2,3,5-trimethylphenol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL was considered to be 300 mg/kg bw for P and F1 generation when Crj: CD(SD) male and female rats were treated with 2,3,5-trimethylphenol orally by gavage for 42 days.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Data is from J-check

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 Toxicity Study with the Reproduction / Developmental Toxicity Screening Test of 2,3,5-trimethylphenol in rats

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

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

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Age at study initiation: 10 weeks old

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

olive oil

Details on 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

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

Details on mating procedure:

No data available

Analytical verification of doses or concentrations:

not specified

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

Details on study schedule:

No data available

Remarks:

0, 100, 300, 1000 mg/kg bw/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:

No data available

Positive control:

No data available

Parental animals: Observations and examinations:

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: No data available
- 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

Oestrous cyclicity (parental animals):

Irregularity in Estrous cyclicity were examined.

Sperm parameters (parental animals):

No data available

Litter observations:

Number of pups born and number of live pups were examined.

Postmortem examinations (parental animals):

Absolute and relative organ weight, gross pathology and histopathology were examined.

Postmortem examinations (offspring):

No data available

Statistics:

No data available

Reproductive indices:

gestation length, copora lutea and number of implantations were examined.

Offspring viability indices:

viability index postnatal day 4 were examined.

Clinical signs:

effects observed, treatment-related

Dermal irritation (if dermal study):

not specified

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

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

effects observed, treatment-related

Reproductive function: sperm measures:

not specified

Reproductive performance:

effects observed, treatment-related

Clinical signs: In male and female rats when treated with 300 and 1000 mg/kg/day, soiled perigenitalia with urine was observed and in male rats at 1000 mg/Kg/day and in female rats at 300 and 1000 mg/kg/day, transient lethargy and ataxic gait after dosing was observed as compared to control.

Mortality: when treated with 300 and 1000 mg/kg/day, One female animal each were died mg/kg/day during the study as compared to control.

Body weight and weight gain: In male rat when treated with 300 mg/kg/day and in male and female rats in recovery at 1000 mg/kg/day, decrease in the body weight gain was observed as compared to control.

Food consumption and compound intake:
In male rats when treated with 300 and 1000 mg/kg/day, decreased in food consumption was observed and increased in 1000 mg/kg/day recovery as compared to control.
In Female rats when treated with 1000 mg/kg/day, decrease in food consumption was observed during dosing and increase in recovery as compared to control.

Haematology:
In treatment:
When treated with 300 mg/kg/day, increase in the RET level were observed in male rat.
When treated with 1000 mg/kg/day, increase in the RET and MCV level were observed male rats and decrease in the RBC, Hgb and MCHC level in female rats during dosing as compared to control.
Recovery:
In male rats when treated with 1000 mg/kg/day, increase in the MCV and decrease in the MCHC were observed as compared to control.
In Female rat when treated with 1000 mg/kg/day, decrease in RBC and Hgb were observed as compared to control.

Clinical chemistry:
In male rats when treated with 1000 mg/kg/day, increase in the TCho, PL and ALT and a decrease in K at were observed as compared to control.
In Female rat when treated with 300 mg/kg/day, increase in TP and Alb level were observed.
When treated with 1000 mg/kg/day, increase in the TP, Alb, TCho, PL, ALP and TBil were observed.
Recovery:
In female rat when treated with 1000 mg/kg/day, increase in the AST and ALT were observed as compared to control.

Urinanalysis:
In male rats when treated with 300 and 1000 mg/kg/day, decrease in the protein and ketone body were observed as compared to control.
Recovery:
In male rats when treated with 1000 mg/kg/day, Decrease in the ketone body were observed as compared to control.

FOB: No effect were observed in treated mael and femaler rats.

Organ weights:
In male rats when treated with 300 mg/kg/day, increase in the kidney and spleen weight (Absolute and relative)
When treated with 1000 mg/kg/day, increase in the kidney and spleen, liver, adrenal weight (Absolute and relative), Increase in Relative testis and brain weight and Decrease in Absolute epididymides weight were observed as compared to control.
In female rats when treated with 300 mg/kg/day, increase in Absolute and relative kidney weight, Relative liver weight and Relative brain weight were observed as compared to control.
When treated with 1000 mg/kg/day, increase in Absolute and relative kidney weight, Relative liver, heart and brain weight and Absolute and Relative spleen weight were observed as compared to control.
Recovery:
In male rats when treated with 1000 mg/kg/day, increase in Absolute and relative adrenal, Relative brain weight and Decrease in Absolute epididymides weight were observed as compared to control.
In female rats when treated with 300 and 1000 mg/kg/day, increase in Absolute and relative kidney weight were observed as compared to control.

Histopathology:
In male rats when treated with 1000 mg/kg/day, Centrilobular hypertrophy of hepatocytes in the liver, Deposit of hemosiderin in the spleen, Vacuolization in the seminiferous tubule, germ cell necrosis and multinucleated giant cell formation in the testis and Inflammatory infiltration in the mucosa and the lamina propria of small and large intestines
In female rats when treated with 1000 mg/kg/day, Increase in the extramedullary hematopoiesis in the liver, Deposit of hemosiderin in the spleen, Increase in the extramedullary hematopoiesis in the spleen, Inflammation in forestomach, Squamous cell hyperplasia in forestomach, Atrophy of the thymus and Deposit of hemosiderin in the spleen were observed as compared to control.
In female rats when treated with 300 mg/kg/day, Atrophy of the thymus and spleen were observed as compared to control.
Recovery:
In male rats when treated with 1000 mg/kg/day, Inflamma tory cell nest in the liver, Deposit of hemosiderin in the spleen, Increase in the extramedullary hematopoiesis in the spleen and Vacuolization in the seminiferous tubule, germ cell necrosis and multinucleated giant cell formation in the testis were observed as compared to control.
In female rats when treated with 1000 mg/kg/day, In flammatory cell nest in the liver, Deposit of hemosiderin in the spleen were observed as compared to control.

Estrous cycle: Abnormal estrous cycle was observed in 1000 mg/kg bw treated female rats as compared to control.

Reproductive performance
Decrease in the gestation length, number of copora lutea, and number of implantations were observed in 1000 mg/kg bw treated female rats as compared to control.

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

food consumption and compound intake

haematology

clinical biochemistry

urinalysis

histopathology: non-neoplastic

reproductive function (oestrous cycle)

reproductive performance

other: No effect observed

Critical effects observed:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

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:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

effects observed, treatment-related

Reproductive function: sperm measures:

not specified

Reproductive performance:

effects observed, treatment-related

Estrous cycle: Abnormal estrous cycle was observed in 1000 mg/kg bw treated female rats as compared to control.

Reproductive performance
Decrease in the gestation length, number of copora lutea, and number of implantations were observed in 1000 mg/kg bw treated female rats as compared to control.

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

food consumption and compound intake

haematology

clinical biochemistry

urinalysis

histopathology: non-neoplastic

reproductive function (oestrous cycle)

reproductive performance

other: No effect

Critical effects observed:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

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:

no effects observed

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Viability:
Significant change in viability of pups on PND 4 were observed in treated rats at 1000 mg/kg bw as compared to control.

Body weight: Significant change in Body weight of pups were observed in treated rats at 1000 mg/kg bw as compared to control.

Gross pathology:
No external abnormality were observed in pups at 100, 300, 1000 mg/kg /day as compared to control.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

300 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

mortality

body weight and weight gain

gross pathology

other: No effect

Critical effects observed:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

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

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

other: not specified

Based on:

not specified

Sex:

not specified

Remarks on result:

other: not specified

Critical effects observed:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Reproductive effects observed:

yes

Lowest effective dose / conc.:

1 000 mg/kg bw/day

Treatment related:

yes

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

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

Conclusions:

NOAEL was considered to be 300 mg/kg bw for P and F1 generation when Crj: CD(SD) male and female rats were treated with 2,3,5-trimethylphenol orally by gavage for 42 days.

Executive summary:

Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test, Crj: CD(SD) male and female rats were treated with2,3,5-trimethylphenol in the concentration of 0, 100, 300, 1000 mg/kg /day orally by gavage. One female animal each were died during the study at300 and 1000 mg/kg/day as compared to control. In male and female rats, soiled perigenitalia with urine was observed at 300 and 1000 mg/kg/day, and in male rats at 1000 mg/Kg/day and in female rats at 300 and 1000 mg/kg/day, transient lethargy and ataxic gait after dosing was observed as compared to control. Decrease in the body weight gain was observed in male rat at 300 mg/kg/day and in male and female rats in recovery at 1000 mg/kg/day as compared to control. Decreased in food consumption were observed at 300 mg/kg /day in male and at 1000 mg/kg/day in male and female rats and increased in 1000 mg/kg/day recovery as compared to control. Similarly, increase in the RET level were observed in male rat at 300 mg/kg/day and increase in the RET and MCV level were observed male rats and decrease in the RBC, Hgb and MCHC level in female rats during dosing at 1000 mg/kg/day as compared to control. Increase in the MCV and decrease in the MCHC were observed at 1000 mg/kg/day in male rats and decrease in RBC and Hgb in female rats in recovery as compared to control. increase in the TCho, PL and ALT in male and TP, Alb, TCho, PL, ALP and TBil in female and a decrease in K in male rats were observed at 1000 mg/kg/day and increase in TP and Alb level were observed at 300 mg/kg/day in female rat as compared to control. Increase in the AST and ALT were observed in female rats at 1000 mg/kg/day in recovery as compared to control. Decrease in the protein and ketone body was observed at 300 and 1000 mg/kg/day in male rat and Decrease in the ketone body in recovery were observed as compared to control. increase in the kidney and spleen weight (Absolute and relative) at 300 mg/kg/day and increase in the kidney, spleen, liver, adrenal weight (Absolute and relative), Increase in Relative testis and brain weight and Decrease in Absolute epididymides weight were observed at 1000 mg/kg/day in male rat as compared to control. In female rats increase in Absolute and relative kidney weight, Relative liver weight and Relative brain weight were observed at 300 mg/kg/day and at 1000 mg/kg/day increase in Absolute and relative kidney weight, Relative liver, heart and brain weight and Absolute and Relative spleen weight were observed as compared to control. In Recovery at 1000 mg/kg/day, increase in Absolute and relative adrenal, Relative brain weight and Decrease in Absolute epididymides weight were observed in male rat and In female rats at 300 and 1000 mg/kg/day, increase in Absolute and relative kidney weight were observed as compared to control. Centrilobular hypertrophy of hepatocytes in the liver, Deposit of hemosiderin in the spleen, Vacuolization in the seminiferous tubule, germ cell necrosis and multinucleated giant cell formation in the testis and Inflammatory infiltration in the mucosa and the lamina propria of small and large intestines were observed in male rats at 1000 mg/kg/day and In female rats at 1000 mg/kg/day, Increase in the extramedullary hematopoiesis in the liver, Deposit of hemosiderin in the spleen, Increase in the extramedullary hematopoiesis in the spleen, Inflammation in forestomach, Squamous cell hyperplasia in forestomach, Atrophy of the thymus and Deposit of hemosiderin in the spleen were observed as compared to control. In female rats when treated with 300 mg/kg/day, Atrophy of the thymus and spleen were observed as compared to control.In Recovery, Inflamma tory cell nest in the liver, Deposit of hemosiderin in the spleen, Increase in the extramedullary hematopoiesis in the spleen and Vacuolization in the seminiferous tubule, germ cell necrosis and multinucleated giant cell formation in the testis were observed in male rats at 1000 mg/kg/day and in female rats, inflammatory cell nest in the liver, Deposit of hemosiderin in the spleen were observed as compared to control. In addition, Abnormal estrous cycle and Decrease in the gestation length, number of copora lutea, and number of implantations were observed in 1000 mg/kg bw treated female rats as compared to control. Significant change in viability of pups on PND 4 and Body weight: Significant change in Body weight of pups were observed in treated rats at 1000 mg/kg bw as compared to control. No external abnormality were observed in pups at 100, 300, 1000 mg/kg /day as compared to control. Therefore, NOAEL was considered to be 300 mg/kg bw for P and F1 generation when Crj: CD(SD) male and female rats were treated with 2,3,5-trimethylphenol orally by gavage for 42 days.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimisch 2 and from peer-reviewed journal

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Toxicity to reproduction:

Ina study, 2,3,5-trimethylphenol has been investigated for reproductive toxicity to a greater or lesser extent. Study based on in vivo experiments data in rodents, i.e. most commonly in rats for 2,3,5-trimethylphenol.

In a experimental study given by National Institute of Technology and Evaluation (Japan Chemicals Collaborative Knowledge database, 2016), Crj: CD(SD) male and female rats were treated with2,3,5-trimethylphenol in the concentration of 0, 100, 300, 1000 mg/kg /day orally by gavage. One female animal each were died during the study at300 and 1000 mg/kg/day as compared to control. In male and female rats, soiled perigenitalia with urine was observed at 300 and 1000 mg/kg/day, and in male rats at 1000 mg/Kg/day and in female rats at 300 and 1000 mg/kg/day, transient lethargy and ataxic gait after dosing was observed as compared to control. Decrease in the body weight gain was observed in male rat at 300 mg/kg/day and in male and female rats in recovery at 1000 mg/kg/day as compared to control. Decreased in food consumption were observed at 300 mg/kg /day in male and at 1000 mg/kg/day in male and female rats and increased in 1000 mg/kg/day recovery as compared to control. Similarly, increase in the RET level were observed in male rat at 300 mg/kg/day and increase in the RET and MCV level were observed male rats and decrease in the RBC, Hgb and MCHC level in female rats during dosing at 1000 mg/kg/day as compared to control. Increase in the MCV and decrease in the MCHC were observed at 1000 mg/kg/day in male rats and decrease in RBC and Hgb in female rats in recovery as compared to control. increase in the TCho, PL and ALT in male and TP, Alb, TCho, PL, ALP and TBil in female and a decrease in K in male rats were observed at 1000 mg/kg/day and increase in TP and Alb level were observed at 300 mg/kg/day in female rat as compared to control. Increase in the AST and ALT were observed in female rats at 1000 mg/kg/day in recovery as compared to control. Decrease in the protein and ketone body was observed at 300 and 1000 mg/kg/day in male rat and Decrease in the ketone body in recovery were observed as compared to control. increase in the kidney and spleen weight (Absolute and relative) at 300 mg/kg/day and increase in the kidney, spleen, liver, adrenal weight (Absolute and relative), Increase in Relative testis and brain weight and Decrease in Absolute epididymides weight were observed at 1000 mg/kg/day in male rat as compared to control. In female rats increase in Absolute and relative kidney weight, Relative liver weight and Relative brain weight were observed at 300 mg/kg/day and at 1000 mg/kg/day increase in Absolute and relative kidney weight, Relative liver, heart and brain weight and Absolute and Relative spleen weight were observed as compared to control. In Recovery at 1000 mg/kg/day, increase in Absolute and relative adrenal, Relative brain weight and Decrease in Absolute epididymides weight were observed in male rat and In female rats at 300 and 1000 mg/kg/day, increase in Absolute and relative kidney weight were observed as compared to control. Centrilobular hypertrophy of hepatocytes in the liver, Deposit of hemosiderin in the spleen, Vacuolization in the seminiferous tubule, germ cell necrosis and multinucleated giant cell formation in the testis and Inflammatory infiltration in the mucosa and the lamina propria of small and large intestines were observed in male rats at 1000 mg/kg/day and In female rats at 1000 mg/kg/day, Increase in the extramedullary hematopoiesis in the liver, Deposit of hemosiderin in the spleen, Increase in the extramedullary hematopoiesis in the spleen, Inflammation in forestomach, Squamous cell hyperplasia in forestomach, Atrophy of the thymus and Deposit of hemosiderin in the spleen were observed as compared to control. In female rats when treated with 300 mg/kg/day, Atrophy of the thymus and spleen were observed as compared to control.In Recovery, Inflamma tory cell nest in the liver, Deposit of hemosiderin in the spleen, Increase in the extramedullary hematopoiesis in the spleen and Vacuolization in the seminiferous tubule, germ cell necrosis and multinucleated giant cell formation in the testis were observed in male rats at 1000 mg/kg/day and in female rats, inflammatory cell nest in the liver, Deposit of hemosiderin in the spleen were observed as compared to control. In addition, Abnormal estrous cycle and Decrease in the gestation length, number of copora lutea, and number of implantations were observed in 1000 mg/kg bw treated female rats as compared to control. Significant change in viability of pups on PND 4 and Body weight: Significant change in Body weight of pups were observed in treated rats at 1000 mg/kg bw as compared to control. No external abnormality were observed in pups at 100, 300, 1000 mg/kg /day as compared to control. Therefore, NOAEL was considered to be 300 mg/kg bw for P and F1 generation when Crj: CD(SD) male and female rats were treated with 2,3,5-trimethylphenol orally by gavage for 42 days.

Thus, based on the above study on 2,3,5-trimethylphenol, it can be concluded that LD50 2,3,5-trimethylphenol is not toxic at dose level 300 mg/kg bw/day. Thus, comparing this value with the criteria of CLP regulation, 2,3,5-trimethylphenol can be “Not classified” for reproductive toxicity.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the above study on 2,3,5-trimethylphenol, it can be concluded that LD50 2,3,5-trimethylphenol is not toxic at dose level 300 mg/kg bw/day. Thus, comparing this value with the criteria of CLP regulation, 2,3,5-trimethylphenol can be “Not classified” for reproductive toxicity.