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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
28/06/1994-24/08/1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study (OECD 421)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report date:
1995

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
draft version 12.01.1993
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
4-(1,1,3,3-tetramethylbutyl)phenol
EC Number:
205-426-2
EC Name:
4-(1,1,3,3-tetramethylbutyl)phenol
Cas Number:
140-66-9
Molecular formula:
C14H22O
IUPAC Name:
4-(1,1,3,3-tetramethylbutyl)phenol
Details on test material:
- Name of test material (as cited in study report): 4(1,1,3,3-tetramethyl-butyl)phenol
- Substance type: pure active substance
- Physical state: solid
- Description: white solid
- Analytical purity: 98.7%
- Lot/batch No.: QS 933212
- Expiration date of the lot/batch: 31 october 1994
- Date of receipt: 16 February 1994
- Stability: stable for duration of the study
- Storage condition of test material: in the dark at room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Stain: Sprague-Dawley Crl:CD BR VAF/Plus strain
- Source: Charles River UK Ltd, Manston Road, Margate.
- Age at study initiation: (P) 11-12 wks males and 7-8 wks females; (F1) 0 days
- Weight at study initiation: before acclimation of 6 days (P) Males: 303-341 g; Females: 147-183 g; after acclimation of 6 days: (P) Males: 361-432 g; Females: 187-232 g; (F1) Males: x-x g; Females: x-x g
- Fasting period before study:
- Housing:
pre-mating period: males and females separated 4 to a cage unless reduced by mortality. Cages of males were interspersed amongst those holding females to promote development of regular oestrous cycles. In addition, the cages constituting each treatment group were dispersed between batteries so that possible environmental influences arising from their spatial distribution were equilibrated as far as possible for all treatment. Suspended stainless steel cages (Biotech®) equipped with solid sides, and wire grid front, back and top were used during the pre-mating period.
Mating period: rats were housed on the basis of one male to one female in plastic breeding cages (North Kent Plastics, RB-3 type). At the end of the mating period the males were re-housed with their former cage mates in metal cages (Biotech®) and the females were housed in individual breeding cages (North Kent Plastics, RB-3 type) prior to the birth and rearing of young. Suitable nesting material was provided.
- Diet (e.g. ad libitum): Special Diet Services (SDS) laboratory Animal Diet No. 1 ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: first period 6 days, second period of 7 days between allocation of animals to groups and commenced of treatment.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21°C
- Humidity (%): 55%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light


IN-LIFE DATES: From: 28.06.1994 To: 08.08.1994

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Homogeneity and stability of the test article in liquid formulation had previously been confirmed in these laboratories as part of the 28-day toxicity study (SAZ 464/942419). A series of suspensions were made dissolving the test substance in corn oil, the concentrations were chosen to give a constant dosage volume of 5 ml/kg bodyweight. All suspensions were prepared daily and administered on the day of preparation. Samples of dose formulations prepared for the first day of the study were analysed for achievement concentration. Analyses were performed at HRC. Control animals received vehicle alone at the same dosage volume as test group animals.

VEHICLE
- Justification for use and choice of vehicle (if other than water): corn oil is use. The test substance is stable in vehicle during storage and forms a homogeneous suspension.
- Concentration in vehicle: 25, 50, 100 mg/ml
- Amount of vehicle (if gavage): 5 ml/kg bodyweight
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: 2 weeks
- After successful mating each pregnant female was caged in individual breeding cages (North Kent Plastics, RB-3 type) prior to the birth and rearing of young. Suitable nesting material was provided.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Formulation Analysis (SAZ 462/942750): This report contains details of the analytical method used and the results obtained for the determination of concentrations of test substance in dose formulations prepared for day 1 of the study. The formulations were prepared as suspensions of 4(1,1,3,3-tetramethyl-butyl)phenol in corn oil by Pharmacy Personnel at Huntingdon Research Centre Ltd. Mean concentrations of 4(1,1,3,3,-tetramethyl-butyl)phenol in dose formulations analysed for Day 1 of the study and the deviation of mean results are recorded: mean results were within 5% of nominal concentrations.



The results for the validation of the method of analysis and determination of the physical and chemical stability of corn oil formulations containing the test substance at concentrations of 1 mg/ml and 200 mg/ml, are presented in HRC Report number SAZ 464/942419 (Repeated dose toxicity: oral)
- Determination of concentrations of test substance in dose formulation analysed for day 1 of the study.
- Determination of chemical stability in corn oil formulations.
- Validation of the method of analysis for the determination of test substance in corn oil formulations
- Determination of the physical stability of the test substance in corn oil formulations.
Formulation Analysis Report (SAZ 464/942419):
Mean results were within +2%/-1%. At nominal concentrations of 1 mg/ml and 200 mg/ml, the test substance produces a homogeneous suspension in the corn oil formulation, which can be maintained for up to 1 hour while magnetically stirred and successfully resuspended following storage at ambient temperature for 4 hours.
At nominal concentrations of 1 mg/ml and 200mg/ml the test substance is chemically stable in the corn oil formulation during storage (ambient temperature during the day, refrigeration overnight) for 24 hours.
Procedural recovery obtained during method validation and determination of stability indicate that the analytical method is both accurate and precise: a mean procedural recovery value of 98.1% ± 1.91% CV (n = 8) was obtained for 1 mg/ml and 98.2% ±
0.99% CV (n = 8) for 200 mg/ml. Results for the analysis of test samples were corrected for the appropriate mean procedural recovery value at analysis.
A typical calibration standard graph confirmed the linearity of detector response for the test substance over the concentration range 2 -10 µ/ml. The absence of a peak at the characteristic retention volume for the test substance in the control sample chromatogram demonstrates the specificity of the HPLC assay.
The analytical results confirm that the doses were accurately formulated for Day 1 of the toxicity study. The results also confirm that specimen formulations were homogeneous and stable for a period representing the time from preparation to completion of dosing.

Duration of treatment / exposure:
2 weeks prior to mating, 2 weeks mating period and until litters reached Day 4 post partum
Frequency of treatment:
once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 125, 250, 500 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations: all animals were weighed initially at grouping up, on the first day of dosing, subsequently ate weekly intervals and finally on the day of sacrifice. During the mating period all females were weighed daily throughout and daily weighing continued until parturition. The occurrence of a positive indication of mating (i.e. sperm or plug) was considered as day 0 of pregnancy. Weights are reported for days 0, 3, 7, 10, 14, 17 and 20 of pregnancy. Weights of pregnant animals without a positive indication of mating were reported for appropriate days taken retrospectively from birth or apparent day of gestation at sacrifice. Dams that littered were weighed once parturition was complete (day 0/1 - reported as day 0) and on day 4.


FOOD CONSUMPTION Yes (g/rat):
Food consumption was recorded weekly for both sexes from initiation of treatment until the animals were placed together for treatment ( weeks 1 to 2). Measurement for males continued weekly during the post mating period (weeks 5 -6). For females was reintroduced on day 1 post partum and recorded on day 4 post partum.

FOOD EFICIENCY
Food conversion ratios were calculated, where possible, over the period weeks 1 to 6 from the bodyweight and food consumption data as weight of food consumed per unit gain in bodyweight.

WATER INTAKE (g/rat)
Water consumption was recorded daily

Oestrous cyclicity (parental animals):
Mating performance: vaginal smears were taken daily for 1 week prior to an during the 14-day mating period to enable the number of animals that mated on specific days to be determined. This information was used in conjunction with other data:
to determine whether or not pregnancy had occurred and continued uninterrupted after mating
to detect marked anomalies of the oestrus cycle
to determine the median pre-coital time and duration of pregnancy for dams that littered.

Duration of pregnancy: the duration of pregnancy for females which littered was taken as the time between the day of successful mating and the day on which pups were first seen.
Sperm parameters (parental animals):
Parameters examined in all male parental generations:
testis weight, epididymis weight.
Histophatological examination of testes and epididymides.
Litter observations:
As soon as possible after parturation the young were counted, individually identified within the litter by toe amputation, sexed, weighed and examined for any physical or behavioural abnormalities. Keeping nest disturbance to a minimum, all litters were examined daily for dead and/or abnormal young. Pups were also weighed on day 4 post partum. Dead young were subjected to an autopsy.
Postmortem examinations (parental animals):
SACRIFICE
- Male and female animals: All surviving animals shortly after day 4 post partum. Apparent non-pregnant females and males were killed in the week following the latest possible date of birth.



GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations. The uterus of each female which gave birth was visually inspected for implantation sites and the number of sites was recorded. The number of implantation sites was not recorded in error for two females. Uteri of apparently non-pregnant females were examined for evidence of implantation using a modified Salewski technique (Salewski, 1964)
The following organs from all animals killed were dissected free of fat and weighed:
adrenals, brain, epididymides individually (identified as left or right), heart, kidneys, liver, lungs, ovaries, pituitary, prostate (with seminal vesicles + coagulating gland), testes individually (identified as left or right), thymus, spleen.

Appropriate organs were weighed as a pair.

Presentation of tissues: Samples of all the tissues listed below from all animals were preserved in buffered 10% formalin (except testes and epididymides, identified left or right and preserved in Bouin's fixative):
adrenals, brain, epididymides, heart, kidneys, liver, lungs, mammary gland, macroscopically abnormal tissues, ovaries, pituitary, prostate, seminal vesicles (with coagulating gland), teste, thymus, thyroids, uterus (with cervix), vagina.


HISTOPATHOLOGY / ORGAN WEIGHTS
Tissues required for microscopic examination from all P adults of the control group and at the highest dosage in this study were: epididymides, ovaries and testes. These tissues were embedded in the paraffin wax.
A transverse sample of testis and longitudinal sample of associated epididymis was mounted in the same paraffin wax block and labelled left or right. A single 2 µm section of each block was taken and stained with PAS (Periodic Acid Schiff) - haematoxylin.
The ovaries were sectioned at 4 µm and stained with haenotoxylin and eosin.
Following treatment associated histological changes to the testes and epididymides of males at the highest dosage, examination was extended to the intermediate dosage.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring were sacrificed shortly after day 4 post partum.
- These animals were subjected to postmortem examinations (macroscopic and microscopic examination) as follows:

Sex of the pups was confirmed by gonadal inspection.


GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations. The following organs from all animals killed were dissected free of fat and weighed:
adrenals, brain, epididymides individually (identified as left or right), heart, kidneys, liver, lungs, ovaries, pituitary, prostate (with seminal vesicles + coagulating gland), testes individually (identified as left or right), thymus, spleen.

Statistics:
Significance test, employing analysis of variance followed by an intergroup comparison with the control, were performed on the following parameters: food consumption, water consumption, weekly bodyweight, bodyweight change, haematology, biochemistry, litter data, organ weights.
Dependent of the heterogeneity of variance between treatment groups, parametric tests (analysis of variance (Snedecor and Cochran 1967) followed by William's test (William 1971/2) or non-parametric tests (Kruskal-Wallis (Hollander and Wolfe 1968) followed by Shirley's test (Shirley 1977) were used to analyse these data, as appropriate. For litter data, the basic sample unit was the litter and, due to the preponderance of non-normal distributions, non-parametric analyses were routinely used. For organ weight data, analysis of variance was performed using terminal bodyweight as covariate when the within group relationship between organ weight and bodyweight was significant at the 10% level.

All significant (ie p≤0.05) intergroup differences from the control are reported and were supported by a significant analysis of variance (P≤0.05) unless otherwise indicated (by parentheses of the superscript) in the tables.
Where 75% or more of the values for a given variable are the same, a Fisher's exact test (Fisher 1950) was used, when considered necessary.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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 / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, treatment-related

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
500 mg/kg/day: a total of 9 male and females were sacrificed or found dead during the treatment, following adverse clinical signs. Clinical signs amongst all animals in the group included post dosing salivation, wet coats, untidy/matted fur, brown stained urogenital region and, under all cages, looses faeces, additionally for mortalities, signs including hunched posture, emaciation, lethargy and abnormal gait were noted.
250 mg/kg/day: Two females were sacrificed around birth - it is uncertain if these were treatment-related. Signs of reactions to treatment included post dosing salivation, wet coats, and, under all cages, loose faeces.
125 mg/kg/day: post dose salivation.


BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
500 mg/kg/day: Mean bodyweight gain in all animals was reduced and lower weight gain of females was apparent at the end of pregnancy and early lactation. Food consumption was reduced.
250 mg/kg/day: Bodyweight gain was reduced and for females, bodyweight gain was also affected at the end of pregnancy/early lactation.
125 mg/kg/day: no effects

WATER CONSUMPTION (PARENTERAL ANIMALS)
500 mg/kg/day: water consumption was markedly increased.
250 mg/kg/day: water consumption was increased.
125 mg/kg/day: slightly elevated water consumption.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)


REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)


REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)


REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
500 mg/kg/day: Mating performance of the animals following two weeks of treatment was impaired with only 4 of 8 paired females conceiving. However, in view of the marked toxicity at this dosage it is uncertain if this is a direct treatment-related effect or is a consequence of the general poor condition. Libido appears unaffected for males but their fertility was lower. Among females that did conceived, mating performance was generally unaffected although the duration of the pregnancy was longer than expected.
The implantation rate was lower than the controls which, together with increased pre and post natal mortality resulted in lower litter sizes.
250 mg/kg/day: no effects
125 mg/kg/day: no effects


ORGAN WEIGHTS (PARENTAL ANIMALS)
500 mg/kg/day: organ weigh analysis in week 7 revealed increased liver and kidney weights and, more predominantly for males, increased adrenal weights. Weights of specific reproductive organs (testes, epididymides, combined prostate/seminal vesicles/coagulating gland, and ovaries) were reduced, as was thymus weight.
250 mg/kg/day: higher liver weights and slightly elevated kidney weights
125 mg/kg/day: no effects


GROSS PATHOLOGY (PARENTAL ANIMALS)
500 mg/kg/day: Macropathological changes included stained fur, alopecia, raised/thickened areas of forestomach (in females), pale foci and in females, uniform cortical scarring of kidneys and enlarged renal lymph nodes.
250 mg/kg/day: macroscopic examination revealed distended caecum (of males) reduced thymus size (in males), enlarged adrenal size (in females) and uniform cortical scarring of kidneys.
125 mg/kg/day: no effects


HISTOPATHOLOGY (PARENTAL ANIMALS)
500 mg/kg/day: microscopical examination was confined to the reproductive tract and revealed minor changes in the testes and epididymides (trace exfoliation of round spermatids into the seminiferous tubular lumen with minimal numbers of abnormal spermatogenic cells in the caput epididymides and/or trace vacuolation of the seminiferous epithelium.
250 mg/kg/day: microscopic examination was performed on testes and epididymides of males (following the effects at 500 mg/kg/day) and revealed no abnormalities.
125 mg/kg/day: no effects


OTHER FINDINGS (PARENTAL ANIMALS):
500 mg/kg/day: in week 5, haematological investigations revealed increased levels of plasma urea nitrogen, creatinine, bilirubin and glyutamic pyruvate transaminase (GPT) and lower levels of certain electrolytes and circulating albumin.
250 mg/kg/day: there were no obvious haematological or biochemical changes.
125 mg/kg/day: no effects

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
125 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: post dose salivation; slightly elevated water consumption.
Dose descriptor:
LOAEL
Remarks:
systemic
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
dose level:
Effect level:
500 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: Marked toxic effects, increased mortality (13/24 adult animals)
Dose descriptor:
NOAEL
Remarks:
reproduction
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects on mating performance or development of the litter
Remarks on result:
other: Generation: P & F1 (migrated information)
Dose descriptor:
LOAEL
Remarks:
reproduction
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: lower implantation rate, lower litter size due to increased pre and post natal mortality, reduced litter weight, suggestion of impaired pup growth to day 4; no gross abnormalities amongst the offspring
Remarks on result:
other: Generation: P & F1 (migrated information)

Results: F1 generation

General toxicity (F1)

Clinical signs:
effects observed, treatment-related
Mortality / viability:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Details on results (F1)

500 mg/kg/day: The implantation rate was lower than the controls which, together with increased pre and post natal mortality resulted in lower litter sizes. Litter weight was reduced and, there was a suggestion of impaired pup growth to day 4. No gross abnormalities were noted amongst the offspring.
250 mg/kg/day: there were no effects of treatment on development of the litter.
125 mg/kg/day: here were no effects of treatment on development of the litter.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

500 mg/kg/day

A total of 9 male and 4 females were sacrificed or found dead during the treatment period, following adverse clinical signs and bodyweight loss. Clinical signs amongst all animals in the group included post dosing salivation, wet coats, untidy matted fur, brown stained urogenital region and, under all cages, loose faeces, additionally for mortalities, signs including hunched posture, emaciation, lethargy and abnormal gait were noted. Mean bodyweight gain of all animals was reduced and lower weight gain of females was apparent at the end of pregnancy and early lactation. Food consumption was reduced and water consumption was markedly increased. In Week 5, haematological investigations revealed higher numbers of white blood cells and platelets and biochemical investigations revealed increased levels of plasma urea nitrogen, creatinine, bilirubin and glutamic pyruvate transaminase (GPT) and lower levels of certain electrolytes and circulating albumin.

Organ weight analysis in Week 7 revealed increased liver and kidney weights and, more predominantly for males, increased adrenal weights. Weights of specific reproductive organs (testes, epididymides, combined prostatelserninal vesicles/coagulating gland, and ovaries) were reduced, as was thymus weight. Macropathological changes included stained fur, alopecia, raised/thickened areas of forestomach (in females), pale foci and in females, uniform cortical scarring of kidneys and enlarged renal lymph nodes. Microscopic examination was confined to the reproductive tract and revealed minor changes in the testes and epididymides (trace exfoliation of round spematids into the seminiferous tubular lumen with minimal numbers of abnormal spermatogenic cells in the caput epididymis andlor trace vacuolation of the seminiferous epithelium.

Mating performance of the animals following two weeks of treatment was impaired with only4of the8paired females conceiving. However, in view of the marked toxicity at this dosage it is uncertain if this is a direct treatment-related effect or is a consequence of the general poor condition. Libido appeared unaffected for males but their fertility was lower. Amongst females that did conceive, mating performance was generally unaffected although the duration of pregnancy was longer than expected. The implantation rate was lower than the controls which, together with increased pre and post natal mortality resulted in lower litter sizes. Litter weight was reduced and, there was a suggestion of impaired pup growth to Day4.No gross abnormalities were noted amongst the offspring.

250 mg/kg/day

Two females were sacrificed around birth-it is uncertain if these were treatment related. Signs of reactions to treatment included post dosing salivation, wet coats, and, under all cages, loose faeces. Bodyweight gain was reduced and for females, bodyweight gain was also affected at the end of pregnancy early lactation. Water consumption was increased. There were no obvious haematological or biochemical changes but organ weight analysis revealed higher liver weights and slightly elevated kidney weights. Macroscopic examination revealed distended caecum (of males) reduced thymus size (in males), enlarged adrenal size (in females) and uniform cortical scarring of kidneys. Microscopic examination was performed on testes and epididymides of males (following the effects at 500 mg/kg bw/day) and revealed no abnormalities.

There were no effects of treatment on mating performance or development of the litter

125 mg/kg/day

The only changes noted were post dose salivation and slightly elevated water consumption.

No effects of treatment were noted on mating performance or development of the litter.

Applicant's summary and conclusion

Conclusions:
Treatment of 500 mg/kg/day produced a marked toxic effect resulting in the death of 13/24 adult animals and slight effects on mating performance and development of conceptus. Clear treatment-related toxic effects were reported at 250 mg/kg/day. The reproductive performance and development of the conceptus was unaffected at this dose.
Executive summary:

In a reproduction/developmental toxicity screening study according OECD 421 4-(1,1,3,3 -tetramethyl-butyl)phenol (98,7%) was administered to 12 SD rats/sex/dose by gavage at dose levels of 0, 125, 250, 500 mg/kg bw/day. 

Treatment at 500 mg/kg/day produced a marked toxic effect resulting in the death of 13/24 adult animals during the treatment period. There were slight effects on mating performance and development of the conceptus. There was a clear, through less marked, treatment-related effect at 250 mg/kg/day upon the treated adults, although reproductive performance and development of the conceptus was unaffected.

 

The systemic LOAEL is 250 mg/kg bw/day, based on body weight gain, water consumption, higher liver weights and slightly elevated kidney weights. Macroscopic examination revealed distended caecum (of males) reduced thymus size (in males), enlarged adrenal size (in females) and uniform cortical scarring of kidneys. There were no treatment related effects on mating performance or development of the litter. The systemic NOAEL is 125 mg/kg bw/day. The only changes at this concentration were post dose salivation and slightly elevated water consumption.

The NOAEL for toxicity to reproduction is 250 mg/kg/d based on a lack of effects on mating performance and development of the conceptus.

 

This study is acceptable and satisfies the guideline requirement for a reproduction/developmental toxicity screening study according OECD 421 in rat.

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