Aluminum, benzoate C16-18 fatty acids complexes - high aluminium

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

3 to 18 October 2017.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

The acute oral toxicity study was undertaken as a bridging study to demonstrate equivalence between the Target substance (XP 453) and the Source Substance (MOL-LUB) for the read-across of other data. Both Target and Source Substances conform to EC 303-385-6 (previously 272-365-6); CAS 94166-87-7 (previously 68815-27-0), but differ in method of manufacture and ratio of components.
A full discussion of read-across and supporting data is given in the attached justification below.

Cross-reference

Reason / purpose for cross-reference:

read-across: supporting information

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

16 October 2012 and 22 November 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system 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:

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.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

(benzoato-O,O')hydroxy(octadecanoato-O,O')aluminium

EC Number:

259-105-7

EC Name:

(benzoato-O,O')hydroxy(octadecanoato-O,O')aluminium

Cas Number:

54326-11-3

Molecular formula:

C25H41AlO5

IUPAC Name:

aluminum hydroxide benzoate stearate

Constituent 2

Reference substance name:

aluminum hydroxide benzoate palmitate

Molecular formula:

C23H37AlO5

IUPAC Name:

aluminum hydroxide benzoate palmitate

Constituent 3

Reference substance name:

Aluminium benzoate salts of other fatty acids

IUPAC Name:

Aluminium benzoate salts of other fatty acids

Constituent 4

Reference substance name:

Aluminium fatty acid salts

Cas Number:

Not available.

Molecular formula:

Not available.

IUPAC Name:

Aluminium fatty acid salts

Test material form:

solid: particulate/powder

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

Housing: in polypropylene/polycarbonate cages.
Cage type: Type III. (1 animal) and Type IV (4 or 5 animals)
Light: 12 hours daily, from 6.00 a.m. to 6.00 p.m.
Temperature: 22 ± 3 °C
Relative humidity: 30 - 70 %
Ventilation: above 10 air exchanges/hour by central air-condition system.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 10% ethyl alcohol plus helianthi annui oleum raffinatum.

Details on oral exposure:

A single oral administration - followed by a fourteen-day observation period - was performed by gavage. The day before treatment the animals were fasted. The food but not water was withheld overnight. Animals were weighed before the application and the food was returned 3 hours after the treatment.

Doses:

Starting dose of the sighting study was selected on the basis of the OECD Guideline No. 420. A sighting study starting dose of 2000 mg/kg followed by dosing of a further four animals at this level as a limit test for relevant guideline.

Control group (five female rats) were put into the study in order to clear up toxicological characteristics of vehicle. This group was treated at first dosing.

No. of animals per sex per dose:

5 female animals at 2000 mg/kg.

Control animals:

yes

Details on study design:

Animals were weighed, observed for lethality and toxic symptoms for 14 days after the treatment. Gross pathological examination was carried out 14th day after the treatment.

Results and discussion

Preliminary study:

The rat (No.: 7535) dosed with the formulation of the test item at 2000 mg/kg bw did not die in sighting study.

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occurred at the 2000 mg/kg single oral dose of the test item in the main study. All rats survived until the end of the 14-day observation period.

Clinical signs:

No treatment related symptoms were observed in the 2000 mg/kg bw dose group throughout the 14-day post-treatment period.

Body weight:

A body weight loss was observed in one female treated with 2000 mg/kg bw dose between Day 7 and Day 14. This body weight loss was approx. 0.9 %.
The body weight exceeded the original body weight by the end of study, thus it can be considered to be due to individual variation without toxicological significance. The body weight development was undisturbed in other animals.

Gross pathology:

All animals treated with 2000 mg/kg bw of the test item survived until the scheduled necropsy on Day 14.
Slight hydrometra was observed in three females (2000 mg/kg bw). Hydrometra is physiological finding and connected to the oestrus cycle of the animal. No pathological changes were found related to the effect of the test item during the macroscopic examination of animals treated with 2000 mg/kg bw of the test item.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The LD50 of the test item XP 453 is higher than 2000 mg/kg bodyweight by oral route in the rat.