2008 "unclassified" and will not require labelling
Executive summary:

This study was performed to assess the acute oral toxicity of DV6850 to the rat. The method followed was that described in EEC Methods for the determination of toxicity, Annex to Directive 96/54/EEC (Official Journal No, L248, 30,9,96). Part B, Method B.1 tris, "Acute toxicity (oral) - acute toxic class method" and OECD Guideline for Testing of Chemicals No.423 “Acute Oral Toxicity - Acute Toxic Class Method” Adopted 22 March 1996.

A group of three fasted female rats received a single oral gavage dose of the test substance, formulated in water for irrigation, at a dose level of 2000 mg/kg. As results at this dosage indicated the acute lethal oral dose of the test material to be greater than 2000 mg/kg bodyweight, in compliance with the study guidelines, a group of three fasted males was dosed at 2000 mg/kg to confirm results at this dosage and complete the study.

All animals were killed as scheduled and examined macroscopically on Day 15, the end of the observation period. No clinical signs of reaction to treatment were observed in any animal throughout the duration of the study. All animals were considered to have achieved satisfactory bodyweight gains throughout the study. No abnormalities were revealed at the macroscopic examination at study termination on Day 15.

The acute lethal oral dose to rats of DV6850 was demonstrated to be greater than 2000 mg/kg bodyweight. DV6850 is in accordance with DSD (Directive 67/548/EEC) or CLP Regulation (EC) No 1272/2008 "unclassified" and will not require labelling.

Endpoint conclusion
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Study was conducted on the test material and followed OECD guidelines
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
not specified
Test type:
fixed dose procedure
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
All animals will be housed individually hourse in stainless steel cages and will be offered food and water ad libitum
Type of coverage:
occlusive
Details on dermal exposure:
Twenty-four hours prior to application of the test material, the trunk of the rabbit is shaved. The 24-hour period between shaving and application of the test material allows recovery of the stratum corneum from hte disturbance caused by shaving. All animals are weighed on day of dosing. Based upon the animal's body weight, the test material is applied and a sleeve of plastic sheeting is fitted oven the shaven trunk of the animals and secured in place with adhesive tape. The test material remains in contact with the skin for a 24 hour period after which time the wrap is removed and any remaining test article wiped off
Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 animals/sex/dose
Control animals:
no
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
no indication of skin irritation up to the relevant limit dose level
Mortality:
No mortalities were recorded during the duration of the study
Clinical signs:
No clinical signs of toxicity were reported
Gross pathology:
No gross chnages observed
Interpretation of results:
GHS criteria not met
Conclusions:
LD50 is greater than 2000 mg/kg
Executive summary:

No mortalities or clinical signs of toxicity were observed during the duration of the study. The LD50 is > 2000 mg/kg and does not meet the criteria for classification under GHS

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2002-07-11 to 2003-03-03
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline-conform study under GLP without deviations
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: Harlan UK Ltd., Bicester, Oxon, England
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 188 to 228 g
- Housing: individually in metal cages (RS Biotech Sub-Dividable Rodent Cages - polished stainless steel)
- Diet (e.g. ad libitum): standard laboratory rodent diet (Special Diet Services RM1(E) SQC expanded pellet) ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3°C
- Humidity (%): 40-70%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12 hours of continuous artificial light in each 24-hour period
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: One day prior to treatment, hair was removed from the dorso-lumbar region of each rat with electric clippers taking care to avoid damaging the skin, exposing an area equivalent to approximately 10% of the total body surface area.
- % coverage: approximately 50 mm x 50 mm was covered with substance
- Type of wrap if used: covered with porous gauze held in place with a non-irritating dressing and further covered by a waterproof dressing encircled firmly around the trunk of the animal

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The treated area of skin was washed with warm water (30 - 40°C) to remove any residual test substance. The treated area was blotted dry with absorbent paper.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bodyweight
- Concentration (if solution): 20% test substance
- Constant volume or concentration used: yes
Duration of exposure:
24 hours
Doses:
2000 mg/kg bodyweight
No. of animals per sex per dose:
5 males
5 females
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 animals were observed once in the morning and again at the end of the experimental day (with the exception of Day 15 - morning only). The nature and severity of the clinical signs and time were recorded at each observation. The bodyweight was recorded on day 1 (prior to dosing), 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: mortality, clinical signs, dermal responses, body weight, organ weights
- Scoring System for dermal observations:
Erythema and eschar formation:
No erythema: 0
Very slight erythema (barely perceptible): 1
Well-defined erythema: 2
Moderate to severe erythema: 3
Severe erythema (beet redness) to eschar formation (injuries in depth): 4

Oedema formation:
No oedema: 0
Very slight oedema (barely perceptible): 1
Slight oedema (edges of area well-defined by definite raising): 2
Moderate oedema (raised approximately 1 mm): 3
Severe oedema (raised more than 1 mm and extending beyond the area of exposure): 4
Sex:
male/female
Dose descriptor:
LD0
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000
Based on:
test mat.
Mortality:
no deaths
Clinical signs:
- no systemic response
- Very slight to moderate to severe dermal irritation (Grade 1 to 3 erythema with or without Grade 1 or 2 oedema) was observed in all animals following removal of the dressings, resolving completely by either Day 7 in males and Day 9 in females. In addition, desquamation (characterised by dryness/exfoliation) was seen in four males and all females from Day 3, resolving in three males by Day 12 and two females by Day 14 and persisting in one male and three females until study termination on Day 15. Spots and/or scabbing (confined to a small area of the dose site) were also observed in one male and four females from Day 7, resolving in the male by Day 9 and persisting in all the females until study termination on Day 15.
Body weight:
No bodyweight gain was recorded for one female (CC9) on both Day 8 and Day 15. A notably low bodyweight gain was seen in one female on Day 8 (CC10) and one female (CC7) on Day 15. All other animals were considered to have achieved satisfactory bodyweight gains throughout the study.
Gross pathology:
Dryness of the dose site was seen at the macroscopic examination of one male and three females with scabbing of the dose site seen in four females. No other abnormalities were revealed at the macroscopic examination at study termination on Day 15.

Table 1 - Dermal reactions

Dose
(mg/kg)

Sex

Animal
No

E=Erythema

O=Oedema

Day

2

3

4

5

6

7

8

9

10

11

12

13 to 15

2000

Male

CCI

E

1

1a

1a

0a

0a

0a

0a

0

0

0

0

0

O

1

1

0

0

0

0

0

0

0

0

0

0

CC2

E

1

1

0

0

0

0

0

0

0

0

0

0

O

0

0

0

0

0

0

0

0

0

0

0

0

CC3

E

1

1

1

1a

0a

0

0

0

0

0

0

0

O

1

1

1

0

0

0

0

0

0

0

0

0

CC4

E

2

1

1

1a

0a

0

0

0a

0a

0a

0

0

O

1

2

2

2

1

0

0

0

0

0

0

0

CC5

E

2

1a

1a

1a

0a

0a

0a

0a

0a

0a

0a

0a

O

1

2

1

1

1

0b

0b

0

0

0

0

0

Female

CC6

E

2

2

2a

1a

0a

0a

0a

0a

0a

0a

0a

0a

O

1

2

1

1

1

1b

1b

0b

0b

0b

0b

0b

CC7

F

3

2

2a

2a

1a

0a

0a

0a

0a

0a

0a

0a

O

2

2

2

1

1

1b

0b

0b

0b

0b

0b

0b

CC8

E

2

2

2a

1a

0a

0a

0a

0

0

0

0

0

O

1

1

1

1

1

0

0

0

0

0

0

0

CC9

E

1

1

1a

1a

0a

0a

0a

0a

0a

0a

0a

0b

O

1

1

1

1

1

0b

0b

0b

0b

0b

0b

0

CC10

E

1

1

1a

1a

0a

0a

0a

0a

0a

0a

0a

0a

O

1

1

1

1

1

1

0

0

0

0b

0b

0b

a Desquamation (characterised by dryness/exfoliation)

b Spots and/or scabbing (confined to small area of dose site)

Table 2- Individual and group mean bodyweights (g)

Dose
(mg/kg)

Sex

Animal
Number

Bodyweight (g) at Day

1*

8

15

2000

Male

CC1

200

236

275

CC2

190

224

260

CC3

192

223

253

CC4

188

232

289

CC5

201

238

277

Mean

194

231

271

Female

CC6

228

238

251

CC7

220

231

237

CC8

209

221

238

CC9

207

207

207

CC10

206

212

225

Mean

214

222

232

 *       Prior to dosing

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute lethal dermal dose to rats of DV6850 was demonstrated to be greater than 2000 mg/kg bodyweight. DV6850 is in accordance with DSD (Directive 67/548/EEC) or CLP Regulation (EC) No 1272/2008 "unclassified" and will not require labelling
Executive summary:

A study was performed to assess the acute dermal toxicity of DV6850 to the rat. The method followed was that described in EEC Methods for the determination of toxicity, Annex to Directive 92/69/EEC (Official Journal No. L383A, 29.12_92), Part B, Method B3. "Acute toxicity (dermal)" and OECD Guideline for Testing of Chemicals No, 402 "Acute Dermal Toxicity". Adopted: 24 February 1987.

A group of ten rats (five males and five females) received a single topical application of the test substance, in water for irrigation, at a dose level of 2000 mg/kg bodyweight. All animals were killed and examined macroscopically on Day 15, the end of the observation period.

There were no deaths and no systemic response to treatment in any animal throughout the study.

Very slight to moderate to severe dermal irritation (Grade 1 to 3 erythema with or without Grade 1 or 2 oedema) was observed in all animals following removal of the dressings, resolving completely by either Day 7 in males and Day 9 in females. In addition, desquamation (characterised by dryness/exfoliation) was seen in four males and all females from Day 3, resolving in three males by Day 12 and two females by Day 14 and persisting in one male and three females until study termination on Day 15. Spots and/or scabbing (confined to a small area of the dose site) were also observed in one male and four females from Day 7, resolving in the male by Day 9 and persisting in all the females until study termination on Day 15.

No bodyweight gain was recorded for one female on both Day 8 and Day 15. A notably low bodyweight gain was seen in one female on Day 8 and one female on Day 15. All other animals were considered to have achieved satisfactory bodyweight gains throughout the study.

Dryness of the dose site was seen at the macroscopic examination of one male and three females with scabbing of the dose site seen in four females. No other abnormalities were revealed at the macroscopic examination at study termination on Day 15.

The acute lethal dermal dose to rats of DV6850 was demonstrated to be greater than 2000 mg/kg bodyweight.

DV6850 is in accordance with DSD (Directive 67/548/EEC) or CLP Regulation (EC) No 1272/2008 "unclassified" and will not require labelling

Endpoint conclusion
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

The acute oral and dermal toxicity of the source 1 substance were assessed in two valid GLP studies according to OECD TG 423 and 402, respectively. In addition the acute oral and dermal toxicity of the target substance were assessed in two studies equivalent or similar to OECD TG 423 and 402, respectively.

The acute oral toxicity of the source 2 substance was also assessed in a study equivalent or similar to OECD TG 401 as an anchor study for read across purposes. 

 

Acute inhalation toxicity was not assessed because the vapour pressure of the substance is very low (9.9 x 10-7 Pa at 25°C) and exposure to aerosols, particles or droplets of an inhalable size is not anticipated with the uses of the target substance.

 

In the oral toxicity tests on the source 1, source 2 and target substance, rats received a single oral gavage dose of the test substance at a dose level of 2000 mg/kg. All animals were killed as scheduled and examined macroscopically at the end of the observation period (day 15). No signs of toxicity were observed and the acute lethal oral dose of source 1, source 2 and target substance in rats was demonstrated to be greater than 2000 mg/kg bodyweight.

 

In the dermal toxicity test on the source 1 and target substance, rats received a single topical application of the test substance at a dose level of 2000 mg/kg bodyweight. In the dermal toxicity test on source 1 substance, all animals were killed and examined macroscopically at the end of the observation period (day 15). Dermal irritation, desquamation, spots and/or scabbing were observed in some animals and persisted until study termination in some of the affected animals. No or notably low bodyweight gains were observed for three females on Day 8 and/or Day 15. All other animals were considered to have achieved satisfactory bodyweight gains throughout the study. There were no deaths and no systemic response to treatment in any animal throughout the study. The acute lethal dermal dose of Source 1 substance in rats was demonstrated to be greater than 2000 mg/kg bodyweight. In the dermal toxicity test on target substance no mortalities or clinical signs of toxicity were observed during the duration of the study. The LD50 is > 2000 mg/kg and does not meet the criteria for classification under GHS.

Justification for classification or non-classification

As the acute lethal oral and dermal dose to rats of the source and target substances were demonstrated to be greater than 2000 mg/kg bodyweight, the source and target does not have to be classified for acute toxicity according to according to the criteria of Directive 67/548/EEC (DSD) or Regulation (EC) No. 1272/2008 (CLP).