2,3,5-trimethylphenol

Repeated dose toxicity: oral

Administrative data

Endpoint:

repeated dose toxicity: oral, other

Remarks:

Combined repeated dose repro-devp. Screen

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from J check

Data source

Reference

Reference Type:

other: J check

Title:

Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD TG422) for 2,3,5 Trimethylphenol

Author:

National Institute of Technology and Evaluation

Year:

2016

Bibliographic source:

Japan Chemicals Collaborative Knowledge database, 2016

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Principles of method if other than guideline:

Combined repeated dose repro-devp. Screen was performed for 2,3,5 Trimethylphenol to determine its repeated oral toxic nature upon repeated exposure to Crl:CD (SD) rats

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2,3,5-trimethylphenol

EC Number:

211-806-9

EC Name:

2,3,5-trimethylphenol

Cas Number:

697-82-5

Molecular formula:

C9H12O

IUPAC Name:

2,3,5-trimethylphenol

Test material form:

solid

Details on test material:

- Name of test material: 2,3,5 Trimethylphenol
- Molecular formula: C9H12O
- Molecular weight: 136.193 g/mol
- Substance type: Organic
- Physical state: Solid
- Purity: No data available
- Impurities (identity and concentrations): No data available

Specific details on test material used for the study:

- Name of test material: 2,3,5 Trimethylphenol
- Molecular formula: C9H12O
- Molecular weight: 136.19 g/mol
- Substance type: Organic
- Physical state: White light yellow powder
- Purity: 99.8%
- Impurities (identity and concentrations): No data available

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Details on species / strain selection:

No data

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: No data available
- Age at study initiation: 10 weeks old
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: No data available
- Diet (e.g. ad libitum): No data available
- Water (e.g. ad libitum): No data available
- Acclimation period: No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%):No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

IN-LIFE DATES: From: To: No data available

Administration / exposure

Route of administration:

oral: gavage

Details on route of administration:

No data

Vehicle:

olive oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: 2,3,5 Trimethylphenol was dissolved in olive oil to give a dose level of 0, 100, 300 or 1000 mg/Kg/day for the test group and 0 or 1000 mg/Kg/day for recovery group

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water): Olive oil
- Concentration in vehicle: Test group: 0, 100, 300 or 1000 mg/Kg/day and Recovery group: 0 or 1000 mg/Kg/day
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

Male: 42 days
Female: 42-46 days (from 14 days before mating to day 4 of lactation)

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

Test group- 0, 100, 300 or 1000 mg/kg/day
Recovery group- 0 or 1000 mg/kg/day

No. of animals per sex per dose:

Total: 116
Test group:
0 mg/Kg/day: 12 males and 12 females
100 mg/Kg/day: 12 males and 12 females
300 mg/Kg/day: 12 males and 12 females
1000 mg/Kg/day: 12 males and 12 females

Recovery group:
0 mg/Kg/day: 5 males and 5 females
1000 mg/Kg/day: 5 males and 5 females

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: No data
- Rationale for animal assignment (if not random): No data
- Rationale for selecting satellite groups: No data
- Post-exposure recovery period in satellite groups: No data
- Section schedule rationale (if not random): No data

Positive control:

No data

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data available
- Time schedule: No data available
- Cage side observations checked in table [No.?] were included. No data available

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data available

BODY WEIGHT: Yes
- Time schedule for examinations: No data

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: No data available

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: No data available

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data available
- Time schedule for examinations: No data available

OPHTHALMOSCOPIC EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available

HAEMATOLOGY: Yes
- Time schedule for collection of blood: No data available
- Anesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined. RBCm hematocrit, hemoglobin, RET, MCV, MCHC and MCH, platelet, PT. APTT, WBC, Differential WBCs like neutrophil, lymphocytes, monocytes, eosinophil, basophil and others

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined. T-Cho, PL, ALT, ALP, K, TP, Alb, AST and T-Bil, A/G ratio, T-Bil, glucose, Triglyceride, phospholipid, LDH, GTP, CK, BUN, creatinine, NA, Cl, Ca, IP

URINALYSIS: Yes
- Time schedule for collection of urine: No data available
- Metabolism cages used for collection of urine: No data available
- Animals fasted: No data available
- Parameters checked in table [No.?] were examined. Protien content, ketone body, ph, urobilinogen, glucose, bilirubin, occlut blood

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data available

OTHER: No data available

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, Gross necropsy was performed and absolute and relative kidney, spleen, liver, adrenal, testes, brain, epididymides weight was measured
HISTOPATHOLOGY: Yes, histopathology was performed for kidney, spleen, liver, adrenal, testes, brain, epididymides, mucosa, small and large intestine

Other examinations:

No data

Statistics:

No data

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

no effects observed

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

Clinical signs and mortality:
Clinical signs:
Males: At 300 and 1000 mg/kg/day soiled perigenitalia with urine was observed and transient lethargy and ataxic gait after dosing was noted at 1000 mg/Kg/day

Females: At 300 and 1000 mg/kg/day concentrations soiled perigenitalia with urine and transient lethargy and ataxic gait after dosing was observed

Mortality:
Males: No data

Female: One female animal each (n: 12) at 300 and 1000 mg/kg/day was found dead during the study

Body weight and weight gain:
Males: At 300 mg/kg/day (test group) and 1000 mg/kg/day (test and recovery group) decrease in the body weight gain was observed

Females: At 1000 mg/kg/day ( test and recovery group), a decrease in the body weight gain was observed.

Food consumption and compound intake:
Males: Food consumption was decreased in 300 and 1000 mg/kg/day test groups and increased in 1000 mg/kg/day recovery group

Females: A decrease in food consumption was noted in 1000 mg/kg/day test group and an increase was noted in 1000 mg/kg/day recovery group

Food efficiency: No data

Water consumption and compound intake: No data

Opthalmoscopic examination: No data

Haematology:
Males: An increase in the RET at 300, 1000 mg/kg/day and in recovery group at 1000 mg/kg/day, increase in the MCV at 1000mg/kg/day, increase in the MCV at recovery in 1000 mg/kg/day and a decrease in the MCHC at recovery in 1000 mg/kg/day was noted

Females: A decrease in the RBC at 1000 mg/kg/day and Recovery at 1000 mg/kg/day, decrease in the Hgb at 1000 mg/kg/day and at recovery in 1000 mg/kg/day concentration, decrease in the MCHC at 1000 mg/kg/day and an increase in the MCV, MCH and RET at 1000 mg/kg/day was noted

Clinical chemistry:
Males: An increase in the TCho, PL and ALT at 1000 mg/kg/d and a decrease in K at 1000 mg/kg/ day dose level was noted

Female: An increase in the TP at 300 and 1000 mg/kg/day, increase in the Alb at 300 and 1000 mg/kg/day, increase in the TCho,PL and ALP at 1000 mg/kg/day, increase in the AST at recovery in 1000 mg/kg/day, increase in the ALT at 1000 mg/kg/day and at recovery in 1000 mg/kg/day and an increase in the TBil at 1000 mg/kg/day dose level was noted

Urinanalysis:
Male: A decrease in the protein at 300 mg/kg/day, decrease in the protein at 1000 mg/kg/day, decrease in the ketone body at 300, 1000 mg/kg/day and in recovery group at 1000 mg/kg/day was observed

Females: No data

Neurobehaviour: No effects were noted in the functional battery examination performed

Organ weights:
Male: An increase in the kidney weight (Absolute and relative) at 300 and 1000 mg/kg/day, increase in the spleen weight (Absolute and relative) at 300 and 1000 mg/kg/day( tendency), increase in the liver weight (Absolute and relative) at 1000 mg/kg/day (tendency), increase in the adrenal weight (Absolute and relative) at 1000 mg/kg/day concentration and at Recovery in 1000 mg/kg/day, increase in the testis weight (Relative) at 1000 mg/kg/day, increase in the brain weight (Relative) at 1000 mg/kg/day and at recovery in 1000 mg/kg/day, decrease in the epididymides weight (Absolute) at 1000 mg/kg/day and at recovery 1000 mg/kg/day dose levels was noted

Female: An increase in the kidney weight (Absolute and relative) at 300, 1000 mg/kg/day and at recovery in 1000 mg/kg/day (tendency), increase in the liver weight (Relative) at 300 and 1000 mg/kg/day, increase in the brain weight (Relative) at 300 and 1000 mg/kg/day, increase in the spleen weight (Absolute and Relative) at 1000 mg/kg/day and an increase in the heart weight (Relative) at 1000 mg/kg/day was observed.

Gross pathology: No data available

Histopathology:
Male: Centrilobular hypertrophy of hepatocytes in the liver in 1000 mg/kg/day, inflammatory cell nest in the liver at Recovery 1000 mg/kg/day, deposit of hemosiderin in the spleen at 1000 mg/kg/day and at recovery in 1000 mg/kg/day, increase in the extramedullary hematopoietic in the spleen (Recovery 1000 mg/kg/day), vacuolization in the seminiferous tubule, germ cell necrosis and multinucleated giant cell formation in the testis (1000mg/kg/day and Recovery 1000 mg/kg/day), inflammatory infiltration in the mucosa and the lamina propria of small and large intestines at 1000 mg/kg/day was noted.

Female: An increase in the extramedullary hematopoiesis in the liver at 1000 mg/kg/day, inflammatory cell nest in the liver at Recovery 1000 mg/kg/day, deposit of hemosiderin in the spleen at 1000 mg/kg/day and Recovery at 1000 mg/kg/day, increase in the extramedullary hematopoiesis in the spleen at 1000 mg/kg/day, inflammation in forestomach at 1000 mg/kg/day, squamous cell hyperplasia in forestomach at 300 and 1000 mg/kg/day and atrophy of the thymus at 300 and 1000 mg/kg/day was observed

Effect levels

Dose descriptor:

NOAEL

Effect level:

100 other: mg/Kg/day (actual dose)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant effects were observed for clinical signs, mortality, body weight and food consumption, urinanalysis, hematology, blood chemistry, organ weights and histopathology at 100 mg/Kg/day

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 1: Urinalysis of male rats treated orally with 2,3,5-trimethylphenol

		Administration period				Recovery period
Dose (mg/Kg)		0	100	300	1000	0	1000
No. of animals examined		12	12	12	11	5	5
pH	6.0	0	0	0	1	0	0
	8.0	3	3	2	3	3	0*
	8.5	9	9	10	7	2	5*
Protein	-	0	0	0	0	0	0
	±	0	0	0	0	1	0
	+	4	0*	8	9*	0	2
	2+	8	12*	4	2*	4	3
Glucose	-	12	12	12	11	5	5
Ketone body	-	3	1	6	8	1	3
	±	8	11	6	3	0	2
	+	1	0	0	0	3	0
	2+	0	0	0	0	1	0
Bilirubin	-	12	12	12	11	5	5
Occult blood	-	11	12	12	11	5	5
	2+	1	0	0	0	0	0
Urobilinogen	±	12	12	12	11	5	5

Grade; －: negative, ±: trace, ＋: slight, 2＋: moderate, 3＋: marked.

Data represent the number of animals.

Significant difference from the control group, * p≦0.05.

Table 2: Hematology of rats treated orally with 2,3,5-trimethylphenol

	Administration period				Recovery period
	0	100	300	1000	0	1000
Males
No. of animals examined	7	12	12	6	5	5
MCV (fL)	49.2±1.6	48.3±1.5	50.0±1.1	51.3±2.1*	48.6±1.1	50.6±2.3
MCHC (g/dL)	38.8±0.3	38.9±0.8	38.4±0.8	38.1±0.7	37.8±0.2	37.1±0.5*
Reticulocyte (%)	1.6±0.3	1.7±0.3	2.3±0.2**	2.4±0.4**	1.8±0.4	2.1±0.4
Females (dam)
RBC (×106/μL)	6.57±0.43	6.27±0.77	6.33±0.65	5.50±0.74**	7.98±0.22	7.52±0.31*
Hemoglobin (g/dL)	13.3±0.8	13.1±1.1	13.1±0.8	11.9±1.4 **	15.6±0.3	15.0±0.3 *
MCV (fL)	53.1±1.8	54.6±3.8	55.3±3.7	59.9±4.5 **	50.8±1.6	52.4±1.5
MCH (pg)	20.2±0.7	21.0±1.2	20.8±1.2	21.6±0.8 **	19.6±0.6	19.9±0.6
MCHC (g/dL)	38.2±.4	38.5±0.9	37.7±1.1	36.2±2.1 *	38.5±0.4	38.1±0.8
Reticulocyte (%)	5.9±1.7	7.0±3.7	6.7±3.3	11.3±5.0 *	1.6±0.5	1.7±0.5
Monocyte	2.7±1.0	3.5±1.5	4.5±2.0 *	3.7±1.1	2.5±0.7	3.0±0.7

Data represent mean ± S.D.

Significant difference from the control group, * p≦0.05, ** p≦0.01.

 

Table 3 Biochemistry of rats treated orally with 2,3,5-trimethylphenol

	Administration period				Recovery period
	0	100	300	1000	0	1000
Males
No. of animals examined	7	12	12	6	5	5
A/G ratio	1.2±0.1	1.2±0.1	1.3±0.1	1.3±0.1	1.0±0.1	1.3±0.2*
Total cholesterol (mg/dL)	63±12	64±12	61±10	86±14 **	73±11	58±11
Phospholipid (mg/dL)	110±20	110±15	105±15	155±30 **	113±9	97±17
ALT (IU/L)	28±4	24±4	59±19 **	32±5	29±7	39±26
K (mEq/L)	4.2±0.3	4.2±0.4	4.2±0.3	3.7±0.2 *	3.7±0.3	3.8±0.3
IP (mg/dL)	6.8±0.4	7.2±1.0	7.5±1.0	6.9±0.7	6.7±0.3	7.9±0.7 **
Females (dam)
Total protein (g/dL)	6.3±0.3	6.4±0.3	6.5±0.6 *	6.6±0.2 *	7.1±0.2	6.9±0.7
Albumin (g/dL)	3.5±0.1	3.7±0.2	3.8±0.3 **	3.7±0.3 *	4.1±0.4	4.0±0.3
Total cholesterol (mg/dL)	70±9	70±9	74±17	87±15 *	73±13	76±17
Phospholipid (mg/dL)	140±16	145±16	160±34	179±30 **	135±21	137±23
AST (IU/L)	92±23	85±14	84±17	93±26	48±6	60±7 *
ALT (IU/L)	48±11	47±7	61±20	80±20 **	17±2	23±5 *
ALP (IU/L)	256±69	267±49	348±157	394±107 **	140±58	169±51
K (mEq/L)	3.5±0.5	3.4±0.4	3.0±0.3**	3.6±0.3	3.3±0.4	3.7±0.2

Data represent mean ± S.D.

Significant difference from the control group, * p≦0.05, ** p≦0.01.

Table 4: Organ weights of rats treated orally with 2,3,5-trimethylphenol

	Administration period				Recovery period
	0	100	300	1000	0	1000
Males
No. of animals examined	7	12	12	6	5	5
Body weight (g)	497±28	496±30	476±26	431±36 **	537±34	466±30 **
Adrenals (g)	0.071± 0.007	0.072± 0.009	0.073± 0.005	0.071± 0.005	0.072± 0.007	0.084± 0.006 *
(%)	0.014± 0.001	0.015± 0.002	0.015± 0.001	0.016± 0.001 *	0.014± 0.002	0.018± 0.002 **
Kidneys (g)	2.898± 0.257	2.955± 0.258	3.107± 0.205	3.110± 0.151	3.113± 0.314	3.030± 0.290
(%)	0.583± 0.031	0.596 ± 0.053	0.653± 0.036 **	0.724± 0.035 **	0.580± 0.052	0.651± 0.061
Spleen (g)	0.707± 0.129	0.677± 0.076	0.811± 0.118	0.777± 0.164	0.765± 0.142	0.780± 0.099
(%)	0.142± 0.023	0.137± 0.017	0.171± 0.028 *	0.179± 0.027 *	0.142± 0.023	0.167± 0.020
Liver (g)	12.899± 1.704	13.245± 0.927	12.922± 0.756	13.378± 1.795	13.670± 1.439	11.982± 1.293
(%)	2.589± 0.216	2.669± 0.104	2.717± 0.152	3.099± 0.260 **	2.541± 0.165	2.564± 0.142
Brain (g)	2.126± 0.084	2.131± 0.086	2.142± 0.094	2.118± 0.057	2.091± 0.106	2.187± 0.067
(%)	0.429± 0.027	0.430± 0.024	0.451± 0.030	0.495± 0.051 **	0.390± 0.013	0.470± 0.021 **
Testes (g)	3.296± 0.297	3.260± 0.241	3.420± 0.268	3.251± 0.472	3.307± 0.521	3.304± 0.243
(%)	0.664± 0.056	0.658± 0.053	0.719± 0.056	0.758± 0.117 *	0.615± 0.085	0.709± 0.049
Epididymides (g)	1.312± 0.053	1.296± 0.105	1.326± 0.095	1.112± 0.121 **	1.347± 0.110	1.184± 0.091 *
Females (dam)
No. of animals examined	12	12	11	10	5	5
Body weight (g)	300±16	293±20	279±32	264±20 **	286±10	270±14
Heart (g)	0.949± 0.076	0.951± 0.097	0.961± 0.113	0.944± 0.091	0.964 ±0.068	0.923± 0.137
(%)	0.341± 0.035	0.337± 0.020	0.359± 0.033 **	0.345± 0.034	0.325± 0.032	0.317± 0.024
Kidneys (g)	1.754± 0.143	1.706± 0.160	1.820± 0.155	1.817± 0.149	1.706± 0.091	1.806± 0.158
(%)	0.585± 0.038	0.583± 0.047	0.659± 0.099 **	0.690± 0.045 **	0.596± 0.038	0.669± 0.034 *
Spleen (g)	0.628± 0.085	0.666 ±0.180	0.659± 0.162	0.907± 0.221 **	0.533± 0.073	0.480± 0.069
(%)	0.210± 0.028	0.228± 0.064	0.236± 0.057	0.345± 0.083 **	0.186± 0.028	0.177± 0.017
Liver (g)	9.325± 0.765	9.666± 0.672	9.714± 1.333	9.609± 1.199	6.881± 0.657	6.944± 0.811
(%)	3.111± 0.174	3.309± 0.265	3.475± 0.316 **	3.639± 0.310 **	2.404± 0.235	2.568± 0.181
Brain (g)	1.939± 0.046	1.893± 0.084	1.970± 0.053	1.978± 0.078	1.991± 0.071	1.992± 0.090
(%)	0.649± 0.032	0.648± 0.043	0.714± 0.085 *	0.755± 0.078 **	0.695± 0.03	0.740± 0.040

Data represent mean ± S.D.

Significant difference from the control group, * p≦0.05, ** p≦0.01

Applicant's summary and conclusion

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for 2,3,5 Trimethylphenol upon repeated oral exposure in male and female Crl:CD (SD) rats is 100 mg/Kg/day.

Executive summary:

Combined repeated dose repro-devp. Screen was performed for 2,3,5 Trimethylphenol to determine its repeated oral toxic nature upon repeated exposure to 12 male and 12 female Crl: CD (SD) rats. The test chemical in olive oil was dosed at dose levels of 0, 100, 300, 1000 mg/kg/day for 42 days in males and 42 -46 days (from 14 days before mating to day 4 of lactation) for females. A recovery group was also included in the study at a dose level of 0 or 1000 mg/Kg/day consisting of 5 males and 5 females. The animals were observed for clinical signs, mortality, body weight and food consumption, urinanalysis, hematology, blood chemistry, organ weights and histopathology parameters.

 

Soiled perigenitalia with urine was noted in male and female animals at 300 and 1000 mg/kg/day, transient lethargy and ataxic gait after dosing was noted in 1000 mg/Kg/day dosed males and 300 and 1000 mg/Kg/day dosed female animals. One female animal each (n: 12) at 300 and 1000 mg/kg/day was found dead during the study. A decrease in body weight gain was observed at 300 mg/kg/day (test group) and 1000 mg/kg/day (test and recovery group) in male animals and at 1000 mg/kg/day in female animals. Food consumption was decreased in 300 and 1000 mg/kg/day test groups and increased in 1000 mg/kg/day recovery group in male rats and a decrease in food consumption was noted in 1000 mg/kg/day test group and an increase was noted in 1000 mg/kg/day recovery group in female rats.

 

Male rats showed an increase in the RET at 300, 1000 mg/kg/day and Recovery 1000 mg/kg/day, increase in the MCV at 1000mg/kg/day, increase in the MCV at Recovery at 1000 mg/kg/day  and decrease in the MCHC at recovery at 1000 mg/kg/day while female rats showed a decrease in the RBC at 1000 mg/kg/day and Recovery at 1000 mg/kg/day, decrease in the Hgb at 1000 mg/kg/day and Recovery  at 1000 mg/kg/day concentration, decrease in the MCHC at 1000 mg/kg/day and  an increase in the MCV, MCH and RET at 1000 mg/kg/day. An increase in the TCho, PL and ALT at 1000 mg/kg/d and a decrease in K at 1000 mg/kg/ day dose level was noted in male animals and an increase in the TP at 300 and 1000 mg/kg/day, increase in the Alb at 300 and 1000 mg/kg/day, increase in the TCho,PL and ALP at 1000 mg/kg/day, increase in the AST at Recovery 1000 mg/kg/day, increase in the ALT at 1000 mg/kg/day and Recovery at  1000 mg/kg/day and an increase in the TBil at 1000 mg/kg/day dose level was noted in female animals.

 

Male rats showed an increase in the absolute and relative kidney weight at 300 and 1000 mg/kg/day, increase in the absolute and relative spleen weight at 300 and 1000 mg/kg/day, increase in the absolute and relative liver weight at 1000 mg/kg/day, increase in the absolute and relative adrenal weight at 1000 mg/kg/day  concentration and Recovery  at 1000 mg/kg/day, increase in the relative weight of testis at 1000 mg/kg/day, increase in the relative brain weight at 1000 mg/kg/day and Recovery at  1000 mg/kg/day and a decrease in the absolute epididymides weight at 1000 mg/kg/day and at Recovery 1000 mg/kg/day dose levels. Female rats showed an increase in the absolute and relative kidney weight at 300, 1000 mg/kg/day and Recovery 1000 mg/kg/day (tendency), increase in the relative weight of liver at 300 and 1000 mg/kg/day, increase in the relative brain weight at 300 and 1000 mg/kg/day, increase in the absolute and relative spleen weight at 1000 mg/kg/day and an increase in the relative heart weight at 1000 mg/kg/day.

 

Centrilobular hypertrophy of hepatocytes in the liver in 1000 mg/kg/day, inflammatory cell nest in the liver at Recovery 1000 mg/kg/day, deposit of hemosiderin in the spleen at 1000 mg/kg/day and Recovery at 1000 mg/kg/day, increase in the extramedullary hematopoietic in the spleen (Recovery 1000 mg/kg/day), vacuolization in the seminiferous tubule, germ cell necrosis and multinucleated giant cell formation in the testis (1000mg/kg/day and Recovery 1000 mg/kg/day), inflammatory infiltration in the mucosa and the lamina propria of small and large intestines at 1000 mg/kg/day was noted in male rats and an increase in the extramedullary hematopoiesis in the liver at 1000 mg/kg/day, inflammatory cell nest in the liver at Recovery 1000 mg/kg/day, deposit of hemosiderin in the spleen at 1000 mg/kg/day and Recovery at 1000 mg/kg/day, increase in the extramedullary hematopoiesis in the spleen at 1000 mg/kg/day, inflammation in forestomach at 1000 mg/kg/day, squamous cell hyperplasia in forestomach at 300 and 1000 mg/kg/day and atrophy of the thymus at 300 and 1000 mg/kg/day was observed in female rats.

 

Based on the observations made, the No Observed Adverse Effect Level (NOAEL) for 2,3,5 Trimethylphenol upon repeated oral exposure in male and female Crl:CD (SD) rats is 100 mg/Kg/day.