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Administrative data

Description of key information

Combined LD50=3354 mg/kg bw by oral route.
LD50>2000 mg/kg bw in a limit test by dermal route.

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:
24 August 1989 - 26 September 1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP study conducted in compliance with international guidelines but with deviations: no certificate of analysis of the test substance, animals exposed occasionally to humidity higher than 70%.
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
yes
Remarks:
No certificate of analysis; humidity higher than 70%
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
No certificate of analysis; humidity higher than 70%
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
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: Bantin & Kingman Ltd, Grimston, U.K.
- Age at study initiation: approximatively 5 to 8 weeks old
- Weight at study initiation: males: 120 to 153 g - females: 120 to 150 g
- Fasting period before study: an overnight fast immediately before dosing and for approximately two hours after dosing
- Housing: the animals were housed in groups of up to five by sex in solid-floor polypropylene cages with sawdust bedding
- Diet (e.g. ad libitum): Rat and Mouse Expanded Diet No. 1 (Special Diet Services Limited, Witham, U.K.), ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 24
- Humidity (%): 54 - 76
- Air changes (per hr): approximately 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark


IN-LIFE DATES: 24 August 1989 - 26 September 1989
Route of administration:
oral: unspecified
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: see table 1
- Amount of vehicle (if gavage): see table 1
Doses:
Range-finding study: 500, 1000, 3000 and 5000 mg/kg
Limit test: 5000 mg/kg
Main study: 2530, 3000, 3557 and 4217 mg/kg
No. of animals per sex per dose:
Range-finding study: 1
Limit test: 5
Main study: 5
Control animals:
no
Details on study design:
- Duration of observation period following administration: range-finding study: 5 days; limit test and main study: 14 days
- Frequency of observations and weighing:
Range-finding study: animals were observed 1 and 4 hours after dosing and subsequently once daily for 5 days. Individual bodyweights were recorded on the day of dosing (day 0). No necropsies were performed.
Limit test and main study: animals were observed 1 and 4 hours after dosing and subsequently once daily for 14 days. Deaths and evidence of over toxicity were recorded at each observation. Individual bodyweights were recorded on the day of dosing (day 0) and on days 7 and 14 or at death. All animals were subjected to gross necropsy examination for any macroscopic abnormalities. No tissues were retained.
Statistics:
The acute oral median lethal dose (LD50) and 95% confidence limits of the test material were calculated using a probit method of Finney D.J. (1971)
Preliminary study:
No deaths were recorded for all the dose levels in the range-finding experiment.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
3 354 mg/kg bw
95% CL:
2 834 - 3 970
Sex:
male
Dose descriptor:
LD50
Effect level:
3 264 mg/kg bw
95% CL:
2 648 - 4 024
Sex:
female
Dose descriptor:
LD50
Effect level:
3 494 mg/kg bw
95% CL:
2 654 - 4 601
Mortality:
See table 2
Clinical signs:
Major signs of toxicity noted in all dose groups were hunched posture, pilo-erection, lethargy, ptosis, decreased or gasping respiration and red/brown staining around the snout or mouth. Additional signs of ataxia and/or increased salivation were also noted. Animals treated with 3000, 3557 or 4217 mg/kg also showed distended abdomen and/or emaciation. Animals treated with 3557 mg/kg showed pallor of the extremities with an isolated incident of tiptoe gait.
Surviving animals treated with 2530, 3000 or 5000 mg/kg appeared normal two to six days after treatment. Surviving animals treated with 3557 or 4217 mg/kg appeared normal eight to fourteen days after treatment with one exception of one female treated with 3557 mg/kg which showed signs of toxicity throughout the study period.
Body weight:
Incidents of reduced bodyweight gain or bodyweight loss were noted in all dose groups (see table 3).
Gross pathology:
Abnormalities noted at necropsy of animals that died during the study were haemorrhagic or abnormally red lungs, dark liver or patchy pallor of the liver, pale spleen, pale or dark kidneys, haemorrhage or sloughing of the glandular gastric epithelium and haemorrhage of the small and/or large intestines. One male treated with 3557 mg/kg which died during the study was found cannibalised. The stomach of one male treated with 4217 mg/kg, which died during the study, was adhered to the liver and intestines.
Abnormalities noted at necropsy of animals treated with 2530 mg/kg which were killed at the end of the study were occasional white foci approximately 1 mm x 1 mm covering 75% of the non-glandular gastric epithelium.
No abnormalities were noted at necropsy of animals treated with 3000 mg/kg or greater which were killed at the end of the study.
Other findings:
No data

Table 2: mortality data in the main study

Dose level

mg/kg

Deaths

Male

%

Female

%

Total

%

2530

0/5

0

1/5

20

1/10

10

3000

4/5

80

2/5

40

6/10

60

3557

3/5

60

3/5

60

6/10

60

4217

4/5

80

4/5

80

8/10

80

5000

4/5

80

3/5

60

7/10

70

Table 3: Individual bodyweights in males

Dose level (mg/kg)

Body weight (g) on day :

Increment during week

0

7

14

At death

1

2

2530

141

137

130

142

122

173

150

150

165

154

220

191

190

205

198

 

32

13

20

23

32

47

41

40

40

44

3000

121

120

122

125

124

-

-

-

-

109

-

-

-

-

168

105

98

115

85

 

-

-

-

-

-15

-

-

-

-

59

3557

120

121

122

150

120

199

-

129

156

-

-

-

167

158

-

63

120

 

 

115

-1

-

7

6

-

-

-

38

2

-

4217

120

121

120

121

122

-

130

-

-

140

-

-

-

-

142

90

83

94

104

 

-

9

-

-

18

-

-

-

-

2

5000

150

149

146

153

129

-

-

-

173

-

-

-

-

200

-

103

122

127

 

114

-

-

-

20

-

-

-

-

27

-

Table 4: Individual bodyweights in females

Dose level (mg/kg)

Body weight (g) on day :

Increment during week

0

7

14

At death

1

2

2530

120

120

126

126

150

-

138

137

149

165

-

155

165

179

143

81

 

 

 

 

-

18

11

23

15

-

17

28

30

-22

3000

134

120

139

124

120

123

-

143

129

-

180

-

177

152

-

 

92

 

 

90

-11

-

4

5

-

57

-

34

23

-

3557

126

120

130

138

120

140

-

-

153

142

180

-

-

-

-

 

96

118

131

160

14

-

-

15

22

40

-

-

-

-

4217

145

125

140

123

120

-

-

-

-

131

-

-

-

-

151

142

118

98

80

 

-

-

-

-

11

-

-

-

-

20

5000

133

129

128

126

130

142

-

-

133

-

179

-

-

163

-

 

122

109

 

111

9

-

-

7

-

37

-

-

30

-

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The combined oral LD50 for test material is 3354 mg/kg in rats. As it is higher than 2000 mg/kg bw, it is not classified according to the Annex VI to the Directive 67/548/EEC and the CLP Regulation (EC) N° (1272-2008).
Executive summary:

In an acute oral toxicity study performed in accordance with GLP and OECD guideline 401, groups (5/sex) of Sprague Dawley rats were given a single oral dose of test material in arachis oil at 2530, 3000, 3557, 4217 and 5000 mg/kg bw. Animals were then observed for mortality, clinical signs and bodyweights for 14 days and were all macroscopically necropsied after death or sacrifice. A preliminary range-finding test was also conducted on 1 rat/sex/dose at 500, 1000, 3000 and 5000 mg/kg and animals were observed for 5 days. In this previous test, no mortality was recorded.

Mortality occurred in the main study at 3000 mg/kg and higher. Major signs of toxicity noted in all dose groups were hunched posture, pilo-erection, lethargy, ptosis, decreased or gasping respiration and red/brown staining around the snout or mouth. Incidents of reduced bodyweight gain or bodyweight loss were noted in all dose groups. Abnormalities noted at necropsy of animals that died during the study were haemorrhagic or abnormally red lungs, dark liver or patchy pallor of the liver, pale spleen, pale or dark kidneys, haemorrhage or sloughing of the glandular gastric epithelium and haemorrhage of the small and/or large intestines.

The combined oral LD50 was 3354 mg/kg with 95% confidence limits between 2834 and 3970 mg/kg.

The oral LD50 for test material is higher than 2000 mg/kg bw in rats therefore it is not classified according to the Annex VI to the Directive 67/548/EEC and the CLP Regulation (EC) N° (1272-2008).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
3 354 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
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22 August 1989 - 5 September 1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP study in compliance with international guidelines but the purity of the substance and the certificate of analysis were not reported.
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
No certificate of analysis, no data about purity of the test substance
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
yes
Remarks:
No certificate of analysis, no data about purity of the test substance
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
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: Bantin & Kingman Ltd., Grimston, U.K.
- Age at study initiation: approximately ten to fourteen weeks old
- Weight at study initiation: males: 201-216 g / females: 201-221 g
- Fasting period before study: no
- Housing: in groups of five by sex in solid-floor polypropylene cages with sawdust bedding
- Diet (e.g. ad libitum): Rat and Mouse Expanded Diet No. 1 (Special Diet Services Limited, Witham, U.K.), ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 54-64
- Air changes (per hr): approximately 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark

IN-LIFE DATES: From: 22 August 1989 To: 5 September 1989
Type of coverage:
semiocclusive
Vehicle:
arachis oil
Details on dermal exposure:
TEST SITE
- Area of exposure: 10% of the total body area
- Type of wrap if used: 7 cm x 4 cm surgical gauze semi-occluded by a piece of self-adhesive bandage (HYPERTIE) and wrapped with BLENDERM

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with cotton wool moistened with arachis oil
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- Concentration (if solution): not applicable
- Constant volume or concentration used: no

VEHICLE
- Amount(s) applied (volume or weight with unit): no data (moistened skin)
Duration of exposure:
24 h
Doses:
2000 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
All animals were observed for overt signs of toxicity and death 1 and 4 h after dosing and subsequently at least once daily for 14 days.
Individual bodyweights were recorded on the day of treatment (day 0) and on days 7 and 14.
All animals were subjected to a gross necropsy examination for any macroscopic abnormalities. No tissues were retained.
Statistics:
None
Preliminary study:
No data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No deaths in males and females
Clinical signs:
Signs of toxicity related to dose levels: hunched posture, lethargy and pilo-erection during the first day.
Adverse dermal reactions noted were oedema, blanching and hard, light brown coloured scabs at the site of application with loss of the upper layers of skin and fur resulting in purple/pink areas.
Body weight:
One male showed a small loss in bodyweight over the first week, all other animals showed expected gain in bodyweight over the study period.
Gross pathology:
No abnormalities were noted at necropsy of animals killed at the end of the study.
Other findings:
No data

No data

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the test conditions, ER 195 should not be classified according to the criteria of the Annex VI of the Directive 67/548/EEC and the CLP Regulation (EC) N° (1272-2008).
Executive summary:

ER 195 was tested for acute dermal toxicity in Sprague-Dawley rats in a limit dose assay according to OECD guideline 402 in compliance with GLP. Groups of rats (5/sex) were administered a single dermal dose of ER 195 at 2000 mg/kg bw on clipped skin moistened with arachis oil using a semi-occlusive patch held in place for 24 h. Skin was washed with a cotton wool moistened with arachis oil at the end of the 24-hour exposure period. Examinations for mortality, clinical signs and body weight gain were performed during a 14-day observation period. All surviving animals were necropsied at the end of the observation period. No deaths and clinical signs occurred during the observation period. Body weight gain was not affected by treatment (except for one male). At necropsy, macroscopic examination of main organs showed no abnormalities. The acute dermal combined LD50 was greater than 2000 mg/kg bw.

Adverse dermal reactions noted were oedema, blanching and hard, light brown coloured scabs at the site of application with loss of the upper layers of skin and fur resulting in purple/pink areas.

Under the test conditions, ER 195 should not be classified according to the criteria of the Annex VI of the Directive 67/548/EEC and the CLP Regulation (EC) N° (1272-2008).

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

Additional information

In an acute oral toxicity study performed in accordance with GLP and OECD guideline 401, the combined oral LD50 was 3354 mg/kg bw with 95% confidence limits between 2834 and 3970 mg/kg bw.

In a limit dose assay performed according to OECD guideline 402 in compliance with GLP, LD50 in Sprague-Dawley rats was higher than 2000 mg/kg bw.

Justification for classification or non-classification

Oral and dermal LD50 are higher than 2000 mg/kg bw in rats therefore Mexoryl SAB does not need to be classified for acute toxicity according to the Regulation (EC) No. 1272/2008 (CLP) and the Directive 67/548/EEC.