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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1988
Report Date:
1988

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: TSCA Health Effects Test guidelines for Specific Organ/Tissue Toxicity - Developmental Toxicity (EPA, 1984,1987)
Principles of method if other than guideline:
The potential of p-cresol to produce maternal and developmental toxicity (including teratogenicity) when administered by gavage during organogenesis was evaluated in Sprague-Dawley CD rats.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Test substance: p-cresol, purity = 98.93%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, NY
- 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

Administration / exposure

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 stocj 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)
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 30, 175, 450 mg/kg bw in corn oil
Basis:
actual ingested
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

Examinations

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

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
see section "Remarks on results"

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
175 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
175 mg/kg bw/day
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
see section "remarks on results"

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

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.

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 an 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.

Applicant's summary and conclusion

Executive summary:

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

developmental toxicity is 175 mg/kg bw/d.