Registration Dossier

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Administrative data

Endpoint:
acute toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route and, in the absence of an in vivo study by the oral route, no systemic effects after dermal exposure are predicted on the basis of non-testing approaches (e.g. read across, QSAR studies)
Cross-referenceopen allclose all
Reason / purpose:
data waiving: supporting information
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
March 11-25, 2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 2X29911A
- Expiration date of the lot/batch: Oct. 28, 2004

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: ambient temperature

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Final dilution of a dissolved solid, stock liquid or gel: 100 mg/mL of test substance in water

FORM AS APPLIED IN THE TEST (if different from that of starting material): solution
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Germany
- Age at study initiation: 7-8 weeks
- Weight at study initiation: 170-184 g
- Fasting period before study: overnight to 4-5 hrs after exposure
- Housing: up to six animals per macrolon cage
- Diet (e.g. ad libitum): standard lab diet ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 degrees C
- Humidity (%): Normally 30-70% with incidental limit of 100% due to cleaning/meteorological conditions
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 hrs light/12 hrs dark

IN-LIFE DATES: From: March 11, 2003 To: March 25, 2003
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 100 mg/mL

MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg
Doses:
2000 mg/kg
No. of animals per sex per dose:
6
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations - 1 and 4 hrs after dosing, and daily thereafter; bodyweights - Day 0, 3, 7, and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, gross pathological changes
Preliminary study:
Three animals were dosed at 2000 mg/kg. Since none of these animals died, a further three animals were given the same dose.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No animals died during the study.
Clinical signs:
No clinical signs were noted during the observation period.
Body weight:
All animals gained weight during the study.
Gross pathology:
No treatment related gross pathological findings were observed.

Bodyweights (g)

Animal Number

Day 0

Day 3

Day 7

Day 14

47

175

193

198

212

49

184

204

206

210

51

181

195

204

214

65

170

186

192

216

67

175

196

201

209

69

171

191

200

204

Interpretation of results:
GHS criteria not met
Conclusions:
The LD50 for the test substance is > 2000 mg/kg bw. The test substance is therefore considered non-toxic.
Executive summary:

Six animals were exposed to a dose of 2000 mg/kg bw of LMD. None of the animals died during the 14 -day post-exposure observation period. No animals exhibited any adverse effects during the observation period either. The test substance is considered non-toxic.

Reason / purpose:
data waiving: supporting information
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
GLP compliance:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 6X07A106
- Expiration date of the lot/batch: May 16, 1997

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: ambient temperature

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Test substance was dispersed in cold water, then heated to 80 degrees C for 10 minutes. Test solutions were stored at 4 degrees C.
- Final dilution of a dissolved solid, stock liquid or gel: 3% and 20% dilution in water

FORM AS APPLIED IN THE TEST (if different from that of starting material): solution
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Broekman Instituut B.V.
- Age at study initiation: young adult
- Weight at study initiation: 1500-1900 g
Type of coverage:
occlusive
Preparation of test site:
clipped
Vehicle:
water
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL
- Concentration (if solution): 3% and 20%

Duration of treatment / exposure:
4 hrs
Observation period:
72 hrs
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: 2.5 cm x 2.5 cm area on each side of backs and flanks
- Type of wrap if used: Test solutions were placed on a patch which were fixed to the animals with adhesive tape, and the trunks then wrapped with impervious material.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes
- Time after start of exposure: 4 hrs

OBSERVATION TIME POINTS
1, 24, 48, and 72 hrs after exposure

SCORING SYSTEM: Draize
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
other: 3% solution
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
other: 3% solution
Irritation parameter:
erythema score
Basis:
mean
Time point:
72 h
Score:
0
Max. score:
4
Remarks on result:
other: 20% solution
Irritation parameter:
edema score
Basis:
mean
Time point:
72 h
Score:
0
Max. score:
4
Remarks on result:
other: 20% solution
Irritant / corrosive response data:
One animal in the 20% group showed minor signs of redness at the 24-hr observation. This animal showed no signs of irritation at subsequent observations. No other signs of irritation were noted in any other animal in either group.

Skin Irritation Scores

Mean Score

1 hr

24 hrs

48 hrs

72 hrs

Erythema
3% Exposure

0

0

0

0

Edema
3% Exposure

0

0

0

0

Erythema
20% Exposure

0

0.5

0

0

Edema
20% Exposure

0

0

0

0

 

Interpretation of results:
GHS criteria not met
Conclusions:
LMD is not irritating to skin at concentrations of up to 20%.
Executive summary:

Three animals were exposed to solutions of 3% and 20% LMD for 4 hrs. After 4 hrs, the test substance was removed. The animals were observed for signs of irritation at 1, 24, 48, and 72 hrs after removal. Only minor irritation was seen in one animal at the 24 hr observation. The irritation was fully reversible by 48 hrs. LMD is therefore not irritating to the skin at concentrations of up to 20%.

Reason / purpose:
data waiving: supporting information
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
LLNA method had not yet been adopted when this study was performed.
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 6X07A106
- Expiration date of the lot/batch: May 16, 1997

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: ambient temperature

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Test substance was dispersed in cold water, then heated to 80 degrees C for 10 minutes.
- Final dilution of a dissolved solid, stock liquid or gel: 10% and 30% dilution in water

FORM AS APPLIED IN THE TEST (if different from that of starting material): solution
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Germany
- Age at study initiation: 2-3 weeks
- Weight at study initiation: 175-400 g
Route:
intradermal and epicutaneous
Vehicle:
water
Day(s)/duration:
one week
Adequacy of induction:
other: Concentration in dermal application was highest tolerable irritating concentration with pretreatment with sodium lauryl sulfate.
Route:
intradermal
Vehicle:
other: FCA and vehicle 1:1
Day(s)/duration:
1 Day
Adequacy of induction:
other: selected test concentration
Route:
intradermal
Vehicle:
other: FCA and isotonic saline 1:1
Concentration / amount:
0%
Day(s)/duration:
1 Day
No.:
#1
Route:
other: epicutaneous
Vehicle:
water
Concentration / amount:
10% and 30%
Day(s)/duration:
14 days after last induction
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
5 males and 5 females in the test group.
3 males and 3 females in the control group.
Details on study design:
RANGE FINDING TESTS:
A preliminary study was performed to determine the highest tolerated concentration. Three animals were injected intradermally with 1%, 3%, 10%, and 30% test substance in water. 30% was the highest concentration that could be injected. All animals showed necrosis at the 3%, 10%, and 30% injection sites at the 24 hr observation. At the 1% injection sites, all animals were given a dermal irritation score of 2, and abscesses were noted at 24 hrs after injection. Another three animals were tested by topical application at 10% and 30% test substance. No animals showed any irritation at either the 24 or 48 hr readings.


MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 2
- Exposure period: 2 exposures 1 week apart
- Test groups: Test animals were injected with a solution of 1:1 FCA/isotonic saline, 0.3% test substance in water, and 0.3% test substance in FCA/water 1:1. One week later they were pretreated with SLS and given topical applicaiton of 30% test substance.
- Control group: Control animals were injected with a solution of 1:1 FCA/isotonic saline, water, and FCA/water 1:1. One week later they were pretreated with SLS and given topical applicaiton of water or empty patches.
- Concentrations: 10% and 30%

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: 14 days after last induction exposure
- Test groups: Topical application of 10% and 30% test substance.
- Control group: Topical application of 10% and 30% test substance.
- Concentrations: 10% and 30%
- Evaluation (hr after challenge): 24 and 48 hrs after removal of the patches.
Positive control substance(s):
no
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
10%
No. with + reactions:
0
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
10%
No. with + reactions:
0
Total no. in group:
10
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
30%
No. with + reactions:
0
Total no. in group:
10
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
30%
No. with + reactions:
0
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
10% and 30%
No. with + reactions:
0
Total no. in group:
6
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
10% and 30%
No. with + reactions:
0
Total no. in group:
6
Group:
positive control
Remarks on result:
not measured/tested

Dermal Reaction Scores In Challenge Test

Animal

24 hrs

48 hrs

Control Group

0

0

76

0

0

78

0

0

80

0

0

75

0

0

77

0

0

79

0

0

10% Test Substance

0

0

66

0

0

68

0

0

70

0

0

72

0

0

74

0

0

65

0

0

67

0

0

69

0

0

71

0

0

73

0

0

30% Test Substance

0

0

66

0

0

68

0

0

70

0

0

72

0

0

74

0

0

65

0

0

67

0

0

69

0

0

71

0

0

73

0

0

Interpretation of results:
GHS criteria not met
Conclusions:
LMD is not sensitizing to skin.
Executive summary:

The skin sensitization potential of LMD was tested in an OECD Guideline 406 study. 5 male and 5 female guinea pigs were exposed to the test substance intradermally, and topically in exposures one week apart. A control group was exposed to vehicles only. 2 weeks later, both groups were exposed to the 10% and 30% of the test substance topically. No reactions were seen in any animals during the challenge exposure. The test substance is therefore not sensitizing to skin.

Reason / purpose:
data waiving: supporting information
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
December 27, 1990-December 27, 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
other: Toxicological Principles for the Safety Assessment of Direct Food Aditives and Color Additives used in Food (FDA, USA, 1982)
Deviations:
yes
Remarks:
Stability testing was performed on feed mixes containing 1 and 5% of test substane after 18 weeks, rather than feed containing 0.1 and 10% of feed after 10 weeks storage in refrigeration.
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Final preparation of a solid: Mixed with basal diet feed.
Species:
rat
Strain:
Fischer 344/DuCrj
Details on species / strain selection:
Strain chosen as it has been used extensively in long-term toxicity study, and therefore sufficient background data is available on it.
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan, Inc.
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 5 weeks
- Weight at study initiation: 73-88 g males, 74-89 g females
- Fasting period before study: No
- Housing: 2 animals in polycarbonate cages with hardwood chip bedding
- Diet: CRF-1, Oriental Yeast Co., radition-sterilized, ad libitum
- Water: filtered, UV sterilized tap water ad libitum
- Acclimation period: 5-8 days

DETAILS OF FOOD AND WATER QUALITY: Food was analyzed by a third party to ensure contaminants were below acceptable levels. Drinking water is tested biannually.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25
- Humidity (%): 40-70
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: January 14, 1991 To: April 26, 1991
Route of administration:
oral: feed
Details on route of administration:
Since the test substance will be taken orally during actual use, it was decided to perform an oral toxicity study in feed.
Vehicle:
other: feed
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): radiation sterilized powdered feed for rats and mice


VEHICLE
- Justification for use and choice of vehicle (if other than water): appropriate feed for species selected
- Concentration in vehicle: 1, 3, and 5%
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were taken from the top, middle, and bottom of the first batch of feed prepared. All lots of feed mix were analyzed. The stability of the test substance with checked after 18 weeks at 5-10 °C storage for the 1 and 5% mixtures. Analysis was done using gas chromatography.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Animals were given feed containing the test substance ad libitum throughout the study period.
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Control group
Dose / conc.:
636 mg/kg bw/day (nominal)
Remarks:
1% of diet male
Dose / conc.:
666 mg/kg bw/day (nominal)
Remarks:
1% of diet female
Dose / conc.:
1 900 mg/kg bw/day (nominal)
Remarks:
3% of diet male
Dose / conc.:
1 950 mg/kg bw/day (nominal)
Remarks:
3% of diet female
Dose / conc.:
3 240 mg/kg bw/day (nominal)
Remarks:
5% of diet male
Dose / conc.:
3 430 mg/kg bw/day (nominal)
Remarks:
5% of diet female
No. of animals per sex per dose:
20
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: 5% was the maximum dose recommended in the guideline.
- Rationale for animal assignment (if not random): random sampling based on body weight stratification
- Section schedule rationale (if not random):
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: survival, clinical signs, appearance, behaviour

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: 3-1 days before study start, and 5-2 days before end of study
- Dose groups that were examined: control, high dose

HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to sacrifice at end of study
- Anaesthetic used for blood collection: Yes (sodium pentobarbital)
- Animals fasted: Yes
- How many animals: all
- Parameters checked: erythrocyte count, leucocyte count, platelet count, hemoglobin concentration, hematocrit, differential leucocyte count, reticulocyte count, prothrombin time, activated partial thromboplastin time, mean corpuscular volume, and mean corpuscular hemoglobin

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to sacrifice
- Animals fasted: Yes
- How many animals: all
- Parameters checked: total protein, glucose, triglycerides, total cholesterol, phospholipids, free fatty acids, urea nitrogen, creatinine, calcium, inorganic phosphorous, GOT, GPT, gamma-GTP, ALP, albumin, A/G ratio, sodium, potassium, and chlorine

URINALYSIS: Yes
- Time schedule for collection of urine: 4-3 days before end of study
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked: pH, occult blood, protein, glucose, ketone bodies, bilirubin, urobilirubin

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
General examination, weights of liver, kidneys, adrenals, testes, ovaries, brain, heart, lung, and spleen

HISTOPATHOLOGY: Yes
brain, pituitary, thyroid/parathyroids, thymus, trachea, lungs, heart, aorta, salivary glands, liver, spleen, adrenals, pancreas, testes, epididymides, prostate gland, seminal vesicle, ovaries, uterus, vagina, skin, tongue, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, kidneys, bladder, lymph nodes, mammary gland, muscle, sciatic nerve, femur, sternum, eyes, spinal cord, any other organs with macroscopic changes
Statistics:
Bartlett's equal variance, ANOVA for homogenous variance, Dunnett's method was used to compare mean values between groups with the same number of animals, Scheffe's method was used to compare mean values between groups with different numbers of animals, heterogeneous variance was analyzed using the Kruskal-Wallis H-test, Data from the urinalysis was analyzed using the Armitage chi-squared test
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Bilateral alopecia of the forelimbs was noted in one female in the low dose group at 10 weeks. As this was not seen in any other group, it was not considered to be related to treatment.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Suppression of weight gain was noted in the medium dose male group in the early to mid-part of the study period. As this effect was not dose dependent, it was not considered treatment related.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Males in the high dose group showed increased food consumption. The increase was not consistent, and the difference was slight. When the weight of test substance was subtracted from the total food weight, the actual consumption in this group was identical.
Food efficiency:
effects observed, non-treatment-related
Description (incidence and severity):
A decrease in food efficiency was observed in some males animals, but this effect was short-term.
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Females in the high dose group showed prolonger activated partial thromboplastin times. As the value was still within the normal range of background data, this effect was concluded to be non-treatment related.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
A significant increase in albumin, and elevation in GPT in the medium and high dose male groups. The high dose males also showed a significant increase in potassium. The increase in albumin and potassium was not considered treatment related. The female high dose group also showed significant elevation of GPT. The increase in GPT values was dose-dependent, but within the range of the control group. Since no changes were seen in the livers, this effect, though treatment related, was considered to be of minor importance. A longer term study would be needed to determine the full significance of this increase. Males in the medium dose group and females in the low dose group showed decreased levels of sodium. As this decrease was not dose-dependent, it was not considered treatment related.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
A decrease of ketone bodies was observed in males in the high dose group. However, this effect is not considered to be toxicologically significant.
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
High and medium dose males showed a significant decrease in absolute kidney weights. A significant decrease in relative kidney weights was seen in all male treatment groups. A decrease in relative liver weight was seen in the high dose male group. These differences were 5% or less, and no other changes relating to the decrease were observed. Thus, these effects were not attributed to treatment. A significant decrease in absolute adrenal weight was seen in the medium dose male group. This decrease was attributed to the decrease in average body weight of the treatment groups, and so the effect was not considered significant.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
One female in the medium dose group showed a unilateral ovarian cyst. Ovarian bursa cysts were also in one female in the low dose group, and two in the medium dose group. Hydrometra was seen in one female in the control, medium, and high dose groups. Partial alopecia was seen in one female in the low dose groups. As none of theses changes was dose-related, they were not considered to be treatment related.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Hyaline droplets in the epithelium of the renal uriniferous tubules were frequently found in the control and high dose male. Since there was no significant difference between the groups, this change was not considered to be treatment related. Other changes noted in various groups were focal myocardial degeneration, dilation of the tracheal glands, calcinosis of the reanal cortico-medullary junction, and regeneration fo the uriniferous tubules. These changes were not dose dependent, and therefore not considered to be treatment related. Changes noted in less than 5 males or females, and therefore not considered to be treatment related, were increased extramedullary hematopoiesis in the spleen, lymphocytic infiltration of the tracheal submucosa, cellular infiltration in Glisson's sheath and focal necrosis in the liver, interstitial ductal proliferation and lymphocytic infiltration in the pancreas, lymphocytic infiltration of the hyaline casts and interstitial tissue in the kidney, interstitial lymphocytic infiltration of the thyroid gland, and interstitial lymphocytic infiltration of the Harderian glands. Cysts formed by the dilation of the lymphatic vessels of the ovaries, hydrometra, and hair loss were also observed. These did not occur often enough to be considered treatment related.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Focal osseous metaplasia of the alveolar wall was seen in less than 5 males or females.
Key result
Dose descriptor:
NOAEL
Effect level:
3 240 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Remarks on result:
other: No adverse effects observed up to the highest dose tested.
Key result
Dose descriptor:
NOAEL
Effect level:
3 430 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Remarks on result:
other: No adverse effects observed up to the highest dose tested.
Key result
Critical effects observed:
no
Lowest effective dose / conc.:
3 240 mg/kg bw/day (nominal)
System:
other: blood
Organ:
blood
Conclusions:
The NOAEL for male rats was 3240 mg/kg bw/day (5% of diet), and the NOAEL for female rats was 3430 mg/kg bw/day (5% of diet).
Executive summary:

The oral toxicity of the test substance was determined in a 13-week feed study. The substance was added to the diet at 0, 1, 3, and 5%. Groups of 20 male and 20 female rats were tested at each dose level. After 13 weeks, the animals were sacrificed and necropsied. A slight mean increase in GPT activity of the medium and high dose males, and high dose females was noted. As all the observed values were within the control range, a longer term test would be needed to determine if this was treatment related. As there were no definitive treatment related effects, the NOAEL for both males and females was the highest dose, 5% of feed. For males, this was the equivalent of 3240 mg/kg bw/day, and for females 3430 mg/kg bw/day.

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion