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Administrative data

Description of key information

In absence of data on Tar acids, Xylenol fraction (CAS 84989-06-0) an analogue read-across approach was conducted:

Repeated dose oral toxicity:

WoE - mixed xylenols (RL1; according to OECD 422 and GLP, rat): NOAEL 100 mg/kg bw/day;

WoE - mixed ethylphenols (RL1; according to OECD 422 and GLP, rat): NOAEL 100 mg/kg bw/day;

WoE - m-cresol (RL1; according to OECD 407 and GLP, rat): NOAEL(males): 300 mg/kg bw/day; NOAEL(females): 100 mg/kg bw/day;

WoE - m-cresol (RL1; according to OECD 408 and GLP, rat): NOAEL: 50 mg/kg bw/day;

WoE - o-cresol (RL1; according to Sontag JM,et al., NCI,  DHEW Publication No (NIH)78-ß01 Guidelines for Carcinogen Bioassay in small rodents, 90 day and GLP, rat): NOAEL: 50 mg/kg bw/day;

WoE - o-cresol (RL1; according to OECD 408 and GLP, rat): NOAEL(males): 247 mg/kg bw/day; NOAEL(females): 256 mg/kg bw/day;

WoE - o-cresol (RL1, according to OECD 408 and GLP, mouse): NOAEL(males): 199 mg/kg bw/day; NOAEL(females): 237 mg/kg bw/day;

WoE - p-cresol (RL1, according to OECD 408 and GLP, rat): NOAEL: 50 mg/kg bw/day;

Repeat Dose Inhalation Toxicity:

WoE - p-cresol (RL4, no guideline study, no data on GLP, rat): LOAEL 0.01 mg/L air;

Data base is very limited and does not allow a final conclusion. Further testing is, however, not required, as there are reliable oral repeated dose toxicity data available for the hazard assessment and therefore, the requirements defined in Regulation (EC) No 1907/2006, Annex IX, 8.6 are fulfilled.

Repeat Dose Dermal Toxicity:

No reliable data available.

Further testing is, however, not required, as there are reliable oral repeated dose toxicity data available for the hazard assessment and therefore, the requirements defined in Regulation (EC) No 1907/2006, Annex IX, 8.6 are fulfilled.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic 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 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories Ladeview,NY
- Age at study initiation: 5-6 weeks
- Weight at study initiation: 152-233 g
- Housing: individually
- Water: ad libitum
- Acclimation period: 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72
- Humidity (%): 50
- Air changes (per hr): 12-17
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
Dosage formulations were prepared fresh weekly throughout the study and stored protected from light at room temperature.


DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:


VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle:
- Amount of vehicle (if gavage):
- Lot/batch no. (if required):
- Purity:
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
the concentration of p-cresol in corn oil was analyzed in week 1, 2, 4, 8 and 13
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
once daily, 7 days/week
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Remarks:
dissolved in corn oil
Dose / conc.:
175 mg/kg bw/day (actual dose received)
Remarks:
dissolved in corn oil
Dose / conc.:
600 mg/kg bw/day (actual dose received)
Remarks:
dissolved in corn oil
No. of animals per sex per dose:
30 rats/sex/dose, for baseline examinations additionally 10 rats/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
Interim kill at week 7
Post-exposure period: no
Positive control:
no
Observations and examinations performed and frequency:
yes, see section "any other information on materials and method"
Sacrifice and pathology:
yes, see section "any other information on materials and method"
Other examinations:
yes, see section "amy other information on materials and method"
Statistics:
yes, see section "any other information on materials and method"
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:
effects observed, treatment-related
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
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:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified
Details on results:
see section "Remarks on results"
Key result
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: >=175 mg/kg bw/d: increased mortality, clinical signs including lethargy, exessive salivation, tremor and occasional convulsions and comas, hepatotoxicity and nephrotoxicity
Critical effects observed:
not specified

600 mg/kg: 3 females died within the first 3 days of dosing.  

Overt signs of toxicity at this dose included lethargy, tremors, convulsions and  coma.  


BODY WEIGHT was sign. reduced (p</=0.05):
50 mg/kg bw: female, at week 1, 2, 3, 4, 5, and 7
175 mg/kg bw: male, at week 2, 3, and 4
600 mg/kg bw: male, except week 1 in all weeks; female, week 2, 3, 4, 5,  6, 7, 8, 9, and 14  


BODY WEIGHT GAIN was sign. reduced (p</=0.05):
50 mg/kg bw: female, week 2, and 3
175 mg/kg bw: male, week 1, 2, and 3; female, week 1 and 2
600 mg/kg bw: male, all weeks; female, week 1, 2, 3, 4, 5, 6, 7, 10, 13

FOOD CONSUMPTION data was sign. reduced (p</=0.05):
50 mg/kg bw: male, week 5, 9; female, week 1 and 2
175 mg/kg bw: male, week 1, and 5
600 mg/kg bw: male, week 1, 2, 3, 4, 5, 6, 7, and 9; female, week 1, 2,  and 5  

CLINICAL PATHOLOGY, only sign. changes (p</=0.05):
Male: 
APTT, 600 mg/kg bw, increased; total protein from 175 mg/kg bw increased; Ca, at 175 mg/kg bw increased; phosphate, 600 mg/kg bw, increased 

Female: 
RBC, HGB, HCT, from 175 mg/kg bw, decreased; CO2, at 175 mg/kg bw,  decreased; SGPT, SGOT, Cholesterin, at 600 mg/kg bw increased;  

OPHTHALMOLOGY:
Treatment related changes were not seen.

ORGAN WEIGHTS (rel. and abs., only sign. changes, p</=0.05):
Male:
Heart, rel., at 600 mg/kg bw increased; liver, 600 mg/kg bw, abs. decrease, rel. increase; spleen, 600 mg/kg bw, absol. decreases; right and left kidney, from 175 mg/kg bw, rel. increased; right and left  testis, at 600 mg/kg bw, rel. increased; brain, at 600 mg/kg bw, abs. decreased, rel. increased; 


Female:
spleen, at 50 mg/kg bw, rel. increased (no histopathologic correlate);  right kidney, at 600 mg/kg bw, rel. increased; right ovary, at 600 mg/kg  bw, ovary and brain, abs. decreased

PATHOLOGY: 
Gross necropsy examinations did not detect treatment- related changes.
Histological examination:

male: 
chronic nephropathy in all rats including controls:
A slight increased incidence in all dosed males when compared to the  controls. The increased incidence was significantly greater (p</=0.05) at  the low and the high dose but not at the middle dose. The proportion of  rats with minimal and mild nephropathy was generally similar for all male  rats including controls:
controls: 4/20 = 20%, severity(s): minimal 3/4, mild 1/4; 
50 mg-gr.: 11/20 = 55%, s: minimal: 3/11, mild: 2/11
175 mg-gr.: 7/20 = 35%, s: minimal: 7/7, mild:0/7
600 mg-gr.: 12/20 = 60%, s: minimal: 9/12, mild: 3/12
(no dose-response relationship, controls also affected, no increase in  percentage of severity in dosed rats when compared to the controls)
male, female:

epithelial metaplasia of the trachea:
sign, at 600 mg/kg bw (p</=0.05), 10/20 males, 9/19 females


The incidence of this lesions was similiar for low dose, mid dose and  control

Conclusions:
In a subchronic toxicity study according to OECD TG 408 p-cresol was administered daily to male and female Sprague-Dawley rats by gavage at dose levels of 0, 50, 175 , 600 mg/kg bw/day diluted in corn oil. Based on increased mortality, clinical signs including lethargy, exessive salivation, tremor and occasional convulsions and comas, hepatotoxicity and nephrotoxicity from 175 mg/kg bw/d onwards the NOAEL is 50 mg/kg bw/d.
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.
Endpoint:
sub-chronic 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 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Principles of method if other than guideline:
Method: 30 rats/sex/dose, add.10 rats/sex for baseline clin. pathol., interim kill at week 7, terminal kill at week 14, blood samples for hematology, clin.chemistry; urinalysis; gross and microsc. pathology; stat. anal.: Dunnett's t-t
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 5-6 weeks
- Housing: 2or 3 per cage during pretest, individually following randomization to groups
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72
- Humidity (%): 50
- Air change: at least 12-15 per hour
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
the test chemical was diluted in corn oiil on a weekly basis to achieve the respective test concentrations which allowed for a dosing volume of 5 mL/kg

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
gas chromatography: m-cresol was found to be stable for at least 14 days at the concentration tested. Additionally the analyses of the dosage form preparations used during test week 1, 2, 4, 8, and 13 indicated that target concentrations were generally within an acceptable range.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
once daily for 13 consecutive weeks
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Remarks:
in corn oil
Dose / conc.:
150 mg/kg bw/day (actual dose received)
Remarks:
in corn oil
Dose / conc.:
450 mg/kg bw/day (actual dose received)
Remarks:
in corn oil
No. of animals per sex per dose:
30 rats/sex/dose group; 10 of each group for interim kill at day 45
Control animals:
yes, concurrent vehicle
Details on study design:
- Post-exposure period: 1 w
- Dose selection rationale: doses were chosen based on the results of a range-finding study
Positive control:
not relevant
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: for moribundity/mortality: twice daily
- for clinical signs: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: at initiation and weekly thereafter

FOOD CONSUMPTION:
Time schedule: weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pretreatment and at termination
- Dose groups that were examined: at termination on all animals designated to be terminated at 13-weeks

HAEMATOLOGY: Yes
- Time schedule for collection of blood: see "Any other information on material and methods"
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals:
10 males and 10 females for baseline examination
10 rats/sex/dose group at interim kill
10 rats/sex/group at termination of the study
- Parameters checked in table were examined (see "Any other information on material and methods")

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: see "Any other information on material and methods"
for details see above
- Parameters checked in table were examined (see "Any other information on material and methods")

URINALYSIS: Yes
- Time schedule for collection of urine: see "Any other information on material and methods"
- Metabolism cages used for collection of urine: No data
- Parameters checked in table were examined (see "Any other information on material and methods")

NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see section: any other information on materials and methods incl. tables)
HISTOPATHOLOGY: Yes
Other examinations:
no
Statistics:
One-way analysis of Variance tests with Dunnett's test: body weight, food consumption, clinical chemistry, hematology and organ weights data
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 specified
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
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:
see section: remarks on results including tables and figures.
Key result
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: dose-dependant body weight reduction
Key result
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: decrease in body weight gain
Critical effects observed:
not specified
MORTALITY/CLINICAL OBSERVATIONS:
450 mg/kg: one high dose male was found dead on day 5 (cause not evident),
signs of intoxication:
450 mg/kg bw, male, female:
lethargy, tremors, hunched posture, rough hair coats post dosing
BODY WEIGHT
was sign reduced (p</=0.05): male, week 2-5, 13 at 450 mg/kg bw and week 6 -12, 14 from 150 mg/kg bw; female, week 11 at 450 mg/kg bw
body weight gain was reduced (p</=0.05): male, week 1-3 at 450 mg/kg bw and week 4-13 from 150 mg/kg bw; female, week 1 at 450 mg/kg bw

FOOD CONSUMPTION
was sign. reduced (p</=0.05): male: 50 mg/kg bw, week 1, 2, 9, 11, 12; 150 mg/kg bw week 3, 6, 8, 12, 13; 450 mg/kg bw week 1 -4, 6 -9, 11; female: 50 mg/kg bw, week 4, 150 mg/kg bw, week 4, 11, 450 mg/kg bw, week 1, 4, 6

CLINICAL PATHOLOGY
clinical chemistry, haematology and urinalyses parameters were not affected by treatment

OPHTHALMOLOGY
treatment related lesions were not seen
ORGAN WEIGHTS
organ weights were not affected by treatment
PATHOLOGY
treatment-related gross and histomorphology lesions were not in evidence
NOAEL (female) = 150 mg/kg bw/day
NOAEL (male) = 50 mg/kg bw/day
Conclusions:
In a study according to OECD TG 408, male and female Sprague Dawley rats received 0, 50,150, 450 mg/kg bw/day diluted in corn oil for a period of 13 weeks by gavage. Dose-dependent body weight decrease resulted in a NOAEL (male rat) of 50 mg/kg bw/day. The NOAEL (female rat) was 150 mg/kg bw/day based on reduced body weight gain in the highest dose group.
Endpoint:
sub-chronic 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
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Taconic Farms, Germantown, N.Y.
- Age at study initiation: 5-6 weeks
- Weight at study initiation: 21.2-22.4 g
- Housing: individually
- Diet:ad libitum
- Water: ad libitum
- Acclimation period: 13-19 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72 +/- 3
- Humidity (%): 50 +/- 15
- Air changes (per hr): 10-12
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
no further data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data reported
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily
Dose / conc.:
1 250 ppm
Remarks:
nominal in diet
Dose / conc.:
2 500 ppm
Remarks:
nominal in diet
Dose / conc.:
5 000 ppm
Remarks:
nominal in diet
Dose / conc.:
10 000 ppm
Remarks:
nominal in diet
Dose / conc.:
20 000 ppm
Remarks:
nominal in diet
No. of animals per sex per dose:
10 mice/sex/dose
Control animals:
yes, concurrent no treatment
Details on study design:
Post-exposure period: no
Positive control:
no
Observations and examinations performed and frequency:
for details see section "any other information on materials and methods

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes

CLINICAL CHEMISTRY: Yes

URINALYSIS: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
for details see section "Any other informaion on materials and methods"
Other examinations:
no further data
Statistics:
see section "Any other informations on materials and methods"
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 examined
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified
Details on results:
see section: remarks on results
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 1 250 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: >=2500 ppm: increased relative and absolute liver and kidney weights
Remarks on result:
other: corresponds to 199 (males) and 237 mg/kg bw/d (females), respectively
Critical effects observed:
not specified
-compound consumption:
dose [ppm] compound [mg/kg bw/day]
males females
1250---------199-------237
2500---------400-------496
5000---------794-------935
10000--------2723------1663
20000--------2723------3205

-mortality
no effect on mortality


-body weight development and food consumption
-females: reduced body weight gain in all dose groups significant from >=10000 ppm
-males: reduced body weight gain in all groups, significant at 1250, 5000-20000 ppm
Reduced food consumption in the high-dose animals during the first week of the study.

-clinical signs
Hunched posture and rough hair coat in all high-dose males and hunched posture in 1/10 male receiving 10000 ppm.
-organ weights
Increased rel. kidney weight in 20000 ppm females.
Increased rel. liver weight in all male dose groups and in femals with >= 5000 ppm.
Increased rel. thymus in males and females at 20000 ppm
Increased rel. testis weight at 20000 ppm

-hematology and clinical chemistry:
No biological significant effects in hematology, clinical chemistry.


-gross and microscopic pathology:
Histopathology revealed minimal forestomach epithelial hyperplasia in some of the high dose animals (4/10 males and 3/10 females) which - according to the authors - maybe the result of direct irritation or secondary to decreased food consumption.

-evaluation of reproductive endpoints:
No change in male reproductive endpoints, but lengthened oestrus cycle in dosed female mice.

Conclusions:
According to OECD TG 408 male and female B6C3F1 mice were fed 0, 1250, 2500, 5000, 10000, 20000 ppm o-cresol for 13 weeks. The NOAEL is 1250 ppm for males and females (199 and 237 mg/kg bw/d, respectively) based on increased relative and absolute liver and kidney weights from 2500 ppm onwards.
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: guideline study
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Taconic farms, Germantown, N.Y.
- Age at study initiation: 6-7 weeks
- Weight at study initiation: 110-143 g
- Housing: 5 rats same sex into a cage
- Diet: ad libitum (NIH-07 rat ration)
- Water: ad libitum
- Acclimation period: 12-19 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72 +/- 3
- Humidity (%): 50 +/- 15
- Air changes (per hr): 10-12
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
no further information
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily
Dose / conc.:
1 880 ppm
Remarks:
nominal in diet
Dose / conc.:
3 750 ppm
Remarks:
nominal in diet
Dose / conc.:
7 500 ppm
Remarks:
nominal in diet
Dose / conc.:
15 000 ppm
Remarks:
nominal in diet
Dose / conc.:
30 000 ppm
Remarks:
nominal in diet
No. of animals per sex per dose:
20 rat/sex/dose group: 10 of each group designed for clinical pathology studies
Control animals:
yes, concurrent no treatment
Details on study design:
Post-exposure period: no
Positive control:
no
Observations and examinations performed and frequency:
observed twice daily, body weights taken weekly and at termination; food consumption by cage recorded twice weekly
Sacrifice and pathology:
see section "Any other information on materials and methods"
Other examinations:
no data
Statistics:
nonparametric multiple comparison test of Dunn and Shirley, Jonckheere's test, arcine transformation, multivariate analysis of variance
Clinical signs:
no effects observed
Mortality:
no mortality observed
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):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified
Details on results:
see section "remarks on results"
Key result
Dose descriptor:
NOAEL
Effect level:
3 750 ppm
Sex:
male/female
Basis for effect level:
other: >= 7500 ppm: increased relative liver and kidney weights
Remarks on result:
other: males ca. 247 mg/kg bw/day; females ca. 256 mg/kg bw/day
Critical effects observed:
not specified
-mean compound consumption
Dose [ppm] compound [mg/kg bw/d]
males females
1880-----------126------129
3750-----------247------256
7500-----------510------513
15000----------1017-----1021
30000----------2028-----2024
-clinical signs
no clinical signs of toxicity
-organ weights
>=15000 ppm, m+f: Increased rel. kidney weights,
>= 7500 ppm, m+f: rel. and abs. liver weights increased
>=15000 ppm(m); 30000 ppm (f): increased rel. thymus weight
30000 ppm males: increased rel. testes weight
-Hematology and clinical chemistry
hematology findings were unremarkable,
no evidence of hepatocellular necrosis (no change in alanine aminotransferase) or overt cholestasis (no change in 5'-nucleotidase or alkaline phosphatase), no effect on urinanalysis (no renal damage)
-Histopathology:
increased incidence of bone marrow hypocellularity with >= 15000 ppm (females) or 30000 ppm (males) were considered likely secondary to the decreased weight gains
-Evaluation of reproductive tissue endpoints
Slight lengthening of estrus cycle in females, no histopathologic changes in ovary or uterus
Conclusions:
According to OECD TG 408 male and female F344 rats were fed 0, 1880, 3750, 7500, 15000, 30000 ppm o-cresol in diet. The NOAEL is 3750 ppm for males and females (247 and 256 mg/kg bw/d, respectively) based on increased relative kidney and liver weights from 7500 ppm onwards, but no histopathological changes were reported.
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.
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.
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
according to
Guideline:
other: Sontag JM, Page NP, Saffotti U, NCI, DHEW Publication No (NIH)78-ß01Guidelines for Carcinogen Bioassay in small rodents
Principles of method if other than guideline:
Method: see section" any other information of materials and methods"
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: 5-6 weeks
- Fasting period before study: 24 hours
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 16 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72
- Humidity (%): 50
- Air changes (per hr): 12-15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
test solution was produced on a weekly basis
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
during test week 1, 2, 4, 8 and 13 by Enseco Inc, Cambridge MA and additionally by American Biogenics Corporation, Decatur IL
Duration of treatment / exposure:
13 w
Frequency of treatment:
once daily
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Remarks:
in corn oil
Dose / conc.:
175 mg/kg bw/day (actual dose received)
Remarks:
in corn oil
Dose / conc.:
600 mg/kg bw/day (actual dose received)
Remarks:
in corn oil
No. of animals per sex per dose:
30 animals /sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: no
Positive control:
no data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for mortality and clinical signs

BODY WEIGHT: Yes
- Time schedule for examinations: day 1 and then weekly

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

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: during quarantine period and in test week 13

HAEMATOLOGY / CLINICAL CHEMISTRY / Urinalysis: Yes
- Time schedule for collection of blood: as baseline clinical pathology, at test week 7 (interim kill), at study termination
- How many animals: 10 rats/sex/dose
- Parameters checked: see section "additional iformation on materials and methods"

NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see section " any other information on materials and method")
HISTOPATHOLOGY: Yes (see section"Any other information on materials and method")
Other examinations:
no data
Statistics:
One-Way Analysis of Variance tests, Dunnett's t 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):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
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:
see section: "Remarks on results "
Key result
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: >= 175 mg/kg bw/day animals revealed central nervous system depression and showed statistically significant reduction in body weight and body weight gain
Critical effects observed:
not specified

600 mg/kg bw/day:
mortality 19/30 females and 9/30 males,
Body weight: reduction

body weight of females were unaffected; 600 mg/kg bw/d, males: significant during week 2 through 10; 175 mg/kg bw/d, males: significant during week 2;

Body weight gain 175 and 600 mg/kg bw/d: reduction in body weight gain (males)

slight decrease in food intake;

600 mg/kg bw/day, males and females, 175 mg/kg bw/d: 1 female d23 and 1 female d27
treatment-related depression of the central nervous system:
lethargy, dyspnoea, tremor and/or convulsions, recovering within 1 h after dosing
No effects on clinical chemistry, hematology, urinalyses parameters, no treatment-related ophthalmic lesions, no effects on organ weights, no treatment-related gross and histomorphologic lesions;

Conclusions:
According to Sontag JM, Page NP, Saffotti U (NCI, DHEW Publication No (NIH)78-ß01 Guidelines for Carcinogen Bioassay in small rodents) male and female rats were applied with 0, 50,175, 600 mg/kg bw/day by gavage for 13 weeks. The NOAEL is 50 mg/kg bw/day based on clinical signs and effects on body weights from 175 mg/kg bw /day onwards.
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
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
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
Critical effects observed:
not specified

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.

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).

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Summary of available 90-day 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
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Key result
Dose descriptor:
NOAEL
Remarks:
rat
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: >= 175 mg/kg bw/day animals revealed central nervous system depression and showed statistically significant reduction in body weight and body weight gain
Remarks on result:
other: Source, CAS 95-48-7, o-cresol, RTI, 1988, 90-day study
Critical effects observed:
not specified

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 95 -48 -7: o-cresol: NOAEL (male/female, rat) = 3750 ppm (corresponds to males ca. 247 mg/kg bw/day; females ca. 256 mg/kg bw/day), based on increased relative and absolute liver and kidney weights; NTP, 1991

Source CAS 95 -48 -7: o-cresol: NOAEL (male/female, mouse) = 1250 ppm (corresponds to 199 (males) and 237 mg/kg bw/d (females), respectively), based on increased relative and absolute liver and kidney weights; NTP, 1991

Source CAS 106 -44 -5: p-cresol: NOAEL (male/female, rat) = 50 mg/kg bw/day, based on increased mortality, clinical signs including lethargy, exessive salivation, tremor and occasional convulsions and comas, hepatotoxicity and nephrotoxicity; RTI, 1988

Source CAS 108 -39 -4: m-cresol: NOAEL (male, rat) = 50 mg/kg bw/day, based on dose-dependent body weight reduction; RTI, 1988

Source CAS 108 -39 -4: m-cresol: NOAEL (female, rat) = 150 mg/kg bw/day, based on decreased body weight gain; RTI, 1988

Conclusions:
The available NOAEL does not markedly deviate from a NOAEL of 100 mg/kg bw/day established in the 28-day studies. Whilst no sub-chronic or chronic studies have been conducted with xylenols or ethylphenols, the plethora of sub-chronic and chronic toxicology data available on cresols would indicated (based on similarities in structure and physical properties) that a read-across approach can be used with comparable NOAEL values expected to be obtained for the target substance.
Executive summary:

In all sub-chronic repeated dose toxicity studies with the different cresol-isomers decreases in food consumption and body weight were reported (which is likely due to lack of palatability of the test materials as they are known irritants). Where changes in organ weights were observed (again liver / kidney, also thymus and testes) no gross histopathological changes accompanied these changes. In the o-cresol dietary study forestomach hyperplasia was noted, which was likely due to the irritant nature of the test material. Furthermore epithelial metaplasia of the trachea was observed in the p-cresol dietary study. These lesions were considered to be an adaptive response due to inhalation exposure resulting from the volatising of the test material from the feed during consumption and not from systemic exposure following oral absorption. Such lesions are commonly observed in NTP (2000) studies on chemicals which are known irritants.

The NOAELs established for all three oral gavage studies were 50 mg/kg bw/day. In the feeding studies with o-cresol in rats and mice the NOAEL was 247 mg/kg bw/day for male and 256 mg/kg bw/das for female rats and 199 mg/kg bw/day for male and 237 mg/kg bw/day for female mice, respectively, indicating no big species differences.

The NOAELs do not markedly deviate from a NOAEL of 100 mg/kg bw/day established in 28-day studies. Whilst no sub-chronic or chronic studies have been conducted with xylenols or ethylphenols, the plethora of sub-chronic and chronic toxicology data available on cresols would indicated (based on similarities in structure and physical properties) that a read-across approach can be used with comparable NOAEL values expected to be obtained for the target substance.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 1) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on data on the constituents of Tar acids, xylenol fraction (CAS 84989-06-0) (refer to endpoint discussion for further details).
Taken together, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VIII, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for read-across

There are no data for repeated dose toxicity available for Tar acids, Xylenol fraction (CAS 84989-06-0). In order to fulfil the standard data requirements defined in Regulation (EC) No 1907/2006, Annex IX, 8.6, read-across from appropriate substances is conducted in accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5.

According to Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met”. In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across) “to avoid the need to test every substance for every endpoint”.

Tar acids, Xylenol fraction (CAS 84989-06-0) is an UVCB substance comprised of the main constituents xylenols (all isomers in total > 60%; 2,4- and 2,5 -xylenol > 40%), ethyl phenols (< 30%) and cresols (< 25%). The read-across approach is therefore based on the main constituents of Tar acids, Xylenol fraction (CAS 84989-06-0), given common functional groups, common precursors and the likelihood of common breakdown products via biological processes. For further details on the read-across approach, please refer to the analogue justification in section 13 of the technical dossier.

For oral repeated dose toxicity read-across from reliable data on the analogue substances mixed xylenols, mixed ethyl phenols as well as from the cresol isomers (m- (CAS 108-39-4), p- (CAS 106-44 5) and o-cresol (CAS 95-48-7)) was conducted. For repeated dose inhalation toxicity data are available on p-cresol (CAS 106-44 5) only. The data base is therefore very limited and does not allow a final conclusion. Further testing is, however, not required, as there are reliable oral repeated dose toxicity data available for the hazard assessment. Therefore, the requirements defined in Regulation (EC) No 1907/2006, Annex IX, 8.6 are fulfilled. Regarding dermal repeated dose toxicity there are no reliable data available. Also for this route, further testing is not required, as there are reliable oral repeated dose toxicity data available for the hazard assessment. Therefore, the requirements defined in Regulation (EC) No 1907/2006, Annex IX, 8.6 are fulfilled.

Repeated oral dose toxicity

Sub-acute

Mixed xylenols

Mixed xylenols were tested for oral repeated dose toxicity in Crj: CD(SD) rats for 28 days for male animals and 54 days for females according to OECD 422 and under GLP (Merisol, 2005c). Ten rats/sex/dose received daily applications (beginning 14 days prior to cohabitation and continuing until the day before sacrifice) of the test substance in corn oil via gavage at dose levels of 30, 100 and 245 mg/kg bw/day. The general NOAEL was shown to be 100 mg/kg bw/day for male and female animals due to clinical observations which included urine-stained fur, increased kidney, liver and ovarian relative weight.

Mixed ethylphenols

Mixed ethylphenols were tested for oral repeated dose toxicity in Crl:CD (SD)IGS BR VAF/Plus rats for 28 days for male animals and 54 days for females according to OECD 422 and under GLP (Merisol, 2005c). Ten rats/sex/dose received daily applications (beginning 14 days prior to cohabitation and continuing until the day before sacrifice) of the test substance in corn oil via gavage at dose levels of 30, 100 and 245 mg/kg bw/day. The NOAEL was determined to be 100 mg/kg bw/day based on clinical signs of toxicity which included urine stained abdominal fur, increased kidney, liver and ovarian relative weight.

m-cresol (CAS 108-39-4)

m-cresol (CAS 108-39-4) was tested for oral repeated dose toxicity in Crj: CD(SD) rats for 28 days according to OECD 407 and under GLP (MHLW, 2001a). Seven rats/sex/dose received daily applications of the test substance in olive oil via gavage at dose levels of 100, 300 and 1000 mg/kg bw/day. A control group and additional seven rats/sex in the highest dose were included for a 14 day-recovery period. Based on histopathological changes in the liver in males at 1000 mg/kg bw/day the NOAEL (males) 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.

p-cresol (CAS 106-44-5)

p-cresol (CAS 106-44-5) was tested for oral repeated dose toxicity (IBTL, 1969b). Male rats were fed with 0, 10, 150, 500 ppm (0, 1.90, 14.2, 45.2 mg/kg bw/day) p-cresol 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 assessed as not reliable for hazard assessment of the target substance.

Additional data:

In the public toxicological evaluation of 2,4-xylenol (CAS 105-67-9) of BG Chemie (No. 137, last updated 02/2005), 2,4-xylenol has been found to be of low toxicity following repeated oral administration. The authors summarised that the top dose of 1000 mg/kg bw (daily treatment for seven days) gives rise to slight to moderate salivation, rough coat and lethargy in male and female rats from day 4 of treatment in a dose-finding study. When treated at dose levels of 60, 120, 600 or 1200 mg/kg bw for 10 days, rats exhibit dose-dependent lesions of the gastric mucosa in all dose groups. At the top dose level, all animals died. No further relevant effects of 2,4-xylenol treatment are observed. In a subacute toxicity study conducted in accordance with OECD 407, 4-week daily oral administration of 2,4-xylenol to rats at dose levels of 30, 100 or 300 mg/kg bw resulted in statistically significant increases in creatinine levels in male rats from the highest dose group as well as causing increased absolute and relative weights of the testes and epididymides in the absence of corresponding histopathological changes. Females treated at the highest dose level exhibited increased absolute liver weights together with sinusoidal dilatation and congestion, and those treated at 100 mg/kg bw and above had increased absolute kidney weights without any corresponding histopathological changes. The no-effect level was 30 mg/kg bw. Also 3,5-xylenol (CAS 108-68-9) was evaluated by BG Chemie (No. 139, last updated 02/2005) and has also been found to be of low toxicity following repeated oral administration for 7days. The authors summarised that the top dose of 1000 mg/kg bw gives rise to slight to moderate salivation, rough coat and lethargy from day 4 of treatment without any abnormal macroscopic or microscopic findings in the organs. In a subacute toxicity study conducted in accordance with OECD 407, the only effects of 4-week daily oral administration of 3,5-xylenol to rats at dose levels of 30, 100 or 300 mg/kg bw were noted at 100 mg/kg bw and above and consisted in decreased body weight gain accompanying reduced food consumption and increased salivation. There were no further significant toxic effects. The no effect level was determined to be 30 mg/kg bw.

Conclusion:

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 similar to that obtained for mixed xylenols and mixed ethylphenols (NOAEL(males) = 300 mg/kg bw/day and NOAEL(females) = 100 mg/kg bw/day), and also the summary of the BG Chemie on the subacute repeated dose toxicity data of 2,4- and 3,5-xylenol confirms these findings, which strengthens the read-across approach.

Increases in liver and/or kidney weights were reported. No histopathological changes accompanied these increases in organ weights (with the exception of 1000 mg/kg bw/day of m-cresol for which histopathological changes were reported). Male rats of the highest dose group treated with 2,4-xylenol showed increases in creatinine levels as well as increased absolute and relative weights of the testes and epididymides in the absence of corresponding histopathological changes.

Sub-chronic and chronic

o-cresol (CAS 95-39-4)

o-cresol (CAS 95-39-4) was tested for oral repeated dose toxicity in Sprague-Dawley rats for 90 days according to Sontag JM et al., DHEW Publication No (NIH)78-ß01 Guidelines for Carcinogen Bioassay in small rodents and under GLP (RTI, 1988a). 30 rats/sex/dose received daily applications of the test substance in corn oil via gavage at dose levels of 50, 175 and 600 mg/kg bw/day. The NOAEL is 50 mg/kg bw/day based on clinical signs (central nervous system depression) and effects on body weights from 175 mg/kg bw /day onwards.

A second study with o-cresol (CAS 95-39-4) was conducted to test the oral repeated dose toxicity in Fischer 344 rats for 90 days according to OECD 408 and under GLP (NTP, 1991). 20 rats/sex/dose (10 of each group designed for clinical pathology studies) received daily applications of the test substance in diet at dose levels of 1880, 3750, 7500, 15000 and 30000 ppm. The NOAEL is 3750 ppm for males and females (247 and 256 mg/kg bw/day, respectively) based on increased relative kidney and liver weights from 7500 ppm onwards, but no histopathological changes were reported.

Another study with o-cresol (CAS 95-39-4) was conducted to test the oral repeated dose toxicity in B6C3F1 mice for 90 days according to OECD 408 and under GLP (NTP, 1991). 10 mice/sex/dose received daily applications of the test substance in diet at dose levels of 1250, 2500, 5000, 10000 and 20000 ppm. The NOAEL is 1250 ppm for males and females (199 and 237 mg/kg bw/day, respectively) based on increased relative and absolute liver and kidney weights from 2500 ppm onwards.

p-cresol (CAS 106-44-5)

p-cresol (CAS 106-44-5) was tested for oral repeated dose toxicity in Sprague-Dawley rats for 90 days according to OECD 408 and under GLP (RTI, 1988b). 30 rats/sex/dose (for baseline examinations additionally 10 rats/sex/dose) received daily applications of the test substance in corn oil via gavage at dose levels of 50, 175 and 600 mg/kg bw/day. Based on increased mortality, clinical signs including lethargy, excessive salivation, tremor and occasional convulsions and comas, hepatotoxicity and nephrotoxicity from 175 mg/kg bw/day onwards the NOAEL is 50 mg/kg bw/day for male and female animals.

m-cresol (CAS 108-39-4)

m-cresol (CAS 108-39-4) was tested for oral repeated dose toxicity in Sprague-Dawley rats for 90 days according to OECD 408 and under GLP (RTI, 1988c). 30 rats/sex/dose (10 of each group for interim kill at day 45) received daily applications of the test substance in corn oil via gavage at dose levels of 50, 150 and 450 mg/kg bw/day. Dose-dependent body weight decrease resulted in a NOAEL (males) of 50 mg/kg bw/day. The NOAEL (females) was 150 mg/kg bw/day based on reduced body weight gain in the highest dose group.

Additional data:

In the public toxicological evaluation of 2,4-xylenol (CAS 105-67-9) of BG Chemie (No. 137, last updated 02/2005), the NOAEL for 3-month subchronic oral administration to rats has been given as 60 mg/kg bw. Dose levels of 180 mg/kg bw and above primarily led to inflammatory lesions in the forestomach that were dose- and concentration-dependent and led to death in the highest dose group. No further marked systemic toxicity was observed at the administered 2,4-xylenol dose levels of 60, 180 and 540 mg/kg bw. However, due to the deaths in the highest dose group after 5 days of treatment the top concentration was halved by increasing the volume. In a 90-day study in mice, 2,4-xylenol was administered by gavage at dose levels of 5, 50 or 250 mg/kg bw/day. Only the top dose level caused treatment-related, statistically significant haematological changes in the females (reduced mean corpuscular volume and reduced mean corpuscular haemoglobin concentration) and clinical signs of toxicity (lethargy, prostration and ataxia) in both sexes, but these occurred only after 6 weeks of treatment. Treatment at dose levels of up to 250 mg/kg bw/day did not affect body weight gain, food consumption or organ weights. Ophthalmological, macroscopic and histopathological examinations were also without abnormal findings. The NOAEL was 50 mg/kg bw and the LOAEL was 250 mg/kg bw for mice, and therefore also no marked species differences could be seen in these studies with rats and mice.

Conclusion:

The NOAELs established for all three oral gavage studies with the cresol isomers were 50 mg/kg bw/day. In the feeding studies with o-cresol in rats and mice the NOAEL was 247 mg/kg bw/day for male and 256 mg/kg bw/day for female rats and 199 mg/kg bw/day for male and 237 mg/kg bw/day for female mice, respectively, indicating no big species differences.

The data available from the 2-year carcinogenicity studies on m/p-cresol (NTP, 2007) were not specifically designed to set a NOAEL, but would imply that a NOAEL of 70 mg/kg bw/day could be set for rats based on the absence of any neoplastic or non-neoplastic findings.

In conclusion, the lowest NOAEL found from all repeated dose studies is 50 mg/kg bw/day. Whilst no sub-chronic or chronic studies are available for xylenols or ethylphenols (besides the summaries of the two 90-day studies in rats and mice with 2,4-xylenol from BG Chemie, which support the lowest NOAEL of 50 mg/kg bw for the cresols), the plethora of sub-chronic and chronic toxicology data available on cresols would indicated (based on similarities in structure and physical properties) that a read-across approach can be used with comparable NOAEL values expected to be obtained.

 

Repeated dose dermal toxicity

Regarding dermal repeated dose toxicity there are no reliable data available. Further testing is, however, not required, as there are reliable oral repeated dose toxicity data available for the hazard assessment of Tar acids, Xylenol fraction (CAS 84989-06-0). Therefore, the requirements defined in Regulation (EC) No. 1907/2006, Annex IX, 8.6, are fulfilled. In accordance with the REACH “Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health” (Version 2.1), November 2012 route to route extrapolation has been undertaken, extrapolating from the oral route to the dermal route for providing a repeated dose dermal systemic DNEL. Due to the expected corrosive properties of Tar acids, Xylenol fraction (CAS 84989-06-0) it is not appropriate to conduct a route-to-route extrapolation for local effects. Based on the available data a qualitative risk assessment approach will be followed as outlined in the REACH “Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health” (Version 2.1), November 2012.

Repeated dose inhalation toxicity

p-cresol (CAS 106-44-5)

p-cresol (CAS 106-44-5) was tested for repeated dose inhalation toxicity in female rats for 4 months (Pereima, 1975). There was a post-exposure period of 2 months. The concentration was 0.01 mg/L air. As this is only secondary literature, there was no further information on the used method and test animals available. Clinical signs of toxicity included loss of appetite, marked emaciation and decreased locomotor activity. Irritative effects, which persisted throughout recovery, were seen on the nose, eye and skin. Decreased body weight gain and lung weight, increased liver weight, oliguria and dystrophic changes in the lung and liver occurred. Therefore, the LOAEL was set at 0.01 mg/L air as this was the only concentration tested.

In addition to the above described data, in the public toxicological evaluation of 2,4-xylenol (CAS 105-67-9) of BG Chemie (No. 137, last updated 02/2005), repeated inhalation exposure of mice to 2,4-dimethylphenol vapours at concentration levels of 23 mg/m³ for 2 hours/day for one month caused a slight decrease in body weight gain. Functional and morphological parameters, metabolism and body temperature, spontaneous motor activity, peripheral blood and internal organs weights remained unchanged (no further details).

Due to the lack of further information on these studies and to the fact that only limited data on p-cresol and 2,4-xylenol are available, the data base is very limited and does not allow a final conclusion on repeated dose inhalation toxicity of Tar acids, Xylenol fraction (CAS 84989-06-0). However, further testing is not required as there are reliable oral repeated dose toxicity data available for the hazard assessment. Therefore, the requirements defined in Regulation (EC) No 1907/2006, Annex IX, 8.6, are fulfilled. In accordance with the REACH “Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health” (Version 2.1), November 2012 route to route extrapolation has been undertaken, extrapolating from the oral route to the inhalation route for providing a repeated dose inhalation systemic DNEL. Due to the expected corrosive properties of Tar acids, Xylenol fraction (CAS 84989-06-0) it is not appropriate to conduct a route-to-route extrapolation for local effects. Based on the available data a qualitative risk assessment approach will be followed as outlined in the REACH “Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health” (Version 2.1), November 2012.

References:

BG Chemie 2005: Toxicological evaluation of 2,4-Dimethylphenol (CAS No. 105-67-9), No. 137, last updated: 02/2005.

BG Chemie 2005: Toxicological evaluation of 3,5-Dimethylphenol (CAS No. 108-68-9), No. 139, last updated: 02/2005.

NTP (2000). Technical report on the toxicology and carcinogenesis studies of naphthalene (CAS no. 91-20-3) in F344/N rats (Inhalation studies). Technical report series No. 500. NIH Publication No. 01-34434. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, N.C.

Justification for classification or non-classification

Based on all available information (weight-of-evidence), following an analogue read-across approach and in the absence of data on repeated oral dose toxicity of Tar acids, Xylenol fraction (CAS 84989-06-0), Tar acids, Xylenol fraction (CAS 84989-06-0) no classification for repeated dose toxicity via the oral route is required according to Regulation (EC) 1272/2008.

The data base regarding repeated dose toxicity via the inhalation and dermal route is not sufficient to allow a final conclusion regarding classification according to Regulation (EC) 1272/2008.