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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Further information is included in the attachment entitled “Read-across between p-tert-amylphenol (CAS 80-46-6) and Sodium p-tertiary amylphenol (CAS 31366-95-7) and p-tert-butylphenol (CAS 98-54-4).

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The target and source chemicals display a high structural similarity.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target chemical is p-tert-amylphenol and the two source chemicals are Sodium p-tertiary amylphenol and p-tert-butylphenol.

3. ANALOGUE APPROACH JUSTIFICATION
All substances consist of a branched tertiary alkyl chain attached to a phenolic ring in the 4-position (para) to the hydroxyl substituent and are close structural analogues. In addition, the target and source chemicals display similar physico-chemical properties. Based on similar structure and function, it can be assumed that Phase 1 and Phrase 2 metabolism will be similar.

4. DATA MATRIX
A detailed data matrix can be found in the attached read-across document.
Reason / purpose for cross-reference:
read-across source
Sex:
male/female
Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
during gestation with 2500/7500 ppm diets
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
during gestation with 2500/7500 ppm diets
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Test substance intake: reduced during gestation with weight loss
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS) There were no clinical observations considered to be related to treatment with
p-tertbutylphenol in either generation.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
F0 – adults: At 7500 p.p.m. there was a decrease in weight gain seen in F0 animals over the first week of treatment. The overall weight gain of the
animals over the treatment period (prior to mating) was ca 70% of the Control weight gain, although absolute body weight was generally 80-90% of
the Controls. At 2500 p.p.m. in both sexes and 800 p.p.m. in females, there was a slight but similar decrease in weight gain, compared to the higher dose. There were no clear effects of treatment in males at 800 p.p.m.

F1 - adults: At 7500 p.p.m. the mean body weight of weaned animals (nominal Week 4) was 79% of the Control weight in males and 84% of the Control weight in females. By the end of the treatment period (prior to mating for females) body weight was still ca 80% of the Controls’ body weight; weight gain throughout was lower than that of the Controls (ca 80%). At 2500 p.p.m. and 800 p.p.m. the mean body weight of weaned animals (nominal
Week 4) was 92% of the Controls for males and 91% and 94% for females.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS): In the F0 generation, in both sexes, the achieved intake was lower than expected in the
highest dose during the first week, and it was considered most likely that this reflected the low food consumption over that period. Thereafter the
intake was as expected, with the intake decreasing proportionally as the animals grew.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS):The stages of the oestrus cycles and their mean duration were similar in all groups.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): There were no effects on the sperm motility, count or morphology at any of the dose levels applied, or in either generation. A lower cauda weight and testes weight in F1 animals was considered most likely to reflect the lower body weight, and did not affect any of the counts.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): There were no clear effects of treatment on mating performance, fertility or duration of
gestation in either generation.

ORGAN WEIGHTS (PARENTAL ANIMALS): Males: here were no statistically significant effects on organ weights at 7500ppm and 2500 p.p.m., and there were none at 800 p.p.m in either the F0 or F1 males.
Females F0: After covariance analysis, decreases in adrenal gland, ovary and pituitary gland weights were significant (P<0.001).
Females F1: Following covariance analysis a number of organs at 7500 p.p.m. achieved significance, and adrenal gland, brain, kidney, ovaries,
pituitary gland and uterus were lower than Control. There was a significant increase in liver weight. At 2500 p.p.m. adrenal gland and brain weight
were lower than Controls, and achieved significance by analysis of variance and covariance. A slightly higher liver weight achieved significance after covariance analysis. There were no other effects on organ weights at 2500 p.p.m., and there were none at 800 p.p.m for either F0 or F1 females.

GROSS PATHOLOGY (PARENTAL ANIMALS):
There were no findings at necropsy considered to reflect an obvious effect of treatment on either the F0 or F1 adults.
In the F0 generation, there was no clear pattern of effect on follicle type or incidence. However, in the F1 generation, at 7500 p.p.m. there was an
increase in the incidence of primordial follicles with a concurrent decrease in the incidence of growing follicles. At 800 and 2500 p.p.m. the type and incidence of follicles was essentially similar to Controls.

HISTOPATHOLOGY (PARENTAL ANIMALS): In the F0 animals there was an increase in atrophy of the vaginal epithelium with 7/28 animals at
2500 p.p.m. and 12/28 animals at 7500 p.p.m. affected. The severity of the finding was split approximately equally between minimal and mild.
In the F1 animals, this finding was increased in severity and incidence at 7500 p.p.m. The severity was mild in the majority of animals (79%) with a
total of 14/24 animals. However there was no atrophy of the vaginal epithelium recorded at 2500 p.p.m.
There was no atrophy of the vaginal epithelium recorded at 800 p.p.m., and no other findings of note at any dose level in either generation.

OTHER FINDINGS (PARENTAL ANIMALS): In the F0 and F1 generations there were a lower number of implant sites and live pups born at 7500 p.p.m.
The lower numbers of implants may be associated with the lower body weights.
Key result
Dose descriptor:
NOEL
Effect level:
70 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other:
Remarks on result:
other: Generation: P and F1
Key result
Dose descriptor:
LOAEL
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Reduced maternal weights
Clinical signs:
no effects observed
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
increased mortality in F1 pups at 7500 p.p.m
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
reduced at 2500 and 7500 p.p.m. in F1&F2
Sexual maturation:
effects observed, treatment-related
Description (incidence and severity):
delays of 3 or 4 days after controls
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
detailed below
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
VIABILITY (OFFSPRING): F0 generation - at 7500 p.p.m. pup survival was poor, particularly over Days 0-4 of lactation when 6 different litters had more than 3 pups dying, and in 2 of these litters all pups died. F1 generation: at 7500 p.p.m. the litter size was clearly smaller than that at any other
level. The survival of these smaller litters was good and exceeded the performance of the Controls. There were no effects of treatment detected at
800 or 2500 p.p.m. There were no effects on sex ratios in either generation.

CLINICAL SIGNS (OFFSPRING): No treatment related effects were seen.

BODY WEIGHT (OFFSPRING): At 7500 p.p.m., in both generations, pup weights at birth were comparable to those of the Controls but the litter size was slightly smaller, and as a result, litter weight was lower than Controls on Day 1 of lactation. After Day 1 of lactation pup weight gain was less than
Control, and by Day 21 of lactation was ca 20% lower than Control weights. Litter weight gain was similarly affected but in the F0 generation this was
also accompanied by a decrease in pup survival. At 2500 p.p.m. pup weight in both generations was lower than Controls from Day 14 of
lactation; with a concurrent decrease in litter weight gain also. There were no effects on litter or pup weight at 800 p.p.m. in either generation.

SEXUAL MATURATION (OFFSPRING): At 7500 p.p.m. vaginal opening and preputial separation occurred 3 and 4 days later than Controls, respectively. The age and body weight at preputial separation or vaginal opening in animals treated with 2500 p.p.m. and 800 p.p.m. p-tertbutylphenol were
essentially similar to Controls.There were no effects of treatment on ano-genital distance, or on nipple/areolar retention.

ORGAN WEIGHTS (OFFSPRING):
Males F0 generation, F1 production
In males treated at 7500 p.p.m. body weight, spleen and thymus weights were all significantly lower than Control.
Brain weight was reduced but did not attain significance. Following covariance analysis none of the findings were evident.
There were no effects on organ weight at 800 or 2500 p.p.m.

Males F1 generation, F2 production
in males treated at 7500 p.p.m., body weight, brain, spleen and thymus weights were all significantly reduced.
Brain weight was reduced but did not attain significance. Following covariance analysis, spleen weight was significantly but slightly lower.
In addition, absolute spleen weight at 2500 p.p.m. was also significantly lower, although this was no longer evident after covariance analysis.
There were no other effects on organ weights at 2500 p.p.m., and there were none at 800 p.p.m.

Females F0 generation, F1 production
In females treated at 7500 p.p.m. all of the same parameters as males were lower, with the brain and thymus slightly reduced at 2500 p.p.m. also.
Following covariance analysis thymus weights at 2500 and 7500 p.p.m. remained marginally lower.
There were no other effects on organ weights at 2500 p.p.m., and there were none at 800 p.p.m.

Females F1 generation, F2 production
In females treated at 7500 p.p.m. body weight, brain and spleen weight were statistically significantly lower than Control; thymus weight was also
lower but did not attain statistical significance. Following covariance analysis, spleen weight was lower than the Control spleen weight, although the
difference did not attain significance. All other weights appeared to be comparable to Controls.
There were no effects on organ weights at 800 or 2500 p.p.m.

GROSS PATHOLOGY (OFFSPRING): At necropsy, there were no findings considered to reflect an obvious effect of treatment on the weanlings of either generation.

HISTOPATHOLOGY (OFFSPRING): There were no findings in the tissue pathology assessed in the offspring that were treatment related.
Key result
Dose descriptor:
LOAEL
Generation:
F1
Effect level:
600 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Increased pup mortality rate; an increase in the incidence of primordial follicles with a concurrent decrease in the incidence of growing follicles; increase in atrophy of the vaginal epithelium.
Key result
Reproductive effects observed:
not specified
Conclusions:
In general, there was no obvious evidence of poorer performance in the second generation compared with the first.
Effects of treatment on reproductive performance were reduced pup weights at 2500 and 7500 p.p.m. in both generations, and increased pup
mortality in F1 pups at 7500 p.p.m.; many of the findings reported appear to be related to maternal size or performance and/ or
direct toxicity. Other findings from this study are those noted in the ovary (follicle changes) and vaginal epithelium atrophy at 2500 and
7500 ppm..
It is therefore considered that the no observed adverse effect level (NOAEL) is 800 ppm pTBP in the diet (ca. 70 mg/kg bw/day intake).
Executive summary:

In a two-generation reproduction study p-tert butyl phenol was administered orally to Sprague Dawley rats (28 males and females F0 generation; 24 males and females F1 generation) at 0, 800, 2500 and 7500 ppm in diet yielding approximate intake levels of 0,70, 200 and 600 mg/kg bw/day.

There were no treatment related clinical signs.

There were no abnormalities noted in the pups associated with treatment.

At 2500 and 7500 p.p.m. there was a decrease in weight gain seen in F0 animals, and in both generations during gestation. In the F1 generation, overall weights of animals at these levels were lower, reflecting the lower weaning weights of these animals.

At 2500 and 7500 p.p.m. food consumption was notably reduced in F0 animals, and in F1 animals at 7500 p.p.m.

The values for achieved intake were generally proportional to the dietary concentrations.

The stages of the oestrus cycles and their mean duration were similar in all groups and there were no clear effects of treatment on mating performance, fertility or duration of gestation in either generation.

In the F0 and F1 generations there were a lower number of implant sites and live pups born at 7500 p.p.m. In the F1 generation, at 7500 p.p.m. there was an increase in the incidence of primordial follicles with a concurrent decrease in the incidence of growing follicles.

At 7500 p.p.m., there was an increase in atrophy of the vaginal epithelium in F0 and F1.

There were no effects on the sperm motility, count or morphology at any of the doseblevels applied, or in either generation.

There was no necropsy findings considered to reflect an obvious effect of treatment on either the F0 or F1 adults, or on the pups of either generation.

In general, there was no obvious evidence of poorer performance in the second generation compared with the first.

No effects of treatment were observed at 800ppm.

The NOAEL is 800 ppm (70 mg/kg bw/day in females).

This study is acceptable and satisfies the guideline requirement for a two-generation reproductive study (OPPTS 870.3800); OECD 416 in rat.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
70 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Good quality data. Klimisch 1 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

The justification for the use of data on a one-to-one read-across analogues substance p-tert butyl phenol is provided in an accompanying read-across report titled 'Read-across between p-tert-Amylphenol (CAS 80-46-6) and p-tert-Butylphenol (CAS 98-54-4) or sodium-p-tert-amylphenol (CAS 31366 -95 -7)'.

In a two-generation reproduction study (Clubb & Jardine, 2006), p-tert butyl phenol was administered orally to Sprague Dawley rats (28 males and females F0 generation; 24 males and females F1 generation) at 0, 800, 2500 and 7500 ppm in diet yielding approximate intake levels of 0, 70, 200 and 600 mg/kg bw/day.

There were no treatment related clinical signs. There were no abnormalities noted in the pups associated with treatment. At 200 and 600 mg/kg bw/day there was a decrease in weight gain seen in F0 animals, and in both generations during gestation. In the F1 generation, overall weights of animals at these levels were lower, reflecting the lower weaning weights of these animals. At 200 and 600 mg/kg/day food consumption was notably reduced in F0 animals, and in F1 animals at 600 mg/kg/day. The values for achieved intake were generally proportional to the dietary concentrations.

The stages of the oestrus cycles and their mean duration were similar in all groups and there were no clear effects of treatment on mating performance, fertility or duration of gestation in either generation.

In the F0 and F1 generations there were a lower number of implant sites and live pups born at 600 mg/kg/day. In the F1 generation, at 600 mg/kg/day there was an increase in the incidence of primordial follicles with a concurrent decrease in the incidence of growing follicles.

At 600 mg/kg/day, there was an increase in atrophy of the vaginal epithelium in F0 and F1. There were no effects on the sperm motility, count or morphology at any of the dose levels applied, or in either generation.

There were no necropsy findings considered to reflect an obvious effect of treatment on either the F0 or F1 adults, or on the pups of either generation. In general, there was no obvious evidence of poorer performance in the second generation compared with the first. No adverse effects of treatment were observed at 70 mg/kg/day. The observed effects at high dose are in the presence of maternal toxicity, and are considered a result of this general toxicity rather than specific targeted toxicity to the reproductive system.   Short description of key information:  Clubb & Jardine (2006) OECD guideline two-generation study on read-across analogue p-tert butyl phenol: NOAEL of 70 mg/kg/day is based on effects of systemic maternal toxicity and reduced weight gain (considered as repeat dose toxicity). There were no specific effects on reproductive function and fertility. Supporting information from an OECD guideline 422 combined repeat-dose and reproductive screening study  Justification for selection of Effect on fertility via oral route:  No study on p-tert amylphenol. Only one OECD guideline 2-gen study for structural analogue p-tert butyl phenol. Also supported by an OECD 422 study on p-tert butyl phenol from the Japanese Ministry of Health.

Effects on developmental toxicity

Description of key information
OECD guideline Teratology study on p-tert amylphenol.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
90-2-23 to 91-4-22
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study with no significant deviations from protocol
Qualifier:
according to guideline
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
Animals were housed throughout the study in an environment controlled room with a 12-hour light/12-hour dark cycle. The controls were
set to maintain a room temperature of 64-79.F and a relative humidity of 40-70%. Room temperature and relative humidity were determined and
recorded daily.
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Dosing solutions were prepared: 10, 40 and 100 mg/mL. Animals were dosed with 5 ml/kg.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical analyses indicated that Nipacide PTAP was homogeneous and stable in aqueous solution when stored for up to eight days at room
temperature. Analysis of dosing solutions resulted in,average test article recoveries ranging from 101.6 to 108.7% indicating that the solutions
were accurately prepared.
Concentration Verification Analysis Data on Week 1 for Nipacide PTAP in Corn Oil
Nominal Actual Average (mg/mL) n=2
10.73, 11.00
41.76, 40.80
107.10, 105.03

Concentration Verification Analysis Data on Week 2 for Nipacide PTAP in Corn O i l
10.55, 10.64
41.55, 41.57
102.47, 100.57
Details on mating procedure:
Animals were acclimated to the laboratory conditions for a period of 12 days prior to mating. At the conclusion of acclimation, the animals were
weighed and examined. Females determined to be suitable test subjects based on age, healthy appearance, and body weight, were cohabitated
with proven resident Sprague-Dawley Crl:CDaBR VAF/Plusa male rats. At the initiation of breeding, all females were approximately 90 days of age with body weights ranging from 220 to 266 g. Evidence of mating was determined by the presence of a copulatory plug in the vagina or a sperm positive vaginal smear. The day evidence of copulation was confirmed was designated as day 0 of gestation. At that time, the female rats were assigned
consecutively, in a block design, to study groups. Gestation day 0 body weights ranged from 215-266 g.
Duration of treatment / exposure:
The dosage preparations were administered orally by gavage as a single dose daily, from gestation day 6 through gestation day 15.
Frequency of treatment:
Once daily. The animals were dosed at approximately the same time each day.
Duration of test:
Gestation day 0 to scheduled caesarian section which took place at gestation day 20.
Remarks:
Doses / Concentrations:
0, 50, 200, 500 mg/kg bw/day
Basis:
nominal conc.
No. of animals per sex per dose:
25 females per dose group
Control animals:
yes, concurrent vehicle
Maternal examinations:
During the experimental period, all animals were observed daily for clinical signs of toxicity including physical or behavioral abnormalities.
Mortality checks were performed twice daily, in the morning and afternoon. In addition, during the treatment period, the rats were observed
between one-half and two hours following dosing for detection of overt signs of toxicity.

Individual body weights were measured on gestation days 0, 6, 9 , 12, 16 and 20. Body weight changes were calculated for the following gestation
intervals: 0-6, 6-9, 9-12, 12-16, 16-20, 6-16 and 0-20. Individual food consumption was measured for gestation days 0-6, 6-9, 9-12, 12-16, 16-20, 6-16 and0-20. Food consumptionwas calculated and reported as grams/animal/day.

All females were sacrificed on gestation day 20 by carbon dioxide, asphyxiation and subjected to a gross necropsy examination. The thoracic,
abdominal and pelvic cavities were opened and the viscera examined. Abnomalities were recorded.
Ovaries and uterine content:
The uterus was removed from the body, examined externally, weighed and then opened for internal examination. The number
of viable fetuses and the presence of any nonviable fetuses and early and late resorptions were then recorded beginning with the left distal uterine
horn, noting the position of the cervix, and continuing up the right uterine horn. Corpora lutea were counted and recorded for each ovary.
Fetal examinations:
Fetuses were examined for external, visceral, and skeletal anomalies. Malformations and variations were classified based upon the severity of the
anatomical change(s) and their potential for interference with organ and/or body functions. The sex of each fetus was determined.
The fetuses were weighed and tagged individually.

Approximately one-half of the fetuses were fixed in Bouin' s solution for subsequent visceral examination by the method of Wilson 1965 [in
Teratology Principles and Techniques, eds. J. G. Wilson and J. Workany, pp. 262-277.] The examination was performed under a low power dissection scope.

Approximately one-half ofthe fetuses were eviscerated and fixed in 95% isopropyl alcohol. Following fixation, the fetuses were macerated
in 1.5% aqueous potassium hydroxide solution, stained with Alizarin Red S, and cleared in 25% aqueous glycerin solution. The examination was
performed under low power magnification.
Statistics:
Statistical analyses were performed by a Digital Vax 11/730 computer. All analyses were two-tailed with a minimum significance level of 5%. One
way analysis of variance followed by Dunnett's test was used to analyze maternal and fetal data including body weights, food consumption, number of
viable fetuses, implantation sites, and corpora lutea. Mann-Whitney U test was used to compare post-implantation loss, dead fetuses, and
resorptions. Fetal sex ratios were analyzed using the Chi-Square test. Fisher's Exact test was used to analyze the incidence and number of fetal
malformations and variations.
Historical control data:
Relevant historical control data for bent ribs observations = 0-3.6%.
All data provided in Appendix N of the study report.
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
All females survived to scheduled caesarean section on gestation day 20.
Treatment-related clinical signs were observed at the 200 and 500 mg/kg/day levels. The most notable findings included urine staining, mucoid
or soft stools, rales, hairloss and post-dose salivation. The hairloss was particularly evident in the abdominal and hip regions of these animals. The
overall severity of the effects were greater at the 500 mg/kg/day level.
External findings of hairloss and urine stain were confirmed at necropsy.
Significant body weight losses occurred at the 200 and 500 mg/kg/day levels during the first three days of dosing (gestation days 6-9). Body weight gains and food consumption were significantly reduced at the 200 and 500 mg/kg/day 'level throughout the treatment period.
Key result
Dose descriptor:
NOEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
A slight, but statistically significant decrease in mean fetal body weight was observed at the 500 mg/kg/day level. All other cesarean section
parameters evaluated, including the number of corpora lutea, implantation sites, viable fetuses, early and late resorptions, fetal sex ratios and
gravid uterus weights, were comparable between the control and treatment.

No statistically significant differences were noted in the fetal malformation data. Observed malformations included one control fetus with
multiple craniofacial anomalies, one 200 mg/kg/day fetus with absent tail and anal atresia, and four fetuses in the 500 mg/kg/daygroup with a
single malformation per fetus (hydrocephaly, forked rib, fused ribs or skull anomaly). The low incidence, lack of statistical significance, and
dissimilar nature of the findings indicated that they were not the result of test article treatment groups.

Evaluation of the fetal variations revealed an apparent dose-related increase in the incidence of fetuses and litters with bent ribs. The
percentage of fetuses with bent ribs in the control, 50, 200 and 500 mg/kg/day groups was 0.6, 2.6, 5.8 and 9.6, respectively. The percentage
of fetuses with bent ribs at the 50 mg/kg/day level was well within the SLS historical control range of 0.0-3.6%. while the percentage of fetuses in
the 200 and 500 mg/kg/day groups slightly exceeded the range. The incidence of litters with bent ribs was statistically increased in the 500 mg/kg/day group when compared to control litters. It is noteworthy that the occurrence of bent ribs was outside the historical control range at the 200 and 500 mg/kg/day levels where overt maternal toxicity was evident.
Key result
Dose descriptor:
NOEL
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: fetotoxicity
Key result
Dose descriptor:
NOEL
Effect level:
> 500 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Key result
Abnormalities:
not specified
Key result
Developmental effects observed:
not specified
Conclusions:
Based on the results of this study, this substance showed now signs of teratogenicity. Some signs of maternal and fetal toxicity were present.
A level of 50 mg/kg/day is considered a no-observed-effect level (NOEL) for maternal toxicity.
A level of 200 mg/kg/day was considered a NOEL for fetal toxicity.
A level of 500 mg/kg/day (top dose tested) was considered a NOEL for teratogenicity.
Executive summary:

In a teratology study, p-tert amylphenol was administered by oral gavage as a suspension in corn oil to Sprague Dawley rats (25 females per dose group) at dose levels of 0, 50, 200 and 500 mg/kg bw/day.

No maternal mortality occurred during the study. Treatment-related clinical signs of toxicity were observed at the 200 and 500 mg/kg/day levels. The most notable findings included urine staining, mucoid or soft stools, rales, hairloss and post-dose salivation. The hairloss was particularly evident in the abdominal and hip regions of these animals. Significant body weight losses occurred at the 200 and 500 mg/kg/day levels during the first three days of dosing (gestation days 6-9). Body weight gains and food consumption were significantly reduced at the 200 and 500 mg/kg/day level throughout the treatment period.

The NOEL for maternal toxicity is 50 mg/kg bw/day in females based on reduced body weight and clinical observations.

The NOEL for fetal toxicity is 200 mg/kg bw/day based upon the presence of bent ribs at the top dose.

The NOEL for teratogenicity is 500 mg/kg bw/day based upon no teratogenic effects seen at the top dose tested.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Good quality OECD 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

In the teratology study, no maternal mortality occurred during the study. Treatment-related clinical signs were observed at the 200 and 500 mg/kg/day levels. The most notable findings included urine staining, mucoid or soft stools, rales, hairloss and post-dose salivation. The hairloss was particularly evident in the abdominal and hip regions of these animals. Significant body weight losses occurred at the 200 and 500 mg/kg/day levels during the first three days of dosing (gestation days 6-9). Body weight gains and food consumption were significantly reduced at the 200 and 500 mg/kg/day level throughout the treatment period.

In this study:
the NOEL for maternal toxicity is 50 mg/kg bw/day in females based on reduced body weight and clinical observation, 

the NOEL for fetal toxicity is 200 mg/kg bw/day based upon decreased mean fetal body weight at the 500 mg/kg dose

the NOEL for teratogenicity is 500 mg/kg bw/day based upon no treatment-related teratogenic effects seen at the top dose tested.

Justification for classification or non-classification

Given there are no specific effects on reproductive function and fertility seen in either the 2-generation study or the OECD 422 combined repeat-dose/reproductive toxicity study, nor any developmental effects seen in the teratogenicity study, p-tert amyl phenol should not be classified as a reproductive or developmental toxin.

Additional information