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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Summary of available 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:
developmental toxicity
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:
other: TSCA Health Effects Test guidelines for Specific Organ/Tissue Toxicity - Developmental Toxicity (EPA, 1984, 1987)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton-Dutchland Laboratories, Inc., Denver, PA, USA
- Age at study initiation: 5.5 months
- Weight at study initiation: 2.5 kg
- Housing: singly
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°F ): 72
- Humidity (%): 40-60
- Photoperiod (hrs dark / hrs light) 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Dosing formulations were prepared by weighing the amount of test chemical into a volumetric flask and diluting to volume with certified corn oil. The resulting solutions were mixed by repeated inversions and stored at room temperature.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
A standard stock solution was prepared as needed by weighing 50 mg p-cresol into a 50 mL volumetric flask and diluting to volume with propanol. Standards ranging from 10 to 100 ng/mL were prepared by diluting the stock solution with propanol. 10 µL of each standard was injected onto the HPLC. The actual concentration of each dosing solution was calculated from the equitation for the standard curve developed by linear regression.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
day 6 - 18 of gestation
Frequency of treatment:
once daily
Duration of test:
until gd 29
Dose / conc.:
5 mg/kg bw/day
Dose / conc.:
50 mg/kg bw/day
Dose / conc.:
100 mg/kg bw/day
Control animals:
yes, concurrent vehicle
Details on study design:
no further details
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: gd 0, 6, 12, 18, 24, 29

FOOD CONSUMPTION: Yes

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: stomach gland, liver, gall bladder, kidneys, uterus
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- Determination of number of fetuses alive: yes
- Detrmination of number of dead fetuses: yes
- Determination of sex ratio: yes
- External examinations: Yes, all per litter
- Soft tissue examinations: Yes, all per litter
- Skeletal examinations: Yes, all per litter
- Head examinations: Yes, half per litter
Statistics:
Levene's test, ANOVA with bonferroni prohability, t-test, Kruskal-Wallis test, Mann-Whithey U-test, Fisher's exact test
Indices:
no data
Historical control data:
no data
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):
no effects observed
Food efficiency:
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
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:
not specified
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Number of abortions:
effects observed, non-treatment-related
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
not specified
Details on maternal toxic effects:
mortality: 100 mg/kg bw: 5/14; 50 mg/kg bw: 2/14; all were pregnant; 1 control female aborted and one each at 5.0 and 50 mg/kg bw was removed due to dosing error, gestational weights and weight changes were not stat. significant different among groups for periodic body weights or weight changes.
50 and 100 mg/kg bw:
clinical signs: included hypoactivity, gasping, cyanosis, laboured rapid and audible respiration and ocular discharge
food consumption: no significant differences among groups for any timeperiod measured; 
no treatment related gross lesions at necropsy of does
maternal organ weights: no significant difference among the groups: terminal bw., gravid uterine weight, corrected bw. or weight change, absolute and relative liver weight
gestational parameters: no significant difference for number of ovarian corpora lutea, number of  implantations sites including total, nonviable (early or late resorptions  or dead fetuses) or viable percent live fetuses per  litter or fetal body  weight per litter; sex ratio was significantly increased (more males) at  50 mg/kg bw but not at 100 mg/kg bw (considered due to  biological  variabilty)

Key result
Dose descriptor:
NOAEL
Effect level:
5 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: >= 50 mg/kg bw/d: clinical signs of toxicity included gasping, cyanosis, audible labored and rapid respiration in additon to increased maternal mortality.
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
effects observed, non-treatment-related
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
fetal evaluation:
No significant differences among groups for any individual malformations, malformations by category or total malformations; no treatment-related significant differences for any individual external variations, variations by category or total variations.
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No indications of developmental toxicity up to the highest dose tested.
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
Developmental toxicity study according to TSCA Health Effects Test guidelines for Specific Organ/Tissue Toxicity - Developmental Toxicity (EPA, 1984, 1987):
Administration of p-cresol by gavage to time-pregnant New Zealand White rabbits during organogenesis at 0.0, 5.0, 50.0 or 100 mg/kg bw/day resulted in maternal toxicity at 50.0 and 100.0 mg/kg bw/d including mortality and clinical signs of toxicity. No indications of developmental toxicity were observed. Thus, the NOAEL (maternal toxicity) is 5 mg/kg bw/d and the NOAEL for developmental toxicity is 100 mg/kg bw/d.
Reason / purpose:
read-across source
Reference
Endpoint:
developmental toxicity
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:
other: TSCA Health Effects Test guidelines for Specific Organ/Tissue Toxicity - Developmental Toxicity (EPA, 1984,1987)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, NY, USA
- Age at study initiation: 56 days at arrival
- Weight at study initiation: 226-230 at gd 0
- Housing: after mating singly
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72
- Humidity (%): 40-60
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Dosing formulations were prepared by weighing the amount of test chemical into volumetric flask and diluting to volume with certified corn oil. The resulting solutions were mixed by repeated inversions and stored at room temperature.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
A standard stock solution (1 mg/mL) was prepared as needed by weighing 50 mg p-cresol into a 50 mL flask and diluting to volume with propanol. Standards ranging from 10 to 100 ng/mL were prepared by diluting the stock solution with propanol. 10 µL of each standard was injected onto the HPLC. The actual concentration of each dosing solution was calculated from the equitationfor the standard curve developed by linear regression.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
- Any other deviations from standard protocol:
Duration of treatment / exposure:
day 6 through day 15 of gestation
Frequency of treatment:
daily
Duration of test:
gd 21 (scheduled sacrifice)
Dose / conc.:
30 mg/kg bw/day
Dose / conc.:
175 mg/kg bw/day
Dose / conc.:
450 mg/kg bw/day
No. of animals per sex per dose:
25 females/group; 50 control females
Control animals:
yes, concurrent vehicle
Details on study design:
no further data
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations : mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: gd 0, 6, 11, 15, 21

FOOD CONSUMPTION : Yes
- Food consumption for each animal determined throughout gestation gd 0-21

WATER CONSUMPTION : No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: body weight, liver, gravid uterine weight, number of corporal lutea, number and status of implementation sites
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes, all per litter
- Soft tissue examinations: Yes, half per litter
- Skeletal examinations: Yes, half per litter
- Head examinations: Yes, half per litter
Statistics:
Levene's test, ANOVA, t-test with bonferroni prohabilities, Kruskal-wallis test, Mann-Whitney U test, Fisher's exact test
Indices:
no data
Historical control data:
no 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 specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
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:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
not specified
Details on maternal toxic effects:
Maternal toxicity:
mortality: 3/25 females at 450 mg/kg bw/day 
No abortions or early deliveries (1 litter at 30 mg/kg bw was fully resorbed)
450 mg/kg bw: decreased food consumption, stat. sign. reduction in periodic maternal body weight  and weight gain during dosing, 
maternal gestational weight gain reduced when corrected for the weight of the gravid uterus and reduced maternal terminal bw, relative but not absolute liver weight was increased
clin. signs  of toxicity: 
hypoactivity, ataxia and tremors, prone position, audible respiration and perioral wetness.
Gestational parameters were unaffected by treatment except fetal body weight per litter were reduced at 450 mg/kg bw.
Key result
Dose descriptor:
NOAEL
Effect level:
175 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: 450 mg/kg bw/d: hypoactivity, ataxia, tremors, twitches, prone positioning, audible respiration and perioral wetness, statistically signifcant reduction in periodic maternal body weights and weight gain during the dosing period
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
effects observed, treatment-related
Visceral malformations:
no effects observed
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
fetal evaluations:
No significant changes in the incidence of any individual malformation, malformation by category (external, visceral including craniofacial or skeletal) or total malformations for any dose group.
450 mg/kg bw: 7 skeletal variations exhibited sign. different incidences relative to those in the control groups: only 3 of these findings indicate slight fetotoxicity: incidence of cervical centrum 6 bilobed, reduced number of ossified caudal segments, unossified sternebrae, reduced incidence of unossified cervical centrum no. 7, poorly ossified parietal skull bone (30 mg/kg bw), reduced incidence of some (1-4) proximal phalanges of the hind limb unossified and increased incidence of of poorly ossified thoracic centrum number 13 (175 mg/kg bw/d)
p-Cresol caused mild fetotoxicity at the 450 mg/kg, as seen by reduced ossification in three skeletal districts. In addition, fetal body weight was reduced at the 450 mg/kg dose level. There was no treatment-related increased incidence of malformations at any dosage.

Key result
Dose descriptor:
NOEL
Effect level:
175 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: 450 mg/kg bw/d: Slight fetotoxicity seen as three skeletal variations consistent with reduced fetal body weights.
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: 450 mg/kg bw/d: skeletal variations (reduced ossification)
Key result
Developmental effects observed:
no
Conclusions:
Developmental toxicity study according to TSCA Health Effects Test guidelines for Specific Organ/Tissue Toxicity - Developmental Toxicity (EPA, 1984,1987):
Administration of p-cresol by gavage to time-pregnant Sprague-Dawley rats during organogenesis at 0.0, 30.0, 175.0, or 450.0 mg/kg bw/d resulted in maternal toxicity at 450 mg/kg bw/d and included mortality, clinical signs of toxicity, reduced weight gain and food consumption during dosing and reduced gestational weight gain corrected for the gravid uterus. Slight developmental toxicity was observed at 450 mg/kg bw/d and included reduced ossification in three skeletal districts in addition with reduced fetal body weight. Thus, the NOAEL for maternal toxicity and the NOEL for developmental toxicity is 175 mg/kg bw/d.
Reason / purpose:
read-across source
Reference
Endpoint:
developmental toxicity
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:
other: TSCA Health Effects Test guidelines for Specific Organ/Tissue Toxicity - Developmental Toxicity (EPA, 1984,1987)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton-Dutchland Laboratories, Inc. , Denver, PA, USA
- Age at study initiation: 5.5 months
- Weight at study initiation: 2.5 kg
- Housing: after malting: singly
- Diet : ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72
- Humidity (%): 40-60
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Dosing formulations were prepared by weighing the amount of test chemical into a volumetric flask and diluting to volume with certified corn oil.
The resulting solutions were mixed by repeated inversions and stored at room temperature.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
A standard stock solution (1 mg/mL) was prepared as needed by weighing 50 mg m-cresol into a 50 mL volumetric flask and diluting to volume with propanol. Standards ranging from 10 to 100 ng/mL were prepared by diluting the stock solution with
propanol. 10 µL of each standard was injected onto the HPLC. The actual conentration of each dosing solution was calculated from the equitation for the standard curve developed by linear regression.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
day 6 through day 18 of gestation
Frequency of treatment:
once daily
Duration of test:
until gd 29
Dose / conc.:
5 mg/kg bw/day
Dose / conc.:
50 mg/kg bw/day
Dose / conc.:
100 mg/kg bw/day
No. of animals per sex per dose:
14 females/group; control females: 28
Control animals:
yes, concurrent vehicle
Details on study design:
no furhter details
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: gd 0, 6, 12, 18, 24, 29

FOOD CONSUMPTION: Yes

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: stomach gland, liver, gall bladder, kidneys, uterus

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
-determination of number of fetuses alive: yes
-determination of number of dead fetuses: yes
-determination of sex ratio: yes
- External examinations: Yes, all per litter
- Soft tissue examinations: Yes, all per litter
- Skeletal examinations: Yes, all per litter
- Head examinations: Yes, half per litter
Statistics:
Levene's test, ANOVA with Bonferroni prohability, t-test, Kruskal-Wallis test, Mann-Whitney U test, Fisher's exact test
Indices:
no data
Historical control data:
no data
Details on maternal toxic effects:
>= 50 mg/kg bw/day: audible respiration, ocular discharge

Key result
Dose descriptor:
NOAEL
Effect level:
5 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: >=50 mg/kg bw clinical signs including audible respiration and ocular discharge
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No developmental effects observed until the highest dose tested.
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
Developmental toxicity study according to TSCA Health Effects Test guidelines for Specific Organ/Tissue Toxicity - Developmental Toxicity (EPA, 1984,1987):
Administration of m-cresol by gavage to time-pregnant New Zealand White rabbits during organogenesis at 0.0, 5.0, 50.0, 100.0 mg/kg bw/d caused clinical signs of toxicity including audible respiration and ocular discharge from 50 mg/kg bw/d onwards (NOAEL (maternal toxicity) 5.0 mg/kg bw/d). No developmental effects were seen at any dosage employed (NOAEL (developmental toxicity) 100 mg/kg bw/d).
Reason / purpose:
read-across source
Reference
Endpoint:
developmental toxicity
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:
other: TSCA Health Effects Test guidelines for Specific Organ/Tissue Toxicity - Developmental Toxicity (EPA, 1984,1987)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding labarotory, Kingston, NY, USA
- Age at study initiation: 56 days at arrival
- Weight at study initiation: 228-231g
- Housing: after mating: singly
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72
- Humidity (%): 40 - 60
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Dosing formulations were prepared by weighing the amount of test chemical into a volumetric flask and diluting to volume with certified corn oil.
The resulting solutions were mixed by repeated inversions and stored at room temperature.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
A standard stock solution (1 mg/mL) was prepared as needed by weighing 50 mg m-cresol into a 50 mL volumetric flask and diluting to volume with propanol. Standards ranging from 10 to 100 ng/mL were prepared by diluting the stock solution with
propanol. 10 µL of each standard was injected onto the HPLC. The actual conentration of each dosing solution was calculated from the equitation for the standard curve developed by linear regression.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
day 6 through day 15 of gestation
Frequency of treatment:
daily
Duration of test:
gd 21 (scheduled sacrifice)
Dose / conc.:
30 mg/kg bw/day
Dose / conc.:
175 mg/kg bw/day
Dose / conc.:
450 mg/kg bw/day
No. of animals per sex per dose:
25 females/ group, 50 control females
Control animals:
yes, concurrent vehicle
Details on study design:
no further data
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: gd 0, 6, 11, 15, 21

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined throughout gestation gd 0-21

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: body weight, liver, gravid uterine weight, number of corpora lutea, number and status of implantation sites


Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes, all per litter
- Soft tissue examinations: Yes, half per litter
- Skeletal examinations: Yes, half per litter
- Head examinations: Yes, half per litter
Statistics:
Levene's test, ANOVA, t-test with Bonferroni prohabilities, Kruskal-Wallis test, Mann-Whitney U test, Fishers exact test
Indices:
no data
Historical control data:
no data
Clinical signs:
effects observed, treatment-related
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
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
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:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
not specified
Details on maternal toxic effects:
no mortality,
no treatment-related abortions or early delivery,
no treatment related lesions in dams at scheduled sacrifice

450 mg/kg bw/day (significant changes only)
significant reduction in mean maternal body weights:
gd 11: 261 g versus 276 g in controls
gd 15: 281 g versus 300 g in controls
reduction in mean weight gain during dosing
reduced mean gestational weight gain
gd 0-21: 145 g versus 163 g in controls
clinical signs of toxicity:
predominantly hypoactivity, ataxia, tremors, twitches, prone positioning, audible rtespiration, perioral wetness
reduction in mean food consumption
pretratment period: day 6-9: 15 g versus 21 g of controls
treatment period gd 6-15: 19 g versus 22 g of controls
relative (not absolute) liver weight was increased
4.9 % versus 4.52 % in controls
Key result
Dose descriptor:
NOAEL
Effect level:
175 mg/kg bw/day
Basis for effect level:
other: 450 mg/kg bw/day: significant reduction in periodic maternal body weights and weight gain during the dosing period in addition with clinical signs of toxicity
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Key result
Dose descriptor:
NOAEL
Effect level:
450 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No developmental effects observed until the highest dose tested.
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
Developmental toxicity study according to TSCA Health Effects Test guidelines for Specific Organ/Tissue Toxicity - Developmental Toxicity (EPA, 1984,1987):
Administration of m-cresol by gavage to time-pregnant-Sprague Dawley rats during organogenesis at 0.0, 30, 175, 450 mg/kg bw/d resulted in maternal toxicity at 450 mg/kg bw/day including significant reduction in periodic maternal body weights and weight gain during the dosing period in addition with clinical signs of toxicity (NOAEL (maternal toxicity) 175 mg/kg bw/d). m-Cresol did not induce fetotoxicity or malformations at any dose level tested (NOAEL (developmental toxicity) >450 mg/kg bw).
Reason / purpose:
read-across source
Reference
Endpoint:
developmental toxicity
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:
other: TSCA Health Effects Test Guidelines for Specific Organ/Tessue Toxicity-Developmental Toxicity (EPA, 1984, 1987)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton-Dutchland Laboratories Inc., Denver, PA, USA
- Age at study initiation: 5.5 months
- Weight at study initiation: 2.5 kg
- Housing: after mating: singly
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72
- Humidity (%): 40-60
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Dosing formulations were prepared by weighing the amount of test chemical into a volumetric flask and diluting to volume with certified corn oil. The resulting solutions were mixed by repeated inversions and stored at room temperature.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
A standard stock solution (1 mg/mL) was prepared as needed by weighing 50 mg o-cresol into a 50 mL volumetric flask and ddiluting to volume with propanol. Standards ranging from 10 to 100 ng/mL were prepared by diluting the stock solution with propanol. 10 mL of each standard was injected onto the HPLC. The actual concentration of each dosing solution was calculated from the equitation for the standard curve developed by linear regression.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
13 d (gd 6-18)
Frequency of treatment:
once daily
Duration of test:
until gd 29
Dose / conc.:
5 mg/kg bw/day
Dose / conc.:
50 mg/kg bw/day
Dose / conc.:
100 mg/kg bw/day
No. of animals per sex per dose:
14 females /group, control females: 28
Control animals:
yes, concurrent vehicle
Details on study design:
no further details
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: gd 0,6, 12, 18, 24, 29

FOOD CONSUMPTION Yes

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: stomach gland, liver, gall bladder, kidneys, uterus
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
-determination of the number of fetuses alive: yes
-determination of the number of dead fetuses: yes
-determination of sex ratio: yes
- External examinations: Yes, all per litter
- Soft tissue examinations: Yes, all per litter
- Skeletal examinations: Yes, all per litter
- Head examinations: Yes, half per litter
Statistics:
Levene's test, ANOVA with Bonferroni prohability, pooled t-test, Kruskal -Wallis test, Mann-Whitney U test, Fisher's exact test
Indices:
no data
Historical control data:
no data
Clinical signs:
effects observed, treatment-related
Dermal irritation (if dermal study):
not examined
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 specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
not specified
Details on maternal toxic effects:
all groups:
no treatment related deaths, no significant changes in periodic maternal body weights or weight gain, no treatment related effects on food consumption, no abortions, no early deliveries, gestational parameters were not affected
clinical observations:
50.0 and 100.0 mg-group: audible respiration, ocular discharge
 

NOEL (general toxicity): 5.0 mg/kg bw/day
NOAEL (developmental): 50 mg/kg bw/day
NOAEL (maternal toxicity): 100 mg/kg bw/d
Key result
Dose descriptor:
NOAEL
Effect level:
5 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: >= 50 mg/kg bw/d: clinical signs of toxicity including hypoactivity, audible respiration, ocular discharge
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Reduction in number of live offspring:
not specified
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
effects observed, treatment-related
Skeletal malformations:
effects observed, treatment-related
Visceral malformations:
no effects observed
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
100.0 mg-group: slight fetotoxicity: ecchymosis on the head: 4/129 fetuses in 4/14 litters versus none in controls, poorly ossified sternum: 52/129 fetuses in 14/14 litters versus 62/212 fetuses in 16/23 litters
NOAEL (developmental): 50 mg/kg bw/day
Key result
Dose descriptor:
NOEL
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: 100 mg/kg bw/day: slight fetotoxicity (increased incidence of 1 external variation and 1 skeletal variation) in the absence of any other indications of toxicity for the conceptus
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: ecchymosis on the head / poorly ossified sternum
Description (incidence and severity):
1 external variation and 1 skeletal variation at 100 mg/kg bw/day
Key result
Developmental effects observed:
no
Conclusions:
Developmetal toxicity study according to TSCA Health Effects Test Guidelines for Specific Organ/Tessue Toxicity-Developmental Toxicity (EPA, 1984, 1987):
Administration of o-cresol by gavage to time-pregnant New Zealand White rabbits during organogenesis at 0.0, 5.0, 50.0 or 100 mg/kg bw/d caused in dams hypoactivity, audible respiration, ocular discharge from 50 mg/kg bw/d onwards (NOAEL general toxicity: 5 mg/kg bw/day) and slight fetotoxicity observed as increased incidence of one external variation and one skeletal variation in the absence of any other indications of toxicity for the conceptus at 100 mg/kg bw/day: NOEL (developmental toxicity): 50 mg/kg bw/d. Based on the fact that no abortions, no early deliveries were observed and gestational parameters were not affected: NOAEL (maternal toxicity): 100.0 mg/kg bw/d.                     
Reason / purpose:
read-across source
Reference
Endpoint:
developmental toxicity
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:
other: TSCA Health Effect Guidelines for Specific Organ/Tissue Toxicity - Developmental Toxicity (EPA 1984, 1987)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratory, Kingston, NY, USA
- Weight at study initiation: 228-230 g
- Housing: after mating singly
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 week

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72
- Humidity (%): 40-60
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Dosing formulations were prepared by weighing the amount of test chemical into a volumetric flask and diluting to volume with certified corn oil. The resulting solutions were mixed by repeated inversions and stored at room temperature.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
A standard stock solution (1 mg/mL) was prepared as needed by weighing 50 mg o-cresol into a 50 mL volumetric flask and diluting to volume with propanol. Standards ranging from 10 to 100 ng/mL were prepared by diluting the stock solution with propanol. 10 µL of each standard was injected onto the HPLC. The actual concentration of each dosing solution was calculated from the equitation for the standard curve developed by linear regression.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
10 d (gd 6-15)
Frequency of treatment:
once daily
Duration of test:
gd 21 (scheduled sacrifice)
Dose / conc.:
30 mg/kg bw/day
Dose / conc.:
175 mg/kg bw/day
Dose / conc.:
450 mg/kg bw/day
No. of animals per sex per dose:
25 females /group, 50 control females
Control animals:
yes, concurrent vehicle
Details on study design:
no further data
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: gd 0, 6, 11, 15, 21

FOOD CONSUMPTION Yes
- Food consumption for each animal determined throughout gestation gd 0-21

WATER CONSUMPTION No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: body weight, liver, gravid uterine weight, number of corpora lutea, number and status of implantation sites



Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes, all per litter
- Soft tissue examinations: Yes, all per litter
- Skeletal examinations: Yes, all per litter
- Head examinations: Yes, half per litter
Statistics:
Levene's test for equal variances, ANOVA, pooled t-test with Bonferroni probabilities for pairwise comparison, Kruskal-Wallis test, Mann-Whitney U-test, Fisher's exact test
Indices:
no data
Historical control data:
no data
Clinical signs:
effects observed, treatment-related
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
not specified
Details on maternal toxic effects:
Maternal toxicity: 450 mg-group: 4/25 died, significant reduction in periodic maternal body weight and weight gain during dosing, reduction of food consumption, clinical signs: at 450 mg/kg bw hypoactivity, ataxia, tremor, twitches, prone positioning, audible respiration, perioral wetness, for all groups: gestational parameters unaffected, no early delivery, no abortion;
 
NOAEL (maternal): 175.0 mg/kg bw/day
Key result
Dose descriptor:
NOAEL
Effect level:
175 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: 450 mg/kg bw/day: treatment related clinical signs including hypoactivity, ataxia, tremor, twitches, prone positioning, audible respiration, perioral wetness, mortality of 4 dams, statistically significant reduction in body weights and body weight gain
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Reduction in number of live offspring:
not specified
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
not specified
Skeletal malformations:
not specified
Visceral malformations:
effects observed, treatment-related
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Evaluation of offspring:
450 mg/kg bw: slight fetotoxicity:
one visceral variation: dilated lateral ventricles of the brain with no tissue compression;
NOAEL (developmental): 175.0 mg/kg bw/day
Key result
Dose descriptor:
NOEL
Effect level:
175 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: 450 mg/kg bw: slight fetotoxicity: one visceral variation: dilated lateral ventricles of the brain with no tissue compression;
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: dilated lateral ventricles of the brain with no tissue compression
Description (incidence and severity):
one variation at 450 mg/kg bw
Key result
Developmental effects observed:
no
Conclusions:
Developmental toxicity study according to TSCA Health Effect Guidelines for Specific Organ/Tissue Toxicity - Developmental Toxicity (EPA 1984, 1987):
Administration of o-cresol by gavage to time-pregnant Sprague-Dawley rats during organogenesis at 0.0, 30.0, 175.0, 450.0 mg/kg bw/d resulted in significant maternal toxicity at 450 mg/kg bw/d including treatment related clinical signs (hypoactivity, ataxia, tremor, twitches, prone positioning, audible respiration, perioral wetness), mortality of 4 dams, statistically significant reduction in body weights and body weight gain (NOAEL (maternal toxicity) 175 mg/kg bw/d). Slight fetotoxicity only at 450 mg/kg bw/d as one visceral variation (dilatated lateral ventricles of the brain with no tissue compression). Thus, the NOEL (developmental toxicity) is 175 mg/kg bw/d.

Data source

Materials and methods

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
rat
Effect level:
175 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: 450 mg/kg bw/day: significant reduction in periodic maternal body weights and weight gains in addition with clinical signs of toxicity / mortality
Remarks on result:
other: Source, CAS 95-48-7, o-cresol / CAS106-44-5, p-cresol / CAS 108-34-9, m-cresol; CMA, 1988
Key result
Dose descriptor:
NOAEL
Remarks:
rabbit
Effect level:
5 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: >= 50 mg/kg bw/d: clinical signs of toxicity /mortality
Remarks on result:
other: Source, CAS 95-48-7, o-cresol / CAS106-44-5, p-cresol / CAS 108-34-9, m-cresol; CMA, 1988

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Details on embryotoxic / teratogenic effects:
In the result table below the most critical and relevant 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 108-34-9: m-cresol: NOAEL (fetuses, rat) 450 mg/kg bw/day / NOAEL (fetuses, rabbit) 100 mg/kg bw/day (no developmental effects observed until the highest dose tested); CMA, 1988
Source CAS 106-44-5: p-cresol: NOAEL (fetuses, rabbit) 100 mg/kg bw/day (no developmental effects observed until the highest dose tested); CMA, 1988

Effect levels (fetuses)

open allclose all
Key result
Dose descriptor:
NOEL
Remarks:
rat
Effect level:
175 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: 450 mg/kg bw: slight fetotoxicity (o-cr.: visceral variation (dilated lateral ventricles of the brain with no tissue compression); p-cr.: three skeletal variations consistent with reduced fetal body weight)
Remarks on result:
other: Source, CAS 95-48-7, o-cresol / CAS106-44-5, p-cresol; CMA, 1988
Key result
Dose descriptor:
NOEL
Remarks:
rabbit
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: 100 mg/kg bw/day: slight fetotoxicity (increased incidence of 1 external variation and 1 skeletal variation) in the absence of any other indications of toxicity for the conceptus
Remarks on result:
other: Source, CAS 95-48-7, o-cresol, CMA, 1988

Fetal abnormalities

open allclose all
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: o-cr.: dilated lateral ventricles of the brain with no tissue compression; p-cresol: skeletal variations (reduced ossification)
Description (incidence and severity):
at 450 mg/kg bw (rat); Source, CAS 95-48-7, o-cresol / CAS106-44-5, p-cresol; CMA, 1988
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: ecchymosis on the head / poorly ossified sternum
Description (incidence and severity):
1 external variation and 1 skeletal variation at 100 mg/kg bw/day (rabbit); Source, CAS 95-48-7, o-cresol, CMA, 1988

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Developmental toxicity studies in rats and rabbits are available with the three isomers o-, p- and m-cresol. Treatment with the source substances resulted in NOAELs for maternal toxicity of 175 mg/kg bw/day in rats and 5 mg/kg bw/day in rabbits. For o- and p-cresol slight developmental toxicity in rats was observed in the hightest dose resulting in a NOEL of 175 mg/kg bw/day for developmental toxicity. In rabbits developmental effects in the highest dose for o-cresol was observed, leading to a NOEL for developmental toxicity of 50 mg/kg bw/day. All effects observed were variations which are considered to be of low concern as a variation can also be defined as a change that occurs within normal population under investigation and is unlikely to affect adversely survival or health. No abnormality, anomaly or malformation was observed. Thus, all effects observed are considered to be not adverse. m-cresol did not show any developmental effects up to the highest dose tested in rats and rabbits. Based on all available information (weight-of-evidence), following an analogue read-across approach, the NOAEL for developmental toxicity of Tar acids, Xylenol fraction (CAS 84989-06-0) is considered to be 100 mg/kg bw/day; this value is taken forward for hazard and subsequent risk assessment.
Executive summary:

Several developmental toxicity studies are available for the source substances o-, p-, and m-cresol in rats and rabbits. No adverse effects were observed in rats and rabbits regarding developmental toxicity up to the highest dose tested (for rats 450 mg/kg bw/day, for rabbits 100 mg/kg bw/day). Whilst no studies on toxicity to development have been conducted with tar acid, xylenol fraction, the experimental data available on cresols are considered to be suitable and meaningful to predict toxicity to reproduction (fertility) of the target substance.