Registration Dossier

Administrative data

Description of key information

Oral (OECD 423), rat: LD50 = 5000 mg/kg bw (cut-off value, limit test)
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:
16 - 31 Oct 2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP - Guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
adopted 2001
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
adopted 2004
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
adopted 2002
Deviations:
no
Qualifier:
according to
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000, including the most recent partial revisions
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
other: Wistar Crl:WI
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approximately 12 weeks
- Weight at study initiation: 214-242 g (range)
- Fasting period before study: maximum 20 hrs prior to the administration until 3-4 hrs after administration
- Housing: animals were housed in groups of 3 animals per cage in labelled Macrolon cages (MIV type; height 18 cm) containing sterilised sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom)
- Diet: pelleted rodent diet SM R/M-Z (SSNIFF Spezialdiäten GmbH, Soest, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.1-23.2
- Humidity (%): 26-63
- Air changes (per hr): approximately 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 16 Oct 2008 To: 31 Oct 2008
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 10 mL/kg bw
- Justification for choice of vehicle: the vehicle was selected based on trial formulations performed at the testing laboratory and on test substance data supplied by the sponsor

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
6 (3 per step)
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 for mortality and morbidity twice daily; the occurrence of clinical signs was recorded at periodic intervals on Day 1 (0, 2, 4 hrs after administration) and once daily thereafter until Day 15; body weight was recorded on Day 1 (prior to administration), 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: According to OECD 423, the LD50 cut-off is set at 5000 mg/kg bw based on a limit test with 2000 mg/kg bw, since no mortality occurred in any step.
Mortality:
No mortality occurred during the study period.
Clinical signs:
A hunched posture was observed in 6/6 rats 2 h after dosing. 3/6 animals had piloerection and the remaining 3/6 rats had slight uncoordinated movements from dosing until 4 h after administration. Slight alopecia was noted 2/6 animals from Day 9 or 10 until the end of the study period.
Body weight:
No effect on body weight was noted.
Gross pathology:
No substance-related findings were noted during macroscopic post mortem examination.

Table 1: Mortality and clinical signs

Dose
[mg/kg bw]

Toxicological results*

Duration of clinical signs

Time of death

Mortality (%)

Females

2000

0/6/6

0-4 h on Day 1, Day 9-15 

-

0

Overall LD50 > 2000 mg/kg bw

* first number = number of dead animals                                 

  second number = number of animals with systemic clinical signs         

  third number = number of animals used

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
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

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:
5 - 19 Dec 2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP - Guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
adopted 1987
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
adopted 1992
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Version / remarks:
adopted 1998
Deviations:
no
Qualifier:
according to
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000, including the most recent partial revisions
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Wistar Crl:WI(Han)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approximately 8 weeks
- Weight at study initiation: 263 ± 11 g (mean ± SD, males); 189 ± 5 g (mean ± SD, females)
- Housing: during the study period, animals were housed individually in labelled Macrolon cages (MII type; height 18 cm) containing sterilised sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom). During the acclimatisation period, animals were housed in groups in Macrolon type MIV cages.
- Diet: pelleted rodent diet SM R/M-Z (SSNIFF Spezialdiäten GmbH, Soest, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.0-21.7
- Humidity (%): 40-59
- Air changes (per hr): approximately 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 5 Dec 2007 To: 19 Dec 2007
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: the test substance was held in contact with the skin with a dressing, consisting of a surgical gauze patch (Surgy 1D), covered with aluminium foil, which was covered with Coban elastic bandage. A piece of Micropore tape was additionally used to fix the wrapping in females only.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the treated site was cleaned of residual test substance using tap water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount applied: 10 mL/kg bw
- Concentration: 200 mg/mL (w/w) (calculated from 10 mL/kg bw amount and 2000 mg/kg bw)
- Constant volume or concentration used: yes

VEHICLE
- Concentration (if solution): 10 mL/kg bw
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
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 for mortality and morbidity twice daily; the occurrence of clinical signs was recorded at periodic intervals on Day 1 (0, 2, 4 h after administration) and once daily thereafter until Day 15; body weight was recorded on Day 1 (prior to administration), 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology
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:
Systemic effects were observed on Day 1 up to 4 h after administration. Flat posture was observed in 2/5 males 2 and 2-4 h after dosing on Day 1, respectively, while chromodacryorrhoea was noted in 4/5 males and 1/5 females 0, 2 or 4 h after administration (see Table 1 and 2).
Body weight:
The body weight gains were within the normal ranges in males and females during the whole study period.
Gross pathology:
No substance-related findings were noted at macroscopic post mortem examination of the animals..
Other findings:
- Other observations: Mild local effects on the treated skin were seen throughout the study period. White staining of the skin was noted in all animals for up to 4 consecutive days in the period Day 2-5. Scales or scabs were seen in 1/5 males and 3/5 females for 1-10 consecutive days in the period Day 4-15, while focal erythema was observed in 2/5 females on Day 3 or 3-4, respectively.

Table 1: Mortality and clinical signs

Dose
[mg/kg bw]

Toxicological results*

Duration of clinical signs

Time of death

Mortality (%)

Males

2000

0/5/5

0 h on Day 1 – Day 10 

-

0

Females

2000

0/5/5

0 h on Day 1 – Day 15 

-

0

Overall LD50 > 2000 mg/kg bw

* first number = number of dead animals                                 

 second number = number of animals with systemic clinical signs         

 third number = number of animals used                               

 

Table 2: Overview of clinical signs and duration

Observations

Males (time of observation)

Females (time of observation)

No.

1

2

3

4

5

1

2

3

4

5

Systemic

Flat posture

 

 

 

2-4 h, Day 1

2 h, Day 1

 

 

 

 

 

Chromodacryorrhoea (snout)

0 h, Day 1

2 h, Day 1

4 h, Day 1

4 h, Day 1

 

4 h, Day 1

 

 

 

 

Treated skin

Scales

grading slight (1) to severe (3)

 

 

Day 6-10

grade: 1

 

 

 

 

 

 

Day 12

grade: 1

White staining

Day 2-5

Day 2-4

Day 2-3

Day 2-3

Day 2

Day 2-4

Day 2-4

Day 2-4

Day 2

Day 2

Scabs

grading slight (1) to severe (3)

 

 

 

 

 

 

Day 4-15

grade: 1

Day 5-14

grade: 1

 

Day 8-11

grade: 1

Focal erythema

grading slight (1) to very severe (4)

 

 

 

 

 

Day 3

grade: 1

 

 

 

Day 3-4

grade: 1

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
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard requirements set out in Annex VIII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

Oral

In a study performed according to the acute toxic class method (OECD Guideline 423), 2-methyl-N-(4-sulfamoylphenyl) prop-2-enamide (SPM-N) in propylene glycol was administered via gavage to two subsequent groups of 3 female Wistar rats at the limit dose of 2000 mg/kg bw (Stitzinger, 2008a). No mortality occurred within the 14-day observation period. A hunched posture was observed in 6/6 rats 2 h after dosing. 3/6 animals had piloerection and the remaining 3/6 rats had slight uncoordinated movements from dosing until 4 h after administration. The body weight was not affected during the observation period and no substance-related findings were noted during macroscopic post-mortem examination. According to OECD Guideline 423, Annex 2d, a cut-off value of 5000 mg/kg bw was derived, since no mortality occurred in any step at the limit dose of 2000 mg/kg bw.

 

Dermal

The acute dermal toxicity of SPM-N was assessed in a limit test performed according to OECD Guideline 402 and under GLP conditions (Stitzinger, 2008b). A single dose of 2000 mg/kg bw of the test substance in propylene glycol was applied to the shaved skin of 5 rats/sex/dose under occlusive conditions for 24 h. There was no mortality and no effects on body weight were noted during the 14-day observation period. Clinical signs were observed on Day 1 up to 4 h after administration: flat posture was observed in 2/5 males, while chromodacryorrhoea was noted in 4/5 males and 1/5 females 0, 2 or 4 h after administration. The necropsy and gross pathological examination did not reveal any treatment-related effects. Slight local effects on the treated skin area were seen throughout the study period. White staining of the skin was noted in all animals for up to 4 days in the period Day 2-5. Scales or scabs were seen in 1/5 males and 3/5 females for 1-10 consecutive days in the period Day 4-15, while focal erythema was observed in 2/5 females on Day 3 or 3-4, respectively. The LD50 value for systemic toxicity is considered to be > 2000 mg/kg bw.


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

Justification for selection of acute toxicity – inhalation endpoint
The acute inhalation toxicity study is not required as no inhalation exposure is expected taking into account the physico-chemical properties and the conditions of use.

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

Justification for classification or non-classification

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