Registration Dossier

Administrative data

Description of key information

An acute oral toxicity study predicts an LD50 as >2000mg/kg bodyweight and an acute dermal toxicity study also predicts an LD50 as >2000 mg/kg bodyweight.  There is no evidence of a relevant intrinsic acute oral or dermal toxicity requiring classification or substance specific Risk Management Measures.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
16 October 2012 and 22 November 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant, guideline study, available as an unpublished report.
Qualifier:
according to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
fixed dose procedure
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Limited, Oxon, UK
- Age at study initiation: At the start of the study the animals were eight to twelve weeks of age
- Weight at study initiation: The bodyweight variation did not exceed ±20% of the bodyweight of the initially dosed animal
- Fasting period before study: Overnight fast immediately before dosing
- Housing: The animals were housed in groups of up to four in suspended solid floor polypropylene cages furnished with woodflakes
- Diet: 2014C Teklad Global Rodent diet supplied by Harlan Laboratorius UK Limited, Oxon, UK, was allowed ad libitum throughout the study
- Water: Free access to mains drinking water
- Acclimation period: At least five days


ENVIRONMENTAL CONDITIONS
- Temperature: 19 to 25°C
- Humidity: Relative humidity 30 to 70%
- Air changes: The rate of air exchange was at least fifteen changes per hour
- Photoperiod: Lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness
- In-life dates: Days 1 to 14
Route of administration:
oral: gavage
Vehicle:
other:
Details on oral exposure:
VEHICLE
- Concentration in vehicle: For the purpose of the study the test item was ground using a mortar and pestle and freshly prepared, as required, as a suspension in arachis oil BP water to give a dose level of 300 or 2000mg/kg bodyweight
- Amount of vehicle: Not stated
- Justification for choice of vehicle: Arachis oil BP was used because the test item did not dissolve/suspend in distilled water
- Lot/batch no. (if required): Not stated
- Purity: Not stated

MAXIMUM DOSE VOLUME APPLIED: 10mL/kg

DOSAGE PREPARATION (if unusual): Not applicable

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: In the absence of data regarding the toxicity of the test material, 300 mg/kg was chosen as the starting dose.

Doses:
Following a sighting test at dose levels of 300 and 2000 mg/kg, an additional four fasted female animals were given a single oral dose of test
material, as a suspension in Arachis oil BP, at a dose level of 2000 mg/kg bodyweight. Clinical signs and bodyweight development were monitored
during the study. All animals were subjected to gross necropsy.
No. of animals per sex per dose:
1 female at 300 mg/kg
1 female at 2000 mg/kg
4 females at 2000 mg/kg
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were made ½, 1, 2, and 4 hours after dosing and then daily for fourteen days. Morbidity and mortality checks were made twice daily. Individual bodyweights were recorded on Day 0 (the day of dosing) and on Days 7 and 14.
- Necropsy of survivors performed: Yes
Statistics:
No statistical analysis was performed.
Preliminary study:
- Preliminary results: A sighting test at a dose levels of 300 and 2000 mg/kg showed no signs of toxicity or mortality
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
- Lethal results: There were no deaths
Clinical signs:
- Non-lethal results: No signs of systemic toxicity were noted during the observation period.
Body weight:
- Bodyweight results: All animals showed expected gains in bodyweight over the observation period

Gross pathology:
- Gross pathology results: No abnormalities were noted at necropsy
Other findings:
No data reported

Table1              Individual Clinical Observations and Mortality Data -300mg/kg

Dose Level mg/kg

Animal Number and Sex

Effects Noted After Dosing
(Hours)

Effects Noted During Period After Dosing
(Days)

½

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

300

1-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0=     No signs of systemic toxicity

Table 2              Individual Bodyweights and Bodyweight Changes -300mg/kg

Dose Level

mg/kg

Animal Number
and Sex

Bodyweight (g) at Day

Bodyweight Gain (g)
During Week

0

7

14

1

2

300

1-0 Female

180

202

212

22

10

Table 3              Necropsy Findings -300 mg/kg

Dose Level
mg/kg

Animal Number
and Sex

Time of Death

Macroscopic Observations

300

1-0 Female

Killed Day 14

No abnormalities detected

Table4              Individual Clinical Observations and Mortality Data -2000mg/kg

Dose Level mg/kg

Animal Number and Sex

Effects Noted After Dosing
(Hours)

Effects Noted During Period After Dosing
(Days)

½

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

2-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-1

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-2

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-3

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0=     No signs of systemic toxicity

Table5              Individual Bodyweights and Bodyweight Changes -2000mg/kg

Dose Level

mg/kg

Animal Number
and Sex

Bodyweight (g) at Day

Bodyweight Gain (g) During Week

0

7

14

1

2

2000

2-0 Female

155

173

193

18

20

3-0 Female

171

201

213

30

12

3-1 Female

172

187

204

15

17

3-2 Female

168

196

215

28

19

3-3 Female

158

176

194

16

18

Table 6              Individual Necropsy Findings-2000mg/kg

Dose Level
mg/kg

Animal Number
and Sex

Time of Death

Macroscopic Observations

2000

2-0 Female

Killed Day 14

No abnormalities detected

3-0 Female

Killed Day 14

No abnormalities detected

3-1 Female

Killed Day 14

No abnormalities detected

3-2 Female

Killed Day 14

No abnormalities detected

3-3 Female

Killed Day 14

No abnormalities detected


Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral median lethal dose (LD50) of aluminum, benzoate C16-18-fatty acids complexes in the female Wistar strain rat was estimated to be greater than 2000 mg/kg bodyweight.
Executive summary:

Introduction. 

The study was performed to assess the acute oral toxicity of the test material in the Wistar strain rat.The acute oral toxicity of the test item to the Wistar strain rat was assessed in a GLP-compliant study following OECD guideline 420 (adopted 2001) and Method B1 bis Acute Toxicity (Oral) of Commission Regulation (EC) No. 440/2008 in a proprietary, experimental study (Harlan 2013). The study is considered reliable and relevant for use for this endpoint.

Method. 

Following a sighting test at dose levels of 300 mg/kg bodyweight and 2000 mg/kg bodyweight, a further group of four fasted females was given a single oral dose of test material, as a suspension in Arachis oil BP, at a dose level of 2000 mg/kg bodyweight. Clinical signs and bodyweight development were monitored during the study period of 14 days. All animals were subjected to gross necropsy.

Mortality. 

There were no deaths.

 

Clinical Observations.

There were no signs of systemic toxicity noted in the animal treated at a dose levels of 300 mg/kg bodyweight or 2000 mg/kg bodyweight.

 

Bodyweight. 

All animals showed expected gains in bodyweight.

 

Necropsy. 

No abnormalities were noted at necropsy.

 

Conclusion. 

The acute oral median lethal dose (LD50) of aluminum, benzoate C16-18-fatty acids complexes in the female Wistar strain rat was estimated to be greater than 2000mg/kg bodyweight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
2 000 mg/kg bw
Quality of whole database:
High. Based on read across from GLP compliant study for aluminum, benzoate C16-18-fatty acids complexes.

Aluminum, benzoate C16-18-fatty acids complexes (CAS No. 94166-87-7, EC No. 303-385-6) is considered suitable for read-across to (benzoato-O,O')hydroxy(octadecanoato-O,O')aluminium as it is structurally similar being an approximate 2:1 mixture of (benzoato-O,O')hydroxy(octadecanoato-O,O')aluminium and (benzoato-O,O')hydroxy(hexadecanoato-O,O')aluminium. The only significant difference is the presence of about 30% of the aluminium complex containing the saturated C16-fatty acid, hexadecanoate in place of the saturated C18-fatty acid, octadecanoate. This small difference in composition is expected to have no adverse influence on acute oral toxicity.

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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
24 October 2012 and 14 November 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant, guideline study, available as an unpublished report.
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:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:

TEST ANIMALS
- Source :Harlan Laboratories UK Ltd., Oxon, UK
- Age at study initiation: Eight to twelve weeks of age
- Weight at study initiation: At least 200g
- Housing: The animals were housed in suspended solid floor polypropylene cages furnished with woodflakes. The animals were housed individually during the 24 Hour exposure period and in groups of up to four, by sex, for the remainder of the study.
- Diet (e.g. ad libitum): 2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK
- Water (e.g. ad libitum): Mains drinking water
- Acclimation period: At least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25 ºC
- Humidity (%): Relative humidity 30 to 70%
- Air changes (per hr): At least fifteen changes per hour
- Photoperiod (hrs dark / hrs light): The lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness
Type of coverage:
semiocclusive
Vehicle:
arachis oil
Details on dermal exposure:
TEST SITE
- Area of exposure: Back and flanks of each anomal
- % coverage: Approximately 10% of the total body surface
- Type of wrap if used: Surgical gauze

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Treated skin and surrounding hair wiped with cotton wool moistened with arachis oil BP to remove any residual test item
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bodyweight
- For solids, paste formed: Yes

VEHICLE
- Amount(s) applied (volume or weight with unit): Not reported
- Concentration (if solution): Not reported
- Lot/batch no. (if required): Not reported
- Purity: Not reported
Duration of exposure:
24 hours contact period.
Doses:
2000 mg /kg body weight
No. of animals per sex per dose:
In the absence of data suggesting the test item was toxic, one male and one female rat were initially treated with the test item at a dose level of 2000 mg/kg. As no mortalities were noted a further group of animals (four males and four females) was similarly treated with the test item at a dose level of 2000 mg/kg bodyweight to give a total of five males and five females.
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days (or other?): 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.
- Frequency of observations and weighing: 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
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:
After removal of the dressings and subsequently once daily for fourteen days, the test sites were examined for evidence of primary irritation and scored according to the following scale from Draize J H (1977) "Dermal and Eye Toxicity Tests" In: Principles and Procedures for Evaluating the Toxicity of Household Substances, National Academy of Sciences, Washington DC p.31:
EVALUATION OF SKIN REACTIONS
Erythema and Eschar Formation Value
No erythema 0
Very slight erythema (barely perceptible) 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beef redness) to slight 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 millimetre) 3
Severe oedema (raised more than 1 millimetre and extending beyond the area of exposure) 4

Statistics:
No statistical analysis was performed.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 95% confidence limits not reported
Mortality:
No deaths occurred during the study.


Clinical signs:
No clinical signs of systemic toxicity were observed during the course of the study.
Body weight:
Animals showed expected gains in bodyweight over the study period, except for three animals which showed bodyweight loss during the first week but expected gain in bodyweight during the second week.
Gross pathology:
No macroscopic findings were recorded at necropsy.
Other findings:
Individual dermal reactions are given in Table 2 and Table 3 in overall remarks section.
Very slight erythema was noted at the test site of three females up to two days after dosing. There were no signs of dermal irritation noted at the test sites of the remaining animals.

Table 1              Individual Clinical Observations and Mortality Data

Dose Level

mg/kg

Animal Number and Sex

Effects Noted After Initiation of Exposure (Hours)

Effects Noted After Initiation of Exposure (Days)

½

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

1-0

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-0

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-1

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-2

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-3

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

4-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

4-1

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

4-2

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

4-3

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0


0 = No signs of systemic toxicity

See Overall remarks for Dermal Reactions Tables 2 and 3.

Table 4              Individual Bodyweights and Weekly Bodyweight Changes

Dose Level mg/kg

Animal Number and Sex

Bodyweight (g) at Day

Bodyweight Change (g) During Week

0

7

14

1

2

2000

1-0 Male

412

403

419

-9

16

3-0 Male

253

271

291

18

20

3-1 Male

252

265

285

13

20

3-2 Male

260

274

296

14

24

3-3 Male

241

251

266

10

15

2-0 Female

252

245

260

-7

15

4-0 Female

203

206

209

3

3

4-1 Female

210

217

222

7

5

4-2 Female

219

217

229

-2

12

4-3 Female

208

209

218

1

9

Table 5              Individual Necropsy Findings

Dose Level

mg/kg

Animal Number
and Sex

Time of Death

Macroscopic Observations

2000

1-0

Male

Killed Day 14

No abnormalities detected

3-0

Male

Killed Day 14

No abnormalities detected

3-1

Male

Killed Day 14

No abnormalities detected

3-2

Male

Killed Day 14

No abnormalities detected

3-3

Male

Killed Day 14

No abnormalities detected

2-0

Female

Killed Day 14

No abnormalities detected

4-0

Female

Killed Day 14

No abnormalities detected

4-1

Female

Killed Day 14

No abnormalities detected

4-2

Female

Killed Day 14

No abnormalities detected

4-3

Female

Killed Day 14

No abnormalities detected

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: other: Draize J H (1977) "Dermal and Eye Toxicity Tests" In: Principles and Procedures for Evaluating the Toxicity of Household Substances, National Academy of Sciences, Washington DC p.31
Conclusions:
The acute dermal median lethal dose (LD50) of aluminum, benzoate C16-18-fatty acids complexes in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.

Executive summary:

Introduction. 

The study was performed to assess the acute oral toxicity of the test material in the Wistar strain rat.The acute oral toxicity of the test item to the Wistar strain rat was assessed in a GLP-compliant study following OECD guideline 402 (adopted 1987) and Method B3 Acute Toxicity (Dermal) of Commission Regulation (EC) No. 440/2008 in a proprietary, experimental study (Harlan 2013). The study is considered reliable and relevant for use for this endpoint.

Method. A group of ten animals (five males and five females) was given a single, 24 hour, semi occluded dermal application of the test material to intact skin at a dose level of 2000 mg/kg bodyweight. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality. There were no deaths.

Clinical Observations. There were no signs of systemic toxicity.

Dermal Irritation.  Very slight erythema was noted at the test site of three females up to two days after dosing. There were no signs of dermal irritation noted at the test sites of the remaining animals.

Bodyweight.  Animals showed expected gains in bodyweight over the study period, except for three animals which showed bodyweight loss during the first week but expected gain in bodyweight during the second week.

Necropsy. No abnormalities were noted at necropsy.

Conclusion. The acute dermal median lethal dose (LD50) of aluminum, benzoate C16-18-fatty acids complexess in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
2 000 mg/kg bw
Quality of whole database:
High. Based on read across from GLP compliant study for aluminum, benzoate C16-18-fatty acids complexes.

Aluminum, benzoate C16-18-fatty acids complexes (CAS No. 94166-87-7, EC No. 303-385-6) is considered suitable for read-across to (benzoato-O,O')hydroxy(octadecanoato-O,O')aluminium as it is structurally similar being an approximate 2:1 mixture of (benzoato-O,O')hydroxy(octadecanoato-O,O')aluminium and (benzoato-O,O')hydroxy(hexadecanoato-O,O')aluminium. The only significant difference is the presence of about 30% of the aluminium complex containing the saturated C16-fatty acid, hexadecanoate in place of the saturated C18-fatty acid, octadecanoate. This small difference in composition is expected to have no influence on acute oral toxicity.

Additional information

As no data was available for the acute oral and dermal toxicity of (benzoato-O,O')hydroxy(octadecanoato-O,O')aluminium, these endpoints were read across from aluminum, benzoate C16-18-fatty acids complexes. Aluminum, benzoate C16 -18 fatty acids complexes were subjected to acute oral and dermal toxicity studies in rats. The results from these two studies showed no evidence of acute toxicity up to the highest dose tested (2000 mg/kg bw in arachis oil BP).

The isolated form of the test material was used for these studies.

Justification for selection of acute toxicity – oral endpoint
Only one study available based on read across from aluminum, benzoate C16-18-fatty acids complexes.

Justification for selection of acute toxicity – dermal endpoint
Only one study available based on read across from aluminum, benzoate C16-18-fatty acids complexes.

Justification for classification or non-classification