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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Summary of available short-term toxicity data used for the endpoint assessment of the target substance
Adequacy of study:
key study
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Cross-referenceopen allclose all
Reason / purpose:
read-across source
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Version / remarks:
14-day recovery period
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 5 or 6 weeks
- Weight at study initiation: males: 135-152 g; females: 122-141 g
- Diet: ad libitum
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-23
- Humidity (%): 36-64
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
test solutions were prepared at least once a week and kept cool and in the dark until dosing
animals were given the test substance in olive oil by gastric intubation daily for 28 days and sacrificed after overnight starvation following the last treatment
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
the stability was confirmed to be at least 8 days
Duration of treatment / exposure:
28 days
Frequency of treatment:
once daily
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
7 rat/sex/group; in addition: 7 rats/sex in the control group and 7 rat/sex in the highest dose for the 14 d-recovery period
Control animals:
yes, concurrent vehicle
Details on study design:
- Post-exposure recovery period in satellite groups: yes
Positive control:
no
Observations and examinations performed and frequency:
as recommended by guideline
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
as recommended by guideline
Statistics:
Bartlett's test, one way analysis of variance, Dunnett's or Scheff'*s test, Kruskal-Wallis testm Mann-Whitney's U test, Fisher's exact prohability test
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 examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not examined
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:
no effects observed
Other effects:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
At 1000 mg/kg bw/day males and females suffered from tremor and/or salivation throughout the administration period.
No animal died during treatment period or during recovery period.

BODY WEIGHT AND WEIGHT GAIN
1000 mg/kg bw/day significant lowered (mean value)
females, treatment period: 186.4 g versus 210 of controls; females, recovery period: 216 g versus 238 g

FOOD CONSUMPTION
1000 mg/kg bw/day: food consumption was low (only graphic)

HAEMATOLOGY
MALES, significant changes only (mean value)
300 mg/kg bw/day:
MCV 64.41 fL versus 61.41 fL in controls
MCH 21.33 pg versus 20.34 pg in controls
Platelet count: 109x10[exp6]/ µL versus 127x10[exp6] /µL in controls
FEMALES no significant changes when compared to the respective controls

CLINICAL CHEMISTRY
MALES, significant changes only (mean value):
1000 mg/kg bw/day
GOT : 59 IU/L versus 68IU/L in controls
total cholesterol : 69 mg/dL versus 52.7 mg/dL in controls
Urea nitrogen: 16.2 mg/dL versus 13.9 mg/dL in controls
these effects were not observed at the end of the recovery period
males: 1000 mg/kg bw/day at the end of the recovery period (mean value)
Glucose 149.7 mg/dL versus 171.6 mg/dL in controls
FEMALES, significant changes only (mean value)
100 mg/kg bw/day
GOT: 65.9 IU/L versus 57.1 IU/L in controls
females: 1000 mg/kg bw/day at the end of the recovery period (mean value)
Glucose: 124 mg/dL versus 138 mg/dL

URINALYSIS
Urinalysis showed increases in the number of animals showing low pH and negative protein in males and females and in urinary volume in males (data not given)

ORGAN WEIGHTS
MALES, ABSOLUTE organ weight, significant changes only (mean value)
1000 mg/kg bw/day at the end of the recovery period:
lungs: 1.286 g versus 1.397 g in controls
liver: 12.27 g versus 13.42 g in controls
spleen: 0.700 g versus 0.866 g in controls
pituitary gland: 11.91 mg versus 13.37 mg in controls
MALES, RELATIVE organ weights, significant changes only (mean value)
1000 mg/kg bw/day
brain: 0.690 g% versus 0.630 g%
liver: 3.647 g% versus 3.240 g%
males: 1000 mg/kg bw/day at the end of the recovery period
liver: 3.076 g% versus 3.341 g%

FEMALES, ABSOLUTE organ weight, significant changes only (mean value)
1000 mg/kg bw/day
spleen: 0.419 g versus 0.509 g in controls
1000 mg/kg bw/day at the end of the recovery period
lungs: 0.986 g versus 1.061 g in controls
liver: 6.189 g versus 6.869 g in controls
pituitary gland: 12.13 mg versus 14.33 mg in controls
FEMALES, RELATIVE organ weight, significant changes only (mean value)
liver: at 1000 mg/kg bw/day: 3.501 g% and at 300 mg/kg bw/day: 3.349 g% versus 3.036 g% in controls
kidneys: at 1000 mg/kg bw/day: 0.924 g% versus 0.790 g% in controls
these effects were not observed at the end of the recovery period

HISTOPATHOLOGY: NON-NEOPLASTIC
MALES, 1000 mg/kg bw/day: 1/7 rats revealed hypertrophy of centrilobular hepatocytes. These changes were not observed at the end of the recovery period
FEMALES: no significant histopathological findings


Key result
Dose descriptor:
NOEL
Effect level:
ca. 300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: based on histopathological changes in the liver at 1000 mg/kg bw/day
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: increase of relative liver weight from 300 mg/kg bw/day onwards
Critical effects observed:
not specified
Conclusions:
Male and female rats were gavaged with mg/kg bw in corn oil for 28 days according to OECD TG 407 followed by a 14-day recovery period. Based on histopathological changes in the liver in males at 1000 mg/kg bw/day the NOAEL (male) is 300 mg/kg bw/day. In females, liver weights were increased from 300 mg/kg bw/day onwards without histopathological correlate leading to a NOAEL of 100 mg/kg bw/day.
Reason / purpose:
read-across source
Reference
Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
26 July 2004 - 17 Sept 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Crl:CD (SD)IGS BR VAF/Plus
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratory, Raleigh, North Carolina
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
- Age at study initiation: 9 weeks (males and females)
- Weight at study initiation: 333 - 365 g (males); 205 -237 g females
- Fasting period before study:
- Housing: F0 generation rats were individually housed except during the cohabitation and postpartum periods. During cohabitation, each pair of rats were housed in the male rat's cage. Each dam and delivered litter was housed in a common nesting box during the postpartum period.
- Diet: Chow (#5002),ad libitum
- Water: Tap water,ad libitum
- Acclimation period: 5 days

DETAILS OF FOOD AND WATER QUALITY:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 26°C
- Humidity (%): 30 - 70%
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
The test substance was prepared as a solution in the vehicle and administered orally by gavage.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
GC/FID analysis of dosing preparation concentration, stability and homogeneity.
Duration of treatment / exposure:
28 days for males and 54 days for females.
Frequency of treatment:
Daily administration beginning 14 days prior to cohabitation and continuing until the day before sacrifice.
Dose / conc.:
30 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
245 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10 rats per sex per group
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least 2/day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION AND COMPOUND INTAKE: daily
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / Not specified
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / Not specified

Observations were performed for viability, clinical signs of toxicity, food consumption, body weight gain, functional observational battery and motor activity, hematology, clinical chemistry, developmental toxicity and reproductive performance, gross and microscopic post-mortem examination.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at necropsy
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: 5 male and 5 female F0 generation animals
- Parameters examined: total leukocyte count, differential leukocyte count (neutrophil, lymphocyte, monocyte, eosinophil, basophil, large unstained cell); RBC indices (mean corpuscular volume, mean corpuscular haemogloblin, mean corpuscular haemoglobin concentration), platelet count, prothombin time and activated partial thromboplastin time)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at necropsy
- Animals fasted: Not specified
- How many animals: 5 male and 5 female F0 generation animals
- Parametersexamined: blood urea nitrogen, alanine aminotransferase activity, aspartate transaminase activity, alkaline phosphatase, glucose, cholesterol, calcium, chloride, phosphorous, potassium, sodium, total protein, albumin, globulin, albumin/globulin ratio, total bilirubin, creatinine, triglycerides

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: once
- Dose groups that were examined: Functional observational battery evaluations were performed once on 5 male and 5 female F0 generation animals.

 
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

F0 generation:
Gross pathological examination was performed on 5 male and 5 females/group of the F0 generation. An initial examination of external surfaces and all orifices, as well as the cranial, thoracic and abdominal cavities, including contents. The epidodymides, seminal vesicles with coagulating gland and prostate were retained.

Dams with no suriving pups were sacrificed after the last pup was found dead, missing or presumed cannibalised. A gross necropsy of the thoracic, abdominal and pelvic viscera was performed.

Organ weights:
The following organs were weighed from 5 male and 5 females/group of the F0 generation at necropsy:
liver, spleen, kidneys, brain, adrenals, heart, thymus. ovaries, testes, uterus (with cervix) and epidiymides. F1 generation pups that died before the initial examination of the litter for pup viability were evaluated for vital status at birth. The lungs were removed and immersed in water. Pups with lungs that sank were considered stillborn; pups with lungs that floated were considered liveborn and to have died shortly after birth. Pups with gross lesions found on days 2 to 4 postpartum were preserved for possible future evaluation. On day 5 postpartum , pups were sacrificed abd examined for gross lesions. Necropsy included a single cross-section of the head at the level of the frontal-parietal suture and examination of the cross sectioned brain.
Statistics:
Body weight, weight gains and reproductive end points analysed by ANOVA and Dunnett's. Reproductive data analysed by Fisher's exact test.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
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:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified
Details on results:
Relative weights of kidney, liver and ovaries were increased in the high dose group.
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Due to clinical observations (urine-stained fur, increased kidney, liver and ovarian relative weight).
Critical effects observed:
not specified

All rats survived the treatment. In males, urine stained fur and excessive salivation was observed at all dose levels. Body weight gain and food consumption were unaffected by treatment. Neurotoxicity was not observed during the study and there were no treatment related effects observed at gross necropsy or histopathologically. Urine staining of the fur was observed in females at the 245 mg/kg bw/day level. F1 animals showed no treatment related clinical or necropsy signs. Relative weights of the kidney, liver and ovaries were observed to be increased in the 245 mg/kg bw/day treatment group.

 

Reproductive effects are discussed under section 7.8.1.

Conclusions:
The test substance mixed ethylphenol isomers was administered to rats by oral gavage at 0, 30, 100 and 245 mg/kg/day. The NOAEL was detemined to be 100 mg/kg bw/day based on clincial signs of toxicity which included urine stained abdominal fur, increased kidney, liver and ovarian relative weight.

The reproductive endpoint is discussed under 7.8.1.
Reason / purpose:
read-across source
Reference
Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
26 July 2004 - 17 Sept 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Crl:CD (SD)IGS BR VAF/Plus
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratory, Raleigh, North Carolina
- Age at study initiation: 9 weeks (males and females)
- Weight at study initiation: 333 - 365 g (males); 205 -237 g females
- Fasting period before study:
- Housing: F0 generation rats were individually housed except during the cohabitation and postpartum periods. During cohabitation, each pair of rats were housed in the male rat's cage. Each dam and delivered litter was housed in a common nesting box during the postpartum period.
- Diet: Chow (#5002),ad libitum
- Water: Tap water,ad libitum
- Acclimation period: 5 days

DETAILS OF FOOD AND WATER QUALITY:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 26°C
- Humidity (%): 30 - 70%
- Photoperiod (hrs dark / hrs light): 12 / 12






 
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
The test substance was prepared as a solution in the vehicle and administered orally by gavage.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
GC/FID analysis of dosing preparation concentration, stability and homogeneity.
Duration of treatment / exposure:
28 days for males and 54 days for females.
Frequency of treatment:
Daily administration beginning 14 days prior to cohabitation and continuing until the day before sacrifice.
Dose / conc.:
30 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
245 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10 rats per sex per group
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least 2/day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION AND COMPOUND INTAKE: daily
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / Not specified
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / Not specified

Observations were performed for viability, clinical signs of toxicity, food consumption, body weight gain, functional observational battery and motor activity, hematology, clinical chemistry, developmental toxicity and reproductive performance, gross and microscopic post-mortem examination.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at necropsy
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: 5 male and 5 female F0 generation animals
- Parameters examined: total leukocyte count, differential leukocyte count (neutrophil, lymphocyte, monocyte, eosinophil, basophil, large unstained cell); RBC indices (mean corpuscular volume, mean corpuscular haemogloblin, mean corpuscular haemoglobin concentration), platelet count, prothombin time and activated partial thromboplastin time)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at necropsy
- Animals fasted: Not specified
- How many animals: 5 male and 5 female F0 generation animals
- Parametersexamined: blood urea nitrogen, alanine aminotransferase activity, aspartate transaminase activity, alkaline phosphatase, glucose, cholesterol, calcium, chloride, phosphorous, potassium, sodium, total protein, albumin, globulin, albumin/globulin ratio, total bilirubin, creatinine, triglycerides

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: once
- Dose groups that were examined: Functional observational battery evaluations were performed once on 5 male and 5 female F0 generation animals.

 
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

F0 generation:
Gross pathological examination was performed on 5 male and 5 females/group of the F0 generation. An initial examination of external surfaces and all orifices, as well as the cranial, thoracic and abdominal cavities, including contents. The epidodymides, seminal vesicles with coagulating gland and prostate were retained.

Dams with no suriving pups were sacrificed after the last pup was found dead, missing or presumed cannibalised. A gross necropsy of the thoracic, abdominal and pelvic viscera was performed.

Organ weights:
The following organs were weighed from 5 male and 5 females/group of the F0 generation at necropsy:
liver, spleen, kidneys, brain, adrenals, heart, thymus. ovaries, testes, uterus (with cervix) and epidiymides. F1 generation pups that died before the initial examination of the litter for pup viability were evaluated for vital status at birth. The lungs were removed and immersed in water. Pups with lungs that sank were considered stillborn; pups with lungs that floated were considered liveborn and to have died shortly after birth. Pups with gross lesions found on days 2 to 4 postpartum were preserved for possible future evaluation. On day 5 postpartum , pups were sacrificed abd examined for gross lesions. Necropsy included a single cross-section of the head at the level of the frontal-parietal suture and examination of the cross sectioned brain.
Statistics:
Body weight, weight gains and reproductive endpoints analysed by ANOVA and Dunnett's. Reproductive data analysed by Fisher's exact test.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
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:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified
Details on results:
Relative weights of kidney, liver and ovaries were increased in the high dose group.
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Due to clinical observations (urine-stained fur, increased kidney, liver and ovarian relative weight).
Critical effects observed:
not specified

All rats survived the treatment. In males, urine stained fur was observed at the 245 mg/kg bw/day level. Body weight gain and food consumption were unaffected by treatment. Mating frequency was reduced at the 245 mg/kg bw/day level. Neurotoxicity was not observed during the study and there were no treatment related effects observed at gross necropsy or histopathologically. Urine staining of the fur was observed in females at the 245 mg/kg bw/day level. F1 animals showed no treatment related clinical or necropsy signs. Haematology and clinical pathology parameters were unaffected.

Reproductive indices are discussed under section 7.8.1.

Conclusions:
The test substance mixed xylenol isomers was administered to rats by oral gavage at 0, 30, 100 and 245 mg/kg/day. The general toxicological No Observable Adverse Effect Level was shown to be 100 mg/kg bw/day.

The reproductive NOAEL is discussed under section 7.8.1.
Reason / purpose:
read-across source
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
disregarded due to major methodological deficiencies
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Study was assessed as not reliable as it was conducted at IBT laboratories in 1969. During the 1960s until 1978 significant discrepancies and deficiencies were noted at least in long-term studies of IBT laboratories.
Principles of method if other than guideline:
Rats were fed wih diet containing the test substance in different concentrations for 28 days, control rats were fed with diet containing the vehicle (corn oil). Determintaion of clinical signs, body weight, food consumption respective compound consumption. At autopsy organ weight determination respective organ body weight ratio and gross pathological examination were conducted.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
no data
Route of administration:
oral: feed
Details on route of administration:
no data
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Test material was prepared as 2% corn oil solution and blended with the basal laboratory ration.

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
details not given
Duration of treatment / exposure:
28 d
Frequency of treatment:
daily
Dose / conc.:
10 ppm
Remarks:
1.90 mg/kg bw/day (nominal in diet; calculated from food consumption)
Dose / conc.:
150 ppm
Remarks:
14.2 mg/kg bw/day (nominal in diet; calculated from food consumption)
Dose / conc.:
500 ppm
Remarks:
45.2 mg/kg bw/day (nominal in diet; calculated from food consumption)
No. of animals per sex per dose:
10 males/dose
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: no
Positive control:
no data
Observations and examinations performed and frequency:
mortality, clinical signs, terminal body weight, organ weight/body weight ratio (no further data given)
Sacrifice and pathology:
terminal sacrifice, gross pathological examination
Other examinations:
no data
Statistics:
yes, but method not mentioned
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified
Details on results:
250 ppm: significant increased mean adrenal weight to mean body weight ratio: 25% versus 19% in controls
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 500 ppm
Based on:
test mat.
Sex:
male
Remarks on result:
other: No adverse effects were reported up to the highest dose tested.
Critical effects observed:
not specified
no deaths, body weight gain comparable to control group, no untoward behavioral  reactions, at autopsy, relative organ weights (liver, kidneys, adremals and testes) of treated males did not differ from relative organ weights of the control animals; no significant gross lesions were noted among experimental animals when compared to control animals.
Conclusions:
Male rats were fed with 0, 10, 150, 500 ppm (0, 1.90, 14.2, 45.2 mg/kg bw/d) for 28 days. No treatment related effects were reported. thus, the NOAEL is 500 ppm (45.2 mg/kg bw/d) under the conditions of this test.

Data source

Materials and methods

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Effect levels

Key result
Dose descriptor:
NOAEL
Remarks:
rat
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Due to clinical observations (urine-stained fur, increased kidney, liver and ovarian relative weight).
Remarks on result:
other: Source, mixed xylenols, Merisol, 2005, OECD 422

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

In the result table above the most critical value of the weight of evidence approach is given. In the following, the results are shown for the other source substances of this weight of evidence approach:

Source CAS 108 -39 -4: m-cresol: NOAEL (male, rat) = 300 mg/kg bw/day, based on histopathological changes in the liver; MHLW, 2001

Source CAS 108 -39 -4: m-cresol: NOAEL (female, rat) = 100 mg/kg bw/day, based on increased relative liver weight; MHLW, 2001

Source CAS mixed ethylphenols: NOAEL (male/feamle, rat) = 100 mg/kg bw/day, based on clinical observations (urine-stained fur, increased kidney, liver and ovarian relative weight); Merisol, 2005

There is an additional study with p-cresol. Male rats were fed with 0, 10, 150, 500 ppm (0, 1.90, 14.2, 45.2 mg/kg bw/d) p-cresol (CAS 106-44-5) for 28 days. No treatment related effects were reported. Thus, the NOAEL is 500 ppm (45.2 mg/kg bw/d) under the conditions of this test. However, the study was assessed as not reliable as it was conducted at IBT laboratories in 1969. During the 1960s until 1978 significant discrepancies and deficiencies were noted at least in long-term studies of IBT laboratories. Therefore, this study was disregared and assessed as not reliable for hazard assessment of the target substance.

Applicant's summary and conclusion

Conclusions:
The available sub-acute repeated dose oral toxicity studies conducted on mixed ethyl phenols and mixed xylenols confirm a NOAEL at 100 mg/kg bw/day for both test materials. The study on m-cresol shows that the NOAEL is quite similar to that obtained for mixed xylenols and mixed ethylphenols (NOAEL(males) = 300 and NOAEL(females) = 100 mg/kg bw/day, which strengthens the argument that the structural similarities of these compounds provides reliable read-across approach to the target substance. 
Executive summary:

The sub-acute repeated dose oral toxicity studies conducted on mixed ethyl phenols and mixed xylenols confirm a NOAEL at 100 mg/kg bw/day for both test materials. The study on m-cresol shows that the NOAEL is quite similar to that obtained for mixed xylenols and mixed ethylphenols (NOAEL(males) = 300 and NOAEL(females) = 100 mg/kg bw/day, which strengthens the argument that the structural similarities of these compounds provides reliable read-across approach to the target substance. 

Increases in liver and/or kidney weights were reported. No histopathological changes accompanied these increases in organ weights (with the exclusion of 1000 mg/kg bw/day of m-cresol which reported histopathological changes).