Registration Dossier

Administrative data

Description of key information

In a repeated dose 28-day oral toxicity study in rats the NOEL was considered to be 60 mg/kg bw/day. In higher doses of 250 or 1000 mg/kg bw/day some substance related effects concerning hematology, blood chemistry, urinalyses and histopathology were noted. The kidney was identified as the target organ.
In a repeated dose 28-day dermal toxicity study in rats the NOAEL was considered to be 1000 mg/kg bw /day, the highest concentration tested, since there were no treatment-related effects observed in mortality, clinical appearance, behavior, in-life body weight, food consumption, hematology or clinical chemistry of male or femal animals.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions. Original reference in Japanese, study summary and tables in English.
Qualifier:
according to guideline
Guideline:
other: guidelines for 28-Day Repeat Dose Toxicity Test of Chemicals (Japan)
Deviations:
not specified
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
not specified
GLP compliance:
yes
Limit test:
no
Species:
rat
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 6 weeks
- Weight at study initiation: males: 358-440 g ; females 221-275 g
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0, 60; 250; 1000 mg/kg bw / day
Basis:
nominal in water
No. of animals per sex per dose:
6 rats
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: 14 days in a recovery group (6/sex) in dosis groups 0, 250 and 1000 mg/kg bw / day
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: every 3 days

FOOD CONSUMPTION AND COMPOUND INTAKE
- food consumption was recorded

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: once during the treatment and recovery periods
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all animals

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: not further described
- Animals fasted: No data
- How many animals: all animals

URINALYSIS: Yes
- Time schedule for collection of urine: not further described
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:
- Animals were sacrificed at day 29  and day 43 after a 14-day recovery period.
- GROSS PATHOLOGY: Yes
- HISTOPATHOLOGY: Yes
Statistics:
The data were subjected to statistical analysis. However, it is not clear which method was used because this is not described in the English language sections of the paper.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
(1) 28-day treatment groups

BODY WEIGHT AND WEIGHT GAIN
Body weight development was very similar in all treated groups and not influenced by the treatment.

FOOD CONSUMPTION
A temporary decrease in the food consumption was noted in females given 250 mg/kg bw / day and in both sexes given 1000 mg/kg bw / day duringthe early administration period

HAEMATOLOGY
Hematology revealed a decrease in hemoglobin concentration in both sexes given 1000 mg/kg bw / day (p<0.01 in males, p<0.05 in females).

CLINICAL CHEMISTRY
Blood chemistry revealed an increase in GOT activity in males given 250 and 1000 mg/kg bw / day (both p<0.05), a decrease in total cholesterol in females given 1000 mg/kg bw / day (p<0.05) and a decrease in chloride concentration in males given 1000 mg/kg bw / day (p<0.05). 

URINALYSIS
Urinalysis revealed an increase in protein concentration in females given 250 mg/kg bw / day and in both sexes given 1000 mg/kg bw / day, an increase in the specific gravity in females given 250 and 1000 mg/kg bw / day (p<0.05 and p<0.01, resp.), and a decrease in urinary volume in females given 1000mg/kg bw / day (p<0.05). 

ORGAN WEIGHTS
Kidneys: increased absolute and relative kidney weights were noted in males and increased relative kidney weights in females p<0.01) given 1000mg/kg bw / day. The relative adrenal weights were decreased in males given 1000 mg/kg (p<0.05) but no associated histopathological lesions were found. 

HISTOPATHOLOGY:
Histopathologically, deposition of amphophilic bodies and swelling in the renal proximal tubules in the cortico-medullary junction were noted in males given 250 mg/kg bw / day and in both sexes given 1000 mg/kg bw / day. Mucosal thickening of the stomach at the limiting ridge was noted in both sexes given 250 and 1000 mg/kg bw / day. 


(2) 14-day recovery groups

Compound-related changes were reversible except for those in the kidney and stomach after a 14-day recovery period, without gaining a level of statistical significance.
Dose descriptor:
NOEL
Effect level:
60 other: mg/kg bw / day
Sex:
male/female
Basis for effect level:
other: urinalysis; kidney weight and kidney histopathology at 250 mg/kg bw/d
Critical effects observed:
not specified

 

Dose [mg/kg bw / d]

Endpoint

Males

Females

 

0

60

250

1000

0

60

250

1000

 

 

 

 

 

 

 

 

 

Weight data at day 28

 

 

 

 

 

 

 

 

Body weight [g]

389

412

386

394

237

248

238

234

Kidneys [g]

2.8

2.95

2.97

3.19**

1.87

1.90

1.94

2.12

Kidneys [%]

0.72

0.72

0.78

0.81**

0.79

0.77

0.82

0.91**

Adrenals [mg]

69

65

64

58

75

75

80

75

Adrenals [%]

18

16

17

15*

32

31

34

32

 

 

 

 

 

 

 

 

 

Clinical chemistry

 

 

 

 

 

 

 

 

Hemoglobin [g/l]

15.8

15.7

16.0

14.9**

15.9

15.5

15.2

14.8*

GOT [IU/l]

65

61

76*

76*

67

70

70

69

Chloride [mEq/l]

110

108

110

107*

111

111

112

110

Cholesterol [mg/dl]

66

64

51*

55

85

72

78

57*

 

 

 

 

 

 

 

 

 

Urinalysis

 

 

 

 

 

 

 

 

Volume [ml]

14.8

17

14.7

13.4

11.4

9.6

7.8

4.5*

Gravity [g/ml]

1.062

1.06

1.069

1.07

1.053

1.073

1.081*

1.1**


Values expressed as means; * = p<0.05; ** = <0.01
Executive summary:

Repeated Dose 28 - Day Oral Toxicity:

In a subacute toxicity study AEEA (99,9 % a.i.) was administered to six Crj:CD (SD) rats per sex per dose by gavage at dose levels of 0, 60, 250 or 1000 mg/kg bw/day for a period of 28 days (Okazaki, 1996). The NOEL was considered to be 60 mg/kg bw/day for both males and females.

In the 28-day treatment a temporary decrease in the food consumption was noted in females given 250 mg/kg bw/day and in both sexes given 1000 mg/kg bw/day during the early administration period. Hematology revealed a decrease in hemoglobin in both sexes given 1000 mg/kg bw/day. Blood chemistry revealed an increase in GOT in males given 250 and 1000 mg/kg bw/day, a decrease in total cholesterol concentration in females given 1000 mg/kg bw/day and a decrease in chloride concentration in males given 1000 mg/kg bw/day. Urinalysis revealed an increase in protein concentration in females given 250 mg/kg bw/day and in both sexes given 1000 mg/kg bw/day, an increase in the specific gravity in females given 250 and 1000 mg/kg bw/day and a decrease in urinary volume in females given 1000 mg/kg bw/day. Increased absolute and relative kidney weights were noted in males and increased relative kidney weights in females given 1000 mg/kg bw/day. The relative adrenal weights were decreased in males given 1000 mg/kg bw/day but no associated histopathological lesions were found. Histopathologically, deposition of amphophilic bodies and swelling in the renal proximal tubules in the corticomedullary junction were noted in males given 250 mg/kg bw/day and in both sexes given 1000 mg/kg bw/day. Mucosal thickening of the stomach at the limiting ridge was noted in both sexes given 250 and 1000 mg/kg bw/day. In the 14 -day recovery groups compound-related changes were reversible. After the 14 -day recovery period minimal (grade 1) focal basophilic changes in the proximal tubule was noted in 2/6 and 5/6 males at 250 and 1000 mg/kg bw/d, respectively. The relevance of this finding is questionable since this effect was observed in males of the recovery group, but neither in males of the 1000 mg/kg bw/d group nor in the 1000 mg/kg bw/d females dosing and recovery group and was also present in 1/6 control females.

This subacute toxicity study in the rat is acceptable and satisfies the guideline requirement for a repeated dose oral toxicity study in rodents (OECD guideline 407).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Comparable to guideline study with acceptable restrictions.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Abstract. Original report not yet available.
Qualifier:
according to guideline
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
not applicable
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
Male and female Fischer 344 rats (approximately five to six weeks of age) purchased from Charles River Laboratories, Inc. Kingston, NY were used in the study. Upon arrival at the laboratory rats were examined by the laboratory veterinarian and acclimated to the laboratory environment according to the SOP of the Subchronic/Chronic Toxicity Section for 16 days. During acclimation, rats were assigned one/cage to test groups using a computergenerated randomization scheme based on body weights. Identification was accomplished by inserting a unique alphanumeric metal tag in one ear of each rat. The animal rooms of the testing facility were designed to maintain adequate environmental conditions (temperature, humidity, and photocycle) for the species used. Tap water and Purina Certified Rodent Chow #5002 (Purina Mills, Inc., St. Louis, MO) were available ad libitum during the pre-study and
study periods. The feed was analyzed by Purina Mills, Inc. and found to be nutritionally adequate and to be free of significant levels of spedfic contaminants. Drinking water was analyzed as outlined in the SOP of The Toxicology Research Laboratory and was also round to be of acceptable quality and free of significant levels of specific contaminants.
All animals were weighed just prior to the initiation of dosing and approximately weekly thereafter. All in-life weights were collected using an in-house Computer system. Feed consumption data was also obtained at approximately weekly intervals.
Type of coverage:
semiocclusive
Vehicle:
other: distilled water
Details on exposure:
Route of Administration: dermal

TEST SITE
- Area of exposure: 5 x 5 cm on the back, representing at least 10 % of the surface area of the animal
- coverage: 100 %
- Type of wrap: absorbent gauze patch which was helt in place with an elastic with wrap which was secured with elastic tape
- Time intervals for shavings or clipplings: prior to study initiation and as needed


REMOVAL OF TEST SUBSTANCE
- Washing: wraps were removed approx. six hours after application and the test site was wiped with a water-dampened disposable
towel to remove any residual test material
- Time after start of exposure: 6 hours

TEST MATERIAL
- Amount applied: 4 ml/kg bw
- Concentration: 2.5, 7.5 or 25 % solution (w/v) at 4 ml/kg bw for rats receiving 100, 300 or 1000 mg/kg bw/day
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The stability of AEEA in distilled water and the potential of the mixing method to produce a homogeneous dosing Solution were verified analyticaUy. In
addition, the concentrations of AEEA in a set of dose solutions were also quantitated analytically during the study.


Duration of treatment / exposure:
4 weeks
Frequency of treatment:
6 hours/day, 5 days/week
Remarks:
Doses / Concentrations:
0, 100, 300 or 1000 mg/kg bw/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5 rats
Control animals:
yes, concurrent vehicle
Details on study design:
In a probe study, two male rats received 1000 mg/kg bw/day as a 25 % solution in distilled deionized water for 6 hours/day for 4 days.



The 4 ml/kg bw dosing volume required to administer the test material represented the maximum volume which could be maintained at the application site.
Observations and examinations performed and frequency:
Observations and Records

A careful clinical examination was conducted on all animals prior to the start of the study and approximately weekly thereafter.
This examination included thorough evaluations ofthe skin, für, mucous membranes, respiration, circulatory system function, autonomic and central
nervous system function (e.g., tremors, convulsions) and behavior pattern.
An additional observation for morbidity, mortality and the availability of feed and water was made each day of the work-week and twice daily on weekends and holidays.

Evaluation of derrnal application site
The condition of the test material application site was subjectively evaluated when wraps were removed on the last day of dosing each week and on theday prior to necropsy. A modification of the acute dermal irritation scoririg system recommended by the OECD (1981b) was utilized:

Erythema abd eschar:

Within normal limits: 0
Very slight erythema (barely perceptible): 1
Well-defined erythema: 2
Moderate to severe erythema: 3
Severe erythema to slight eschar formation: 4

Edema:

Within normal limits: 0
Very slight (barely perceptible): 1
Well-defined (edges raised) : 2
Moderate (raised approximately 1 millimeter): 3
Severe (raised more than 1 millimeter: 4

Scaling and fissuring:

Within normal limits: 0
Slight scaling: 1
Moderate - severe scaling: 2
Slight fissuring: 3
Moderate - severe fissuring: 4


In addition, necrosis, scabs and/or scars were noted if present; however, they were not graded


Clinical Pathology:

Hematology:
Blood samples were collected from all surviving animals via orbital sinus puncture following anethesia with methoxyflurane and just prior to necropsy. The following hematologic parameters were evaluated for each animal:
hematocrit (HCT), hemoglobin (HGB), erythrocyte count (RBC), total leukocyte count (WBC), and platelet counts (PLAT). Blood smears were prepared and stained with Wright's stain for all animals from which blood samples were collected. Complete blood smear examinations were conducted which included differential leukocyte counts (the number of leukocytes counted were specified if other than 100 cells were counted) and an assessment of erythrocyte, leukocyte and platelet morphology. Any morphologic abnormalities observed were reported.

Clinical Chemistry
Blood samples were collected from all surviving animals via orbital sinus puncture following anethesia with methoxyflurane and just prior to necropsy. The following parameters were evaluated for each animal:
alkaline phosphatase activity (AP), alanine aminotransferase activity (ALT), aspartate aminotransferase activity (AST), total protein (TP), albumin (ALB),
globulin (GLOB) (calculated), total bilirubin (TBILI), glucose (GLUC), urea nitrogen (UN), creatinine (CREAT), phosphorus (PHOS), caldum (CALC), sodium (NA), potassium (K) and chloride (CL).

Pathology.
All surviving rats were fasted overnight and presented for necropsy approximatdy 24 hours after the final administration of test material. Rats were weighed, anesthetized with methoxyflurane and humanely euthanatized. All animals were examined for gross pathological changes by a veterinary pathologist. The necropsy included examination of the eyes by visual inspection of the cornea, lens and other internal components via placement of a moistened glass slide on the corneal surface. Weights of the brain, heart, liver, kidneys, adrenals and testes were recorded for each animal. Lungs were distended to an approximately normal inspiratory volume with neutral, phosphate-buffered 10 % formalin solution by tracheal instillation using a hand-operated syringe. The nasal cavity was flushed by a similar method via the pharyngeal duct. Representative samples of tissues and any masses or lesions were preserved in formalin. Special attention was given to the skin at the site of application of the test material. Samples of skin from the clpped site where the test material was applied and from an unshaven and untreated site just caudal to this were excised and preserved. Both areas were covered by the wrappings used to maintain the test material at the application site. Thus, the untreated skin served as a control for the possible confounding effects of mechanical irritation of the skin by the wrapping materials, A third skin sample was also collected from the abdomen to include mammary gland tissue; however, this was not used for comparative purposes. Tissues were prepared for light microscopic evaluation by standard procedures sectioned at approximately 6 um and stained with hematoxylin and eosin. Samples of skin obtained from the application site and the adjacent, untreated site, liver, kidneys and any masses and lesions were examined from all control and high dose group animals. Treated and untreated skin from all intermediate dose group animals and all grossly observed lesions were also examined histologically.
Other examinations:
For the probe study, animals were observed for any signs of systemic or dermal treatment-related effects over the dosing period.
Statistics:
In-life body weights were evaluated using a three-way repeated measures analysis of variance (ANOVA) for time, sex and dose. In the three-way repeated measures ANOVA, differences between groups were primarily detected by the time-dose interaction. Terminal body weight, organ weight (absolute and relative, excluding testes), hematologic parameters (excluding differential WBC counts), clinical chemistry parameters, and urine specific gravity were evaluated using a two-way ANOVA with the factors of sex and dose; differences between groups were primarily detected by the dose factor. Results for testes weight(absolute and relative) were analyzed using a one-way ANOVA. A Bonferroni correction was used to compensate for the multiple comparisons with the control group. Final interpretation of numerical data considered statistical analyses along with other factors, such as dose-response relationships and whether the results were plausible in light of other biological and pathological findings.
Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND DERMAL IRRITATION:
Evaluation of the skin at the application site revealed a minimal degree of erythema in a single high dose female and scabbing in 3/5 male and 3/5 femal rats administered 1000 mg/kg bw/day on day 30 of the dosing period.

GROSS PATHOLOGY:
Treatment-related gross pathologic observations were limited to the skin at the site of test material application.
Dermal crusts were observed in 3 of 5 males and 3 of 5 females administered 1000 mg/kg bw/day AEEA.
No gross lesions were observed in the application site skin of any other treatment or control group.

HISTOPATHOLOGY:
There were no treatment-related histopathologic changes indicative of systemic toxicity observed in rats administered AEEA. Coagulative necrosis and inflammation of hepatic tissue was noted in superficial areas of the caudal lobe of the livers of a high dose group male and female; however these changes were consistent with localized anoxia secondary to compression of the tissue during the wrapping process. Tissues in the remaining lobes of the liver of these animals were normal. Histopathologic examination of the skin at the application site revealed ulcers, accompanied by inflammation of the dermis and epidermis of several male and female rats administered 1000 mg/kg bw/day AEEA.

The separation of epidermal cells (epidermal vacuolation), interpreted to be a precursor of ulcer formation, was also observed in a single high dose group male and female rat. In addition a minimal degree of epidermal hyperplasia was observed in application site skin and untreated skin from contro and treatment groups of rats alike. This change, consisting in most cases of a 1-2 cell increase in epidermal thickness, was primarily attributed to mechanical irritation of the skin from wrapping materials and/or clipping. However, the incidence of a more pronounced degree of hyperplasia, consisting of increases of 2-4 cells over a larger area, was higher in rats administered 1000 mg/kg bw/day AEEA than in controls.


Dose descriptor:
NOAEL
Effect level:
1 000 other: mg/kg bw / day
Sex:
male/female
Critical effects observed:
not specified

In the 4-day dermal probe, there was no evidence of dermal or systemic toxicity.

Executive summary:

In a 4 -day dermal probe when two rats received 1000 mg/kg bw/day there was no evidence of dermal or systemic toxicity.

In a subacute toxicity study AEEA (99,9 % a.i.) was administered to five Fisher 344 rats per sex per dose by dermal application 6 hours/day, 5 day/week for a period of approximately 4 weeks at dose levels of 0, 100, 300 or 1000 mg kg bw/day.

There were no treatment-related effects observed in mortality, clinical appearance, behavior, in-life body weight, food consumption, hematology or clinical chemistry of male or female rats administered AEEA relative to controls. Treatment-related gross pathologic observations were limited to the skin at the site of test material application. There were no treatment-related histopathologic changes indicative of systemic toxicity observed in rats administered AEEA.

The NOAEL was considered to be 1000 mg/kg bw/day for both males and females.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Comparable to Guideline study

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated Dose 28 - Day Oral Toxicity:

In a subacute toxicity study AEEA (99,9 % a.i.) was administered to six Crj:CD (SD) rats per sex per dose by gavage at dose levels of 0, 60, 250 or 1000 mg/kg bw/day for a period of 28 days (Okazaki, 1996). The NOEL was considered to be 60 mg/kg bw/day for both males and females.

In the 28-day treatment a temporary decrease in the food consumption was noted in females given 250 mg/kg bw/day and in both sexes given 1000 mg/kg bw/day during the early administration period. Hematology revealed a decrease in hemoglobin in both sexes given 1000 mg/kg bw/day. Blood chemistry revealed an increase in GOT in males given 250 and 1000 mg/kg bw/day, a decrease in total cholesterol concentration in females given 1000 mg/kg bw/day and a decrease in chloride concentration in males given 1000 mg/kg bw/day. Urinalysis revealed an increase in protein concentration in females given 250 mg/kg bw/day and in both sexes given 1000 mg/kg bw/day, an increase in the specific gravity in females given 250 and 1000 mg/kg bw/day and a decrease in urinary volume in females given 1000 mg/kg bw/day. Increased absolute and relative kidney weights were noted in males and increased relative kidney weights in females given 1000 mg/kg bw/day. The relative adrenal weights were decreased in males given 1000 mg/kg bw/day but no associated histopathological lesions were found. Histopathologically, deposition of amphophilic bodies and swelling in the renal proximal tubules in the corticomedullary junction were noted in males given 250 mg/kg bw/day and in both sexes given 1000 mg/kg bw/day. Mucosal thickening of the stomach at the limiting ridge was noted in both sexes given 250 and 1000 mg/kg bw/day. In the 14 -day recovery groups compound-related changes were reversible. After the 14 -day recovery period minimal (grade 1) focal basophilic changes in the proximal tubule was noted in 2/6 and 5/6 males at 250 and 1000 mg/kg bw/d, respectively. The relevance of this finding is questionable since this effect was observed in males of the recovery group, but neither in males of the 1000 mg/kg bw/d group nor in the 1000 mg/kg bw/d females dosing and recovery group and was also present in 1/6 control females.

This subacute toxicity study in the rat is acceptable and satisfies the guideline requirement for a repeated dose oral toxicity study in rodents (OECD guideline 407).

 

Repeated Dose 28 - Day Dermal Toxicity:

In a 4 -day dermal probe when two rats received 1000 mg/kg bw/day there was no evidence of dermal or systemic toxicity.

In a subacute toxicity study AEEA (99,9 % a.i.) was administered to five Fisher 344 rats per sex per dose by dermal application 6 hours/day, 5 day/week for a period of approximately 4 weeks at dose levels of 0, 100, 300 or 1000 mg kg bw/day (Dow Chemical Company, 1991).

There were no treatment-related effects observed in mortality, clinical appearance, behavior, in-life body weight, food consumption, hematology or clinical chemistry of male or female rats administered AEEA relative to controls.Treatment-related gross pathologic observations were limited to the skin at the site of test material application. There were no treatment-related histopathologic changes indicative of systemic toxicity observed in rats administered AEEA.

The NOAEL was considered to be 1000 mg/kg bw/day for both males and females.

This subacute toxicity study in the rat is acceptable and satisfies the guideline requirement for a subacute dermal study in rats (OPPTS870.3200, 21/28-Day Dermal Toxicity).


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The key study was selected. (only one study available)

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
The key study was selected. (only one study available)

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys

Justification for classification or non-classification

AEEA did not induce adverse effects indicative of serious damage at dose levels relevant for classification and labelling when tested for oral and dermal repeated dose toxicity.

Therefore AEEA is not subject to classification and labelling for repeated dose toxicity according to Directive 67/548/EEC and Regulation 1272/2008/EC. This is in line with the classification adopted in Commission Regulation 790/2009/EC to Regulation 1272/2008/EC.