Registration Dossier
Registration Dossier
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EC number: 253-326-2 | CAS number: 37052-78-1
Toxicity to reproduction
Administrative data
- Endpoint:
- toxicity to reproduction
- Remarks:
- other: subacute repeated dose study
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- Data is from study report
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 014
- Report date:
- 2012
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: OECD 407
- Principles of method if other than guideline:
- Repeated dose 28- days oral toxicity study of test chemical was performed in Sprague Dawley (SD) rats to assess the reproductive toxicity.
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Methyl 2-naphthyl ether
- EC Number:
- 202-213-6
- EC Name:
- Methyl 2-naphthyl ether
- Cas Number:
- 93-04-9
- Molecular formula:
- C11H10O
- IUPAC Name:
- 2-methoxynaphthalene
- Details on test material:
- - Name of test material
(as cited in study report): Methyl 2-naphthyl ether (MNE) (Batch no. 0001)
- Molecular formula
(if other than submission substance): C11H10O
- Molecular weight
(if other than submission substance): 158.19999999999999 g/mol
-Substancetype: Organic
-Physicalstate: Solid
-Impurities (identity and concentrations): Impurity : 1.34 %
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- No Data Available
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Source: Central Animal Facility (CAF), NIPER, Sector-67, S.A.S. Nagar, Punjab, India
- Age at study initiation: 7 to 8 weeks old
- Weight at study initiation: Male 184.38-234.56 g, Female 176.90-208.56 g
- Fasting period before study: No data available
- Housing: Four rats per sex per cage were housed in sterilized solid bottom polypropylene cages with stainless steel grill tops with bedding of clean paddy husk. The cages were suspended on stainless steel racks in a controlled environment.
- Diet (e.g. ad libitum): Standard laboratory sterile extruded pelleted rodent feed (Provimi Animal Nutrition India Pvt. Ltd, Bangalore, India), ad libitum
- Water (e.g. ad libitum): Potable tap water filtered through Reviva Reverse Osmosis System (water filter cum purifier), adlibitum
- Acclimatization period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%):30-70 %
- Air changes (per hr): 25 ± 5 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light
IN-LIFE DATES: From: 11.04.2014 (Male), 13.04.2014 (Female); To: 17.05.2014 (Male), 19.05.2014 (Female)
Administration / exposure
- Route of administration:
- oral: gavage
- Type of inhalation exposure (if applicable):
- not specified
- Vehicle:
- other: Dissolved the chemical in Groundnut oil.
- Details on exposure:
- Details on exposure
PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): Groundnut oil
- Concentration in vehicle: 0, 125, 250 or 500 mg/kg body weight/day
- Amount of vehicle (if gavage): 5 ml/kg body weight
- Lot/batch no. (if required): No data available
- Purity: No data available 98.66%
- Details on mating procedure:
- - M/F ratio per cage: No data available
- Length of cohabitation: No data available
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: No data available
- After successful mating each pregnant female was caged (how): No data available
- Any other deviations from standard protocol: No data available - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- No Data Available
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- Daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 125 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 250 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- Total animals: 56
Control: 7 males, 7 females
125 mg/kg/day: 7males, 7 females
250 mg/kg/day: 7 males, 7 females
500 mg/kg/day: 7 males, 7 females - Control animals:
- yes, concurrent vehicle
- Details on study design:
- No Data Available
- Positive control:
- No Data Available
Examinations
- Parental animals: Observations and examinations:
- The mortality and changes in body weight, food consumption and water consumption were recorded.
- Oestrous cyclicity (parental animals):
- No data available
- Sperm parameters (parental animals):
- No data available
- Litter observations:
- No data available
- Postmortem examinations (parental animals):
- The testes, ovaries and uterus were pathologically examined after termination. Examinations also included weight of brain, testes and ovaries (incl. paired ovaries and uterus, including cervix).
- Postmortem examinations (offspring):
- No data available
- Statistics:
- Statistical analysis was carried out by using Microsoft Excel and IBM SPSS statistics version -20. All analyses and comparisons were evaluated at the 5 % level, statistically significant differences (p0.05) indicated by appropriate notation. PAIRED T-Testing procedure was used to check the significance between above mentioned groups. For multiple comparisons Turkey’s HSD test was applied.
- Reproductive indices:
- No data available
- Offspring viability indices:
- No data available
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Abnormalities such as nasal discharge, red crust around the nostrils was observed in all treatment groups. In addition, a few cases of snuffling, eye lid swelling and hunched back posture were also observed in the treated groups.
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- All animals except two animals of high dose group survived throughout the treatment period.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Treatment with 500 mg/kg body weight/day showed a significant reduction in body weights in male rats on the first, second and fourth week of treatment. In female rats, a significant decrease in body weight was observed on the first, second and third week of treatment.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No difference was observed among the groups.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Description (incidence and severity):
- No difference in water consumption was observed among the groups.
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- No difference in opthalmological changes was observed among the groups.
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In male rats, significant increase in the platelet count was observed along with decrease in MCV and MCH levels at 125 mg/kg body weight/day.
Treatment with 250 mg/kg body weight/day showed significantly decreased values of hemoglobin and MCHC in male rats. The level of MCHC was also found to be significantly decreased when treated with 500 mg/kg body weight/day.
In female rats, treatment with 125 mg/kg body weight/day showed significant alterations in platelet count and MCV. At 250 mg/kg body weight/day, a significant decrease was noticed in neutrophils along with altered values of MCV in female rats. - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In female animals, the level of total bile acid was decreased at 250 mg/kg body weight/day. A significant increase was noticed in the level of estrogen in the same group. A similar trend was also noticed at 125 and 500 mg/kg body weight/day, but was statistically non-significant.
At 250 and 500 mg/kg body weight/day the levels of potassium and albumin were found to be significantly increased. The cholesterol level in the 250 mg/kg body weight/day group was noticed to be significantly elevated in the mid-dose group.
In male rats, the level of testosterone was significantly increased after treatment with 500 mg/kg body weight/day. - Urinalysis findings:
- not specified
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- No statistically significant difference was observed in the motor activity scores for any dose group when compared with the control animals.
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No remarkable changes observed in control and the 500 mg/kg body weight/day-treated animals.
A few microscopic findings observed in 500 mg/kg body weight/day-treated animals included collapsed lung with focal inflammation, focal fatty change and excess of lymphocytes in liver, inflammation in small intestine, reactive spleen and excess of mucous in colon. However, these findings were also observed in the control animals. - Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- not specified
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 125 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- food consumption and compound intake
- water consumption and compound intake
- ophthalmological examination
- haematology
- clinical biochemistry
- organ weights and organ / body weight ratios
- gross pathology
- histopathology: non-neoplastic
- other: No effect observed
- Dose descriptor:
- LOAEL
- Effect level:
- 250 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- organ weights and organ / body weight ratios
- other: effect observed on reproductive organs
Target system / organ toxicity (P0)
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 125 mg/kg bw/day (nominal)
- System:
- female reproductive system
- Organ:
- ovary
- Treatment related:
- yes
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- not specified
- Body weight and weight changes:
- not specified
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Histopathological findings:
- not specified
- Other effects:
- not specified
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not specified
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not specified
Effect levels (F1)
- Dose descriptor:
- other: not specified
- Generation:
- other: not specified
- Based on:
- not specified
- Sex:
- not specified
- Basis for effect level:
- other: not specified
- Remarks on result:
- not measured/tested
Target system / organ toxicity (F1)
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
- Treatment related:
- not specified
Any other information on results incl. tables
SUMMARY OF BODY WEIGHTS(g)
Male
|
SUMMARY OF BODYWEIGHTS(g)
Female
Group |
Dose mg/kg |
|
Day1 |
Day8 |
Day15 |
Day22 |
Day28 |
Terminal Day |
1 |
Vehicle |
Mean |
191.17 |
200.82 |
208.91 |
215.94 |
227.15 |
219.85 |
S.D. |
7.12 |
12.39 |
16.56 |
15.30 |
17.64 |
19.32 |
||
S.E.M. |
3.72 |
6.17 |
7.93 |
7.09 |
7.77 |
8.79 |
||
2 |
125 |
Mean |
192.17 |
201.14 |
208.56 |
214.38 |
220.79 |
216.51 |
S.D. |
9.31 |
10.16 |
8.58 |
7.62 |
10.76 |
10.09 |
||
S.E.M. |
4.85 |
5.05 |
4.11 |
3.55 |
4.87 |
4.66 |
||
3 |
250 |
Mean |
194.94 |
202.08 |
209.12 |
216.24 |
228.85 |
226.38 |
S.D. |
9.45 |
8.89 |
8.24 |
7.85 |
7.51 |
8.75 |
||
S.E.M. |
4.85 |
4.40 |
3.94 |
3.63 |
3.28 |
3.87 |
||
4 |
500 |
Mean |
190.49 |
182.52 |
192.46 |
205.74 |
216.14 |
212.37 |
S.D. |
8.82 |
9.74 |
12.73 |
11.46 |
11.61 |
12.10 |
||
S.E.M. |
4.63 |
5.34 |
6.61 |
5.57 |
5.37 |
5.70 |
SUMMARY OF HEMATOLOGY DATA Male
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SUMMARY OF HEMATOLOGY DATA Female
emaleGroup/Dose |
|
WBC (x103/mm3) |
RBC (x106/mm3) |
PLT (x103/mm3) |
Hct (%) |
Hgb (g/dl) |
MCV(fl) |
MCH (pg) |
MCHC (g/dl) |
Lym % |
Mon % |
Nut % |
Eos % |
Bas% |
||||
Vehicle |
Mean |
11.66 |
62.20 |
4.41 |
30.31 |
1.39 |
0.87 |
10.18 |
49.90 |
50.74 |
15.44 |
30.97 |
15.71 |
994.57 |
||||
±S.D. |
2.19 |
8.62 |
1.09 |
8.69 |
1.61 |
0.17 |
0.55 |
2.34 |
2.56 |
0.68 |
0.31 |
0.84 |
520.25 |
|||||
± S..E..M. |
0.8 |
3.3 |
0.4 |
3.3 |
0.6 |
0.1 |
0.2 |
0.9 |
1.0 |
0.3 |
0.1 |
0.3 |
196.6 |
|||||
|
||||||||||||||||||
2 / 125mg/kg |
Mean |
12.28 |
67.97 |
4.34 |
25.10 |
0.94 |
0.90 |
10.13 |
51.66＊ |
52.26 |
15.86 |
30.71 |
16.06 |
518.71 ＊ |
||||
±S.D. |
4.51 |
6.98 |
0.78 |
6.78 |
0.47 |
0.18 |
0.47 |
1.36 |
1.39 |
0.73 |
0.71 |
0.45 |
114.08 |
|||||
±S.E.M. |
1.7 |
2.6 |
0.3 |
2.6 |
0.2 |
0.1 |
0.2 |
0.5 |
0.5 |
0.3 |
0.3 |
0.2 |
43.1 |
|||||
|
||||||||||||||||||
3 / 250mg/kg |
Mean |
11.94 |
69.24 |
4.13 |
21.83＊ |
2.93 |
1.07 |
10.18 |
51.76＊ |
52.76 |
15.71 |
30.37 |
15.99 |
585.00 |
||||
±S.D. |
3.21 |
7.96 |
0.54 |
7.77 |
2.71 |
0.24 |
0.45 |
1.55 |
3.36 |
0.75 |
1.44 |
1.17 |
213.78 |
|||||
±S.E.M. |
1.2 |
3.0 |
0.2 |
2.9 |
1.0 |
0.1 |
0.2 |
0.6 |
1.3 |
0.3 |
0.5 |
0.4 |
80.8 |
|||||
|
||||||||||||||||||
4 / 500mg/kg |
Mean |
11.37 |
66.26 |
4.36 |
26.57 |
1.06 |
1.03 |
10.00 |
51.77 |
51.79 |
15.79 |
30.47 |
15.79 |
614.29 |
||||
±S.D. |
2.10 |
9.91 |
0.99 |
9.88 |
1.34 |
0.19 |
0.73 |
0.85 |
3.90 |
0.57 |
0.92 |
1.41 |
139.13 |
|||||
±S.E .M. |
0.8 |
3.7 |
0.4 |
3.7 |
0.5 |
0.1 |
0.3 |
0.3 |
1.5 |
0.2 |
0.3 |
0.5 |
52.6 |
|||||
|
||||||||||||||||||
SUMMARY OF CLINICAL BIOCHEMISTRY DATA Male Rats
Group/Dose |
|
Sod.(mmol/L) |
Pot.(mmol/L) |
ALB(g%) |
CHOL(mg%) |
CRT(mg%) |
SGOT(IU/L) |
SGPT (IU/L) |
GLU(mg%) |
TP(g%) |
BUN(mg%) |
TBA |
Test |
|||||
ng/L |
nmol/L |
|||||||||||||||||
1 / 0 |
Mean |
131.5 |
7.0 |
3.9 |
83.9 |
0.9 |
33.1 |
32.9 |
117.0 |
6.5 |
12.5 |
490.1 |
4.363 |
|||||
±S.D. |
8.6 |
0.5 |
0.3 |
18.1 |
0.2 |
4.0 |
5.1 |
7.1 |
0.4 |
3.0 |
44.82 |
1.02 |
||||||
±S.E.M. |
3.2 |
0.2 |
0.1 |
6.8 |
0.1 |
1.5 |
1.9 |
2.7 |
0.1 |
1.1 |
16.94 |
0.387 |
||||||
|
||||||||||||||||||
2 /125 mg/kg |
Mean |
130.0 |
7.6 |
3.7 |
87.6 |
0.9 |
33.9 |
32.5 |
119.1 |
6.5 |
14.4 |
485.4 |
5.421 |
|||||
±S.D. |
3.3 |
0.7 |
0.3 |
10.7 |
0.2 |
8.2 |
7.6 |
4.9 |
0.5 |
3.0 |
36.17 |
1.03 |
||||||
±S.E.M. |
1.2 |
0.3 |
0.1 |
4.0 |
0.1 |
3.1 |
2.9 |
1.9 |
0.2 |
1.1 |
13.67 |
0.392 |
||||||
|
|
|
||||||||||||||||
3 /250 mg/kg |
Mean |
130.1 |
7.1 |
3.7 |
87.7 |
0.9 |
65.4 |
30.0 |
121.0 |
6.7 |
12.1 |
465.4 |
4.716 |
|||||
±S.D. |
9.8 |
1.0 |
0.2 |
17.4 |
0.1 |
90.0 |
7.0 |
9.5 |
0.5 |
2.8 |
35.10 |
1.28 |
||||||
±S.E.M. |
3.7 |
0.4 |
0.1 |
6.6 |
0.1 |
34.0 |
2.6 |
3.6 |
0.2 |
1.1 |
13.26 |
0.487 |
||||||
|
||||||||||||||||||
4 / 500 mg/kg |
Mean |
124.5 |
11.0 |
3.7 |
96.2 |
0.9 |
31.1 |
30.5 |
121.6 |
6.4 |
13.7 |
485.2 * |
6.289* |
|||||
±S.D. |
11.1 |
8.4 |
0.3 |
12.1 |
0.2 |
7.5 |
6.4 |
13.8 |
0.5 |
4.0 |
23.33 |
0.398 |
||||||
±S.E.M. |
5.0 |
3.8 |
0.1 |
5.4 |
0.1 |
3.3 |
2.8 |
6.2 |
0.2 |
1.8 |
10.43 |
0.178 |
||||||
|
||||||||||||||||||
SUMMARY OF CLINICAL BIOCHEMISTRY DATA - Female
Group /Dose |
|
Sod. |
Pot. |
ALB |
CHOL |
CRT |
SGOT |
SGPT |
GLU |
TP |
BUN |
TBA |
Est |
(mmol/L) |
(mmol/L) |
(g%) |
(mg%) |
(mg%) |
(IU/L) |
(IU/L) |
(mg%) |
(g%) |
(mg%) |
ng/L |
ng/L |
||
1 / 0 mg/kg |
Mean |
139.2 |
7.2 |
3.3 |
93.0 |
1.1 |
32.3 |
39.9 |
110.4 |
7.0 |
12.9 |
485 |
9.156 |
±S.D. |
9.3 |
0.6 |
0.3 |
14.5 |
0.2 |
15.3 |
21.7 |
14.2 |
0.5 |
4.3 |
30.60 |
1.47 |
|
±S.E.M. |
3.5 |
0.2 |
0.1 |
5.5 |
0.1 |
5.8 |
8.2 |
5.4 |
0.2 |
1.6 |
11.56 |
0.558 |
|
|
|||||||||||||
2 / 125 mg/kg |
Mean |
136.6 |
7.8 |
3.4 |
98.0 |
1.1 |
28.8 |
39.6 |
100.0 |
7.3 |
12.5 |
475.1 |
9.869 |
±S.D. |
4.3 |
0.9 |
0.1 |
17.1 |
0.4 |
7.4 |
9.0 |
8.9 |
0.5 |
2.1 |
30.59 |
1.27 |
|
±S.E.M. |
1.6 |
0.3 |
0.1 |
6.5 |
0.1 |
2.8 |
3.4 |
3.4 |
0.2 |
0.8 |
11.56 |
0.482 |
|
|
|
|
|||||||||||
3 / 250 mg/kg |
Mean |
141.6 |
8.1 |
3.8 |
119.9 |
1.1 |
27.9 |
40.0 |
100.2 |
7.0 |
12.5 |
425.5* |
10.478* |
±S.D. |
7.3 |
0.9 |
0.4 |
24.7 |
0.2 |
6.0 |
8.1 |
9.0 |
0.6 |
2.8 |
52.38 |
1.33 |
|
±S.E.M. |
2.8 |
0.4 |
0.2 |
9.3 |
0.1 |
2.3 |
3.0 |
3.4 |
0.2 |
1.1 |
19.79 |
0.505 |
|
|
|||||||||||||
4 / 500 mg/kg |
Mean |
137.0 |
8.1 |
3.7 |
113.4 |
1.1 |
32.3 |
43.5 |
100.1 |
7.0 |
14.1 |
448.5 |
9.842 |
±S.D. |
5.9 |
0.8 |
0.2 |
23.6 |
0.2 |
8.4 |
9.8 |
5.8 |
0.6 |
2.3 |
31.16 |
1.93 |
|
±S.E.M. |
2.2 |
0.3 |
0.1 |
8.9 |
0.1 |
3.2 |
3.7 |
2.2 |
0.2 |
0.9 |
13.93 |
0.73 |
|
|
|||||||||||||
SUMMARY OF ABSOLUTE ORGAN WEIGHTS(g) - Male Rats
Group/ Dose |
|
Brain |
Thymus |
Liver |
Kidneys |
Adrenals |
Ovaries |
Spleen |
Heart |
Epididymides |
1 Vehicle |
Mean |
1.79 |
0.30 |
10.72 |
1.98 |
0.03 |
2.79 |
1.04 |
0.55 |
0.88 |
±S.D. |
0.28 |
0.06 |
1.48 |
0.30 |
0.01 |
0.27 |
0.15 |
0.11 |
0.09 |
|
±S.E.M. |
0.11 |
0.02 |
0.56 |
0.11 |
0.01 |
0.10 |
0.05 |
0.04 |
0.03 |
|
|
||||||||||
2 (125) mg/kg |
Mean |
1.89 |
0.46 |
11.54 |
2.09 |
0.07 |
2.75 |
1.05 |
0.54 |
0.89 |
±S.D. |
0.12 |
0.16 |
0.70 |
0.11 |
0.08 |
0.22 |
0.06 |
0.13 |
0.08 |
|
±S.E.M. |
0.05 |
0.06 |
0.26 |
0.04 |
0.03 |
0.08 |
0.02 |
0.05 |
0.03 |
|
|
||||||||||
3 (250)mg/kg |
Mean |
1.87 |
0.32 |
11.25 |
2.04 |
0.04 |
2.81 |
1.10 |
0.63 |
0.91 |
±S.D. |
0.07 |
0.06 |
1.96 |
0.23 |
0.01 |
0.14 |
0.12 |
0.19 |
0.10 |
|
±S.E.M. |
0.02 |
0.02 |
0.74 |
0.09 |
0.00 |
0.05 |
0.05 |
0.07 |
0.04 |
|
|
||||||||||
4 (500) mg/kg |
Mean |
1.79 |
0.28 |
10.61 |
1.93 |
0.04 |
2.87 |
1.03 |
0.54 |
0.88 |
±S.D. |
0.07 |
0.05 |
0.51 |
0.17 |
0.01 |
0.13 |
0.06 |
0.11 |
0.05 |
|
±S.E.M. |
0.03 |
0.02 |
0.19 |
0.06 |
0.00 |
0.05 |
0.02 |
0.04 |
0.02 |
|
SUMMARY OF ABSOLUTE ORGAN WEIGHTS(g)
Femalerats
Group/ Dose |
|
Brain |
Thymus |
Liver |
Kidneys |
Adrenals |
Ovaries |
Spleen |
Heart |
Uterus |
|||||
1/0 (mg/kg) |
Mean |
1.79639 |
0.69686 |
8.13916 |
1.66367 |
0.0451 |
0.14289 |
0.63041 |
0.79684 |
0.46711 |
|||||
±S.D. |
0.13458 |
0.547 |
0.47047 |
0.18627 |
0.01172 |
0.02302 |
0.11848 |
0.11455 |
0.07792 |
||||||
±S.E.M. |
0.05087 |
0.20675 |
0.17782 |
0.0704 |
0.00443 |
0.0087 |
0.04478 |
0.04329 |
0.02945 |
||||||
|
|||||||||||||||
2/(120) mg/kg |
Mean |
1.78147 |
0.28884 |
8.15586 |
1.55246 |
0.04734 |
0.08319＊ |
0.63869 |
0.77013 |
0.39303 |
|||||
±S.D. |
0.11628 |
0.1304 |
1.06437 |
0.16655 |
0.00937 |
0.01815 |
0.24329 |
0.06459 |
0.08246 |
||||||
±S.E.M. |
0.04395 |
0.04929 |
0.40229 |
0.06295 |
0.00354 |
0.00686 |
0.09196 |
0.02441 |
0.03117 |
||||||
|
|||||||||||||||
2/
250 mg/kg |
Mean |
1.6069 |
0.3289 |
8.3645 |
1.566 |
0.0395 |
0.0935＊ |
0.4718 |
0.7185 |
0.4667＊ |
|||||
±S.D. |
0.27569 |
0.12711 |
0.78925 |
0.15522 |
0.01286 |
0.02423 |
0.11176 |
0.06134 |
0.07708 |
||||||
±S.E.M. |
0.1042 |
0.04804 |
0.29831 |
0.05867 |
0.00486 |
0.00916 |
0.04224 |
0.02319 |
0.02913 |
||||||
|
|||||||||||||||
4 / (500) mg/kg |
Mean |
1.75207 |
0.42151 |
7.9445 |
1.525＊ |
0.04407 |
0.07481 |
0.49059＊ |
0.70961 |
0.34757＊ |
|||||
±S.D. |
0.12692 |
0.20921 |
0.63133 |
0.13336 |
0.00665 |
0.01518 |
0.09178 |
0.02657 |
0.10007 |
||||||
±S.E.M. |
0.04797 |
0.07907 |
0.23862 |
0.05041 |
0.00251 |
0.00574 |
0.03469 |
0.01004 |
0.03782 |
||||||
SUMMARY OF RELATIVE ORGAN WEIGHTS Male Rats
Group/Dose |
|
Brain |
Thymus |
Liver |
Kidneys |
Adrenals |
Testes |
Splee n |
Heart |
epididymide s |
1/
0 |
Mean |
0.6051 |
0.1009 |
3.6170 |
0.6680 |
0.0110 |
0.9447 |
0.1846 |
0.2970 |
0.3521 |
±S.D. |
0.1132 |
0.0236 |
0.4211 |
0.0880 |
0.0052 |
0.1114 |
0.0407 |
0.0210 |
0.0527 |
|
±S.E.M. |
0.0428 |
0.0089 |
0.1592 |
0.0333 |
0.0020 |
0.0421 |
0.0154 |
0.0079 |
0.0199 |
|
|
|
|
||||||||
2/ 125 mg/kg |
Mean |
0.6466 |
0.1549 |
3.9569* |
0.7236 |
0.0243 |
0.9377 |
0.1856 |
0.3060 |
0.3599 |
±S.D. |
0.0330 |
0.0515 |
0.2711 |
0.0369 |
0.0274 |
0.0434 |
0.0428 |
0.0262 |
0.0299 |
|
±S.E.M. |
0.0125 |
0.0195 |
0.1025 |
0.0139 |
0.0104 |
0.0164 |
0.0162 |
0.0099 |
0.0113 |
|
|
|
|
||||||||
3 / 250 mg/kg |
Mean |
0.6674 |
0.1140 |
3.9886 |
0.7207 |
0.0143 |
1.0007 |
0.2209 |
0.3220 |
0.3883 |
±S.D. |
0.0627 |
0.0252 |
0.6023 |
0.0431 |
0.0021 |
0.0816 |
0.0608 |
0.0367 |
0.0346 |
|
±S.E.M. |
0.0237 |
0.0095 |
0.2277 |
0.0163 |
0.0008 |
0.0309 |
0.0230 |
0.0139 |
0.0131 |
|
|
|
|
||||||||
4 / 500 mg/kg |
Mean |
0.5317 |
0.0868 |
3.1877 |
0.5684 |
0.0110 |
0.8401 |
0.1709 |
0.2618* |
0.3071* |
±S.D. |
0.3033 |
0.0461 |
1.7161 |
0.3359 |
0.0062 |
0.4873 |
0.0898 |
0.1468 |
0.1775 |
|
±S.E.M. |
0.1357 |
0.0206 |
0.7675 |
0.1502 |
0.0028 |
0.2179 |
0.0402 |
0.0656 |
0.0794 |
|
SUMMARY OF RELATIVE ORGAN WEIGHTS- Females
Group/Dose |
|
Brain |
Thymu s |
Liver |
Kidneys |
Adrenal s |
Ovaries |
uterus |
Spleen |
Heart |
||
1/0 |
Mean |
0.8181 |
0.3176 |
3.7199 |
0.7573 |
0.0200 |
0.0654 |
0.2107 |
0.2849 |
0.3614 |
||
±S.D. |
0.0380 |
0.2566 |
0.3170 |
0.0667 |
0.0045 |
0.0141 |
0.0202 |
0.0354 |
0.0334 |
|||
±S.E.M. |
0.0144 |
0.0970 |
0.1198 |
0.0252 |
0.0017 |
0.0053 |
0.0076 |
0.0134 |
0.0126 |
|||
|
||||||||||||
2 / 125 mg/kg |
Mean |
0.8227 |
0.1324 |
3.7541 |
113.7454 |
0.0214 |
*0.0380 |
0.1824 |
0.2926 |
0.3557 |
||
±S.D. |
0.0439 |
0.0598 |
0.3280 |
299.0822 |
0.0053 |
0.0090 |
0.0439 |
0.1052 |
0.0323 |
|||
±S.E.M. |
0.0166 |
0.0226 |
0.1240 |
113.0424 |
0.0020 |
0.0034 |
0.0166 |
0.0398 |
0.0122 |
|||
|
||||||||||||
3 / 250 mg/kg |
Mean |
0.7137 |
0.1443 |
3.6900 |
0.6917 |
0.0171 |
0.0406* |
0.2054 |
0.2077* |
0.3169* |
||
±S.D. |
0.1425 |
0.0553 |
0.2348 |
0.0629 |
0.0053 |
0.0089 |
0.0298 |
0.0487 |
0.0212 |
|||
±S.E.M. |
0.0539 |
0.0209 |
0.0887 |
0.0238 |
0.0020 |
0.0034 |
0.0113 |
0.0184 |
0.0080 |
|||
|
||||||||||||
4 / 500mg/kg |
Mean |
0.8253 |
0.1970 |
3.7417 |
0.7173 |
0.0203 |
0.0349* |
0.1636 |
0.2304* |
0.3341 |
||
±S.D. |
0.0546 |
0.0920 |
0.2484 |
0.0423 |
0.0028 |
0.0080 |
0.0463 |
0.0405 |
0.0130 |
|||
±S.E.M. |
0.0206 |
0.0348 |
0.0939 |
0.0160 |
0.0011 |
0.0030 |
0.0175 |
0.0153 |
0.0049 |
|||
Applicant's summary and conclusion
- Conclusions:
- NOAEL was considered to be 125 mg/kg bw for male rats and LOAEL was considered to be 250 mg/kg body weight/day for female when Sprague Dawley male and female rats were exposed daily to the test chemical by oral route for 28 days.
- Executive summary:
In a 28 days repeated dose toxicity study, the effect of the test chemical was evaluated in male and female Sprague Dawley rats. The test chemical was administered by oral gavage in the concentration of 0, 125, 250 or 500 mg/kg body weight/day. The results showed that the test chemical significantly increased the level of testosterone in the 500 mg/kg body weight/day group as well as it significantly increased the level of estrogen in the 250 mg/kg body weight/day group .The relative and absolute organ weight of ovaries decreased when treated with 125, 250 or 500 mg/kg body weight/day. In similarity, the relative and absolute organ weight of uterus decreased in the 125 or 500 mg/kg body weight/day groups.No significant changes in were detected in hematology,clinical biochemistry,mortality ororgan weight, and no effects were observed in water consumption,opthalmoscopic examination or locomotor activity. In male rats, the relative organ weights of the testes and epididymides increased when rats were treated with 500 mg/kg body weight/day. Histopathology performed on reproductive organs after treatment with 500 mg/kg body weight/day did not reveal any toxic lesions as compared to control. Hence, NOAEL was considered to be 250 mg/kg bw for male rats and LOAEL was considered to be 125 mg/kg body weight/day for female when Sprague Dawley male and female rats were exposed daily to the test chemical by oral route for 28 days.
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