m-cresol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity was examined in a two-generation toxicity study according to TSCA Health Effects Test Guideline for specific organ/tissue toxicity - Reproduction/Fertility effects (Union Carbide for CMA 1988). Sprague-Dawley rats were given daily 0, 30, 175, or 450 mg/kg bw/day m-cresol in corn oil by gavage. No effects on fertility were detected despite overt general toxicity. Thus, the NOAEL(fertility) was 450 mg/kg bw/day and the NOAEL(general toxicity) was 30 mg/kg bw/day.

Two studies have evaluated the effects of o-cresol and a mixture of m/p-cresol on reproductive function end points in CD-1 mice using a continuous breeding protocol (NTP 1992). End points evaluated included fertility, mean number of litters per pair, live litter size, weight and histopathology of reproductive organs, vaginal cytology, and sperm parameters. Both studies started with a 14-week cohabitation period in which males and females received the test material in the diet. The highest doses during this period were 660 mg/kg/day for o-cresol and 1,682 mg/kg/day for m/p-cresol. No significant alterations were observed with o-cresol at any stage of the study. However, the highest dose of m/p-cresol significantly decreased the number of live pups/litter and increased the cumulative days to litter; a dose level of 1,390 mg/kg/day was a NOAEL. To determine which sex was the affected sex during the cohabitation period, a 1-week crossover mating trial was conducted, but the results indicated that either sex could have been affected. In neither study was fertility affected. In addition, sperm parameters and gross and microscopic morphology of reproductive organs were not affected by treatment with the cresols (U. S. DEPART- MENT OF HEALTH AND HUMAN SERVICES, Public Health Service, Agency for Toxic Substances and Disease RegistrySeptember 2008).

Link to relevant study records

Reference

Endpoint:

two-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

other: TSCA Health Effects Test Guideline for specific organ/tissue toxicity - Reproduction/Fertility effects (EPA, 1983)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, NY
- Age at study initiation: 6 wks (P) ;
- Weight at study initiation: (P) Males: 189.4-191.1 g; Females: 141.1-142.7 g;
- Housing: initially 2/same sex during acclimation period; and then singly except for the cohabitation and lactation periods
- Diet : ad libitum
- Water : ad libitum
- Acclimation period: 14 days


ENVIRONMENTAL CONDITIONS
- Temperature :68-74°F
- 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.

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: 21 days
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After 7 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged singly
- Any other deviations from standard protocol: no

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

A standard stock solution was prepared (1mg/ml propanol),which was used to prepare standards ranging fron 10 to 100 ng/µl. With these solutiower a standard curve was generated using HPLC. Dosing formulation concentrations were veryfied by preparing aliquots which were injected onto the HPLC column. The measured concentration of each dosing solution was then calculated from the equitation for the standard curve developed by linear regression.

Duration of treatment / exposure:

Exposure period: 27 w
Premating exposure period (males): 10 w
Premating exposure period (females): 10 w
Duration of test: 29 w

Frequency of treatment:

P- and F1-generation: once/day, 5 days/week
F1- generation producing F2: once/day , 7 days/week

Details on study schedule:

at day 28-40 post partum F1 animals selected to be parents of the F2 generation were gavaged with their respective formulations for at least
11 weeks 5 days/week.
the F1 animals ere approximately 15 to 17 weeks of age at the initiation of the mating period.
They were dosed from that time point 7 days/week. Mating procedure was performed as done with the P-generation

Remarks:

Doses / Concentrations:
0, 30, 175 or 450 mg/kg bw/d in corn oil (P and F1, m/f)
Basis:
actual ingested

No. of animals per sex per dose:

25 rat/sex/dose

Control animals:

yes, concurrent vehicle

Details on study design:

no further data

Positive control:

no data

Parental animals: Observations and examinations:

Mortality: twice daily
General conditon: daily throughout the course of the study including skin and fur, eyes and mucous membranes, respiratory symptoms, circulatory system, autonomic and central nervous system, somatomotor activity, behavior pattern
Body weight determination
male, female: initially and then weekly until mating
female during gestation : day 0, 7, 13, 20 post partum: day 0, 4, 7, 14, 21
Food consumption
measured weekly during pre-breed dosing period for P and F1 generation; all other phases of this sutdy determination was made visually

Oestrous cyclicity (parental animals):

vaginal smears were examined to determine pregnancy

Sperm parameters (parental animals):

no data

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter (4 sex/litter as nearly as possible); excess pups were killed and discarded.


PARAMETERS EXAMINED
The following parameters were examined in F1 / F2 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities


GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death/was not determined for pups born or found dead.

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals after the completion of the mating period
- Maternal animals: All surviving animals after the F1 and F2 litters have been weaned


GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
A complete gross necropsy was conducted for any parental animal dying on test.


HISTOPATHOLOGY
Male and female adult rats of the highest dose groups and the controls
The tissues as indicated below, were prepared for microscopic examination and weighed, respectively:
pituitary, vagina, uterus, ovaries, testes, epididymides, seminal vesicles, prostate and other tissues with gross lesions identified as being
potentially treatment-related.
A complete histopathological examination was conducted for any parental animal dying on test.

Postmortem examinations (offspring):

All pups dying during lactation are neccropsied to investigate the cause of death.

At weaning , postnatal day 21 , 1 female and 1 male from each F1 litter is selected on a random basis to become parents of the next
generation.
The remaining offspring is cexamined for gross external abnormalities , euthanized and discarded.

Statistics:

Levine's test, ANOVA, t-test corrected by Bonferroni method, Kruskal-Wallis test, Mann Whitney U-test, Fishers exact test

Reproductive indices:

calculated for P and F1 animals:
Mating Index (%):
---for males: number of males impregnating females devided through the total number of males paired multiplied by 100
---for females: number of females with copulation plugs devided through the mumger of females cohabited multiplied by 100

Fertility Index(%):
---for males: number of males producing pregnant females devided through number of males impregnating females multiplied by 100
---for females. number of pregnant females devided through number of plug-positive females multiplied by 100

Gestational Index (%)
number of females with live litters devided through number of females pregnant multiplied by 100

Offspring viability indices:

calculated for F1 and for F2 animals
live birth index
number of live pups at birth devided through the toal number of pups born
4-Day Survival Index (%):
number of pups surviving 4 days devided through total number of live pups at birth multiplied by 100
7-Day Survival Index(%):
number of pups surviving 7 days devided through total number of live pups at 4 days multiplied by 100
14- Day Survival Index (%):
number of pups surviving 14 days devided through total number of live pups at 7 days multiplied by 100
21-day survival index (%):
number of pups surviving 21 days devided through total number of live pups at 14 days multiplied by 100
Lactation index (%):
number of pups surviving 21 days devided through total number of live pups at 4 days multiplied by 100

Clinical signs:

effects observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Other effects:

not examined

Reproductive function: oestrous cycle:

effects observed, treatment-related

Reproductive function: sperm measures:

effects observed, treatment-related

Reproductive performance:

no effects observed

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
P, pre-breed period:
450 mg/kg bw
clinical signs: hypoactivity, ataxia, twitches, tremors, prostration, unkempt appearance(males), urine stains, audible respiration, perinasal encrustration, perioral wetness
mortality 7/25 males; 5/25 females
175 mg/kg bw/day
sacrifice due to trauma of 1/25 male
F1, pre-breed period
450 mg/kg bw/day:clinical signs: hypoactivity, ataxia, twitches, tremors, prostration, unkempt appearance(males), urine stains, audible respiration, perinasal encrustration, perioral wetness (also at 175 mg/kg bw/day)
mortality: 450mg/kg bw/day: 3 males and 4 females
F1 breed period,
mortality during gestation: 1 female in control and 30 and 175 mg/kg bw/day groups and 3 females in the 450 mg/kg bw/day group
mortality during lactation : 3 females at 450 mg/kg bw/day group

BODY WEIGHT (PARENTAL ANIMALS)
P, pre-breed period:
450 mg/kg bw/day, male, female: reduced body weight gain
P, breed period
mortality. 450 mg/kg bw 2/20 females; 175 mg/kg bw:: 1/24 female
F1, pre-breed period:
slightly reduced body weight in males (450, and 175, 30 mg/kg bw) and in females (450 and 30 mg/kg bw/day)
F1-breed period
450, 175, 30 mg/kg bw/day: reduced bw in males
450 mg/kg bw/day females: reduced maternal gestational and lactational body weights

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
P-generation:
reproductive parameters including gestational length were unaffected by treatment
F1-generation:
reproductive parameters including gestational length were unaffected by treatment
ORGAN WEIGHTS, GROSS PATHOLOGY, HISTOPATHOLOGY (PARENTAL ANIMALS).
all groups:
there were no treatment related gross or histological lesions in P, F1 andF2 rats which survivied to sheduled sacrifice
animals that died prior sheduled:
P and F1 males: lesions in brain, lungsm thymic regions, decrease in number of sperm in epididymides, atrophied seminal vesicles and coagulation glands, epididymitis
P and F1 females: lesions in brain and lungs

OTHER FINDINGS (PARENTAL ANIMALS)

Dose descriptor:

other: NOAEL (offspring)

Effect level:

ca. 175 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: In F1 the female pups had reduced body weights in the highest dose tested, but pup survival was not affected. In F2 pup body weight , pup body weight gain and pup lacational index were reduced and pup mortality was increased at the highest dose.

Remarks on result:

other: Generation: F1 and F2

Dose descriptor:

other: NOAEL (fertility)

Effect level:

ca. 450 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: Effects on reproduction function or on morphology of reproductive tissues were not detected.

Remarks on result:

other: Generation: P and F1

Dose descriptor:

other: NOAEL (general toxicity)

Effect level:

ca. 30 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: >= 175 mg/kg bw/d: signs of overt toxicity : hypoactivity, ataxia, twitches, tremors, prostration, urine staining, audible respiration and perioral wetness

Remarks on result:

other: Generation: P and F1

Clinical signs:

effects observed, treatment-related

Mortality / viability:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Sexual maturation:

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings:

effects observed, treatment-related

F1 offspring:
litter size, sex ratio, litter viability and pup survival were unaffected by treatment
450 mg/kg bw/day, femle: reduced female pup body weight
F2-generation:
litter size andsex ratio were unaffected by treatment
450 mg7kg bw/day lactational index was reduced, pups body weight and body weight gain was reduced and pup deaths increased
Pathology:
all groups:
there were no treatment related gross or histological lesions in F1 and F2 rats which survivied to sheduled
sacrifice.

Dose descriptor:

NOAEL

Remarks:

offspring

Generation:

F1

Effect level:

175 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: In F1 the female pups had reduced body weights in the highest dose tested, but pup survival was not affected. In F2 pup body weight , pup body weight gain and pup lactational index were reduced and pup mortality was increased at the highest dose.

Critical effects observed:

yes

Lowest effective dose / conc.:

450 mg/kg bw/day (nominal)

Organ:

other: In F1 the female pups had reduced body weights in the highest dose tested, but pup survival was not affected. In F2 pup body weight , pup body weight gain and pup lactational index were reduced and pup mortality was increased at the highest dose.

Treatment related:

yes

Dose response relationship:

yes

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

175 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: In F1 the female pups had reduced body weights in the highest dose tested, but pup survival was not affected. In F2 pup body weight , pup body weight gain and pup lactational index were reduced and pup mortality was increased at the highest dose.

Critical effects observed:

yes

Lowest effective dose / conc.:

450 mg/kg bw/day (nominal)

System:

other: In F1 the female pups had reduced body weights in the highest dose tested, but pup survival was not affected. In F2 pup body weight , pup body weight gain and pup lactational index were reduced and pup mortality was increased at the highest dose.

Treatment related:

yes

Dose response relationship:

yes

Reproductive effects observed:

no

F0: pre-breed dosing period:
450 mg/kg: f,m: significant reduced body weight, signs of toxicity: hypoactivity, ataxia, twitches, tremors, prostration, unkempt appearance(males), urine stains, audible respiration perinasal encrustration and perioral wetness; mortality: 7/25 m, 5/25 f;
175 mg/kg: sacrifice due to trauma 1/25 m.

F0: breed period:
450 mg/kg: maternal gestat. and lactat. bw sign. reduced,

Mortality: 450 mg/kg: 2/20 f; 175 mg/kg: 1/25 f;
Reproductive parameters including gestational length were unaffected by treatment.

F1:
Litter size, sex ratio, litter viability, pup survival were unaffected by treatment;

450 mg/kg: reduced female pup bw.

F1 pre-breed period:
Slightly reduced bw in m (450, 175,30 mg/kg) and in f (450,30 mg/kg); signs of toxicity: 450 mg/kg bw: hypoactivity, ataxia twitches, tremors prostration urine stains, audible respiration and perioral wetness (also at 175 mg/kg females);

Mortality: 450 mg/kg 3 m and 4 f.

F1 breed period:
450, 175, 30 mg/kg: reduced bw in m; maternal gestational and lactational bw reduced in 450 mg/kg f;

Mortality during gestation: 1 f each at control, 30, 175 mg/kg and 3 f at 450 mg/kg, mortality during lactation: 3 f at 450 mg/kg.
Reproductive parameters including gestational parameters were unaffected by treatment.

F2:
litter size and sex ratio unaffected; F2 pup lactational index was reduced at 450 mg/kg
450 mg/kg: pup bw and pup bw gain was reduced and pup deaths increased.

Pathology:
All groups: there were no treatment related gross lesions or histologic lesions in F0, F1 and F2 rats which survived to scheduled sacrifice.
Dead prior to schedule: F0,F1 m: lesions in brain , thymic regions, lungs, decrease in number of sperm in epididymides, atrophied seminal vesicles and coagulation glands, epididymitis;

F0,F1 f: lesions in the brain, lungs.

NOAEL (fertility): 450 mg/kg bw

The exact A/D ratio cannot be calculated. But it can be assumed that the A/D ratio would be less than 1 (<30.0 mg/kg bw/day/175.0 mg/kg bw) indicating no increased risk to
offspring in the absence of parental toxicity.

A/D ratio: exposure level at which there were no observable effects in adults/the exposure level at which there were no observable effects in offspring

Executive summary:

Two-generation study according to TSCA Health Effects Test Guideline for specific organ/tissue toxicity - Reproduction/Fertility effects (EPA, 1983):

Sprague-Dawley rats were given daily 0, 30, 175, 450 mg/kg bw/daym-cresol in corn oil by gavage. Effects on reproductive function or on morphology of reproductive tissues were not detected even at doses producing overt toxicity in adult rats (hypoactivity, ataxia, twitches, tremors, prostration,urine stains, audible respiration, and perioral wetness). The NOAEL (fertility) was 450 mg/kg bw/day. The NOAEL (toxicity) was 30 mg/kg bw/d. In F1 and F2 , litter size, sex ratio, and litter viablity was unaffected by treatment. In F1 the female pups had reduced body weights in the highest dose tested, but pup survival was not affected. In F2, pup body weight, pup body weight gain and pup lactational index were reduced and pup mortality was increased at the highest dose. Thus the NOAEL (offspring) was 175 mg/kg bw/d

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

450 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

GLP guideline study

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Two-generation study according to TSCA Health Effects Test Guideline for specific organ/tissue toxicity - Reproduction/Fertility effects (EPA, 1983): Sprague-Dawley rats were given daily 0, 30, 175, or 450 mg/kg bw/day m-cresol in corn oil by gavage.

Effects on reproductive function or on morphology of reproductive tissues were not detected even at doses producing overt toxicity in adult rats (hypoactivity, ataxia, twitches, tremors, prostration,urine stains, audible respiration, and perioral wetness). The NOAEL (fertility) was 450 mg/kg bw/day. The NOAEL (toxicity) was 30 mg/kg bw/d. In F1 and F2 , litter size, sex ratio, and litter viablity was unaffected by treatment. In F1 the female pups had reduced body weights in the highest dose tested, but pup survival was not affected. In F2, pup body weight, pup body weight gain and pup lactational index were reduced and pup mortality was increased at the highest dose. Thus the NOAEL (offspring) was 175 mg/kg bw/d

Effects on developmental toxicity

Description of key information

In a developmental toxicity study according to TSCA Health Effects Test guidelines for Specific Organ/Tissue Toxicity - Developmental Toxicity (CMA 1988): m-cresol was administered by gavage to time-pregnant-Sprague Dawley rats during organogenesis at 0.0, 30, 175, 450 mg/kg bw/d and resulted in maternal toxicity at 450 mg/kg bw/day (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/day).

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

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 or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding labarotory, Kingston, NY
- 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)

Remarks:

0.0, 30, 175, 450 mg/kg bw/d.

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 implantaion sites


OTHER:

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

Details on maternal toxic effects:

Maternal toxic effects: yes

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 canges 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 inmean 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

Dose descriptor:

NOAEL

Effect level:

ca. 175 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

ca. 450 mg/kg bw/day

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects: no effects

Details on embryotoxic / teratogenic effects: no effects

Dose descriptor:

NOAEL

Effect level:

450 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: m-cresol did not induce fetotoxicity or malformations at any dose level tested.

Abnormalities:

no effects observed

Developmental effects observed:

no

Maternal toxicity: no deaths, no abortions or early deliveries
450 mg/kg:
Significant reduced food consumption, reduced maternal body weights and weight gain during dosing period; reduced gestational weight gain (day 0-21).
Clinical signs of toxicity: hypoactivity, ataxia, tremors, audible respiration, perioral wetness; increased relative but not absolute liver weights no embryotoxicity or teratogenicity was observed at any dosage level.

Conclusions:

m-Cresol did not induce fetotoxicity or malformations at any dose level tested.(NOAEL (developmental toxicity) 450 mg/kg bw).

Executive summary:

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).

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

450 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP guideline study

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Developmental toxicity study was performed 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).

In addition. in a further developmental toxicity study according to TSCA Health Effects Test guidelines for Specific Organ/Tissue Toxicity - Developmental Toxicity (EPA, 1984,1987): m-cresol was administered by gavage to time-pregnant New Zealnd White rabbits during organogenesis at 0.0, 5.0, 50.0, 100.0 mg/kg bw/d resulting in 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).

Toxicity to reproduction: other studies

Additional information

no data

Justification for classification or non-classification

No classification or labelling is required.