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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1988-09-16 to 1990-05-19
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report date:
1990

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Version / remarks:
1981
Deviations:
yes
Remarks:
Study performed to the OECD 416. It differs from the current guideline with: the performance of histopathological examination of the pups and the organ weight of brain, pituitary, thyroid and adrenal glands, prostate and seminal vesicles.
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1-[(4-chlorophenyl)methyl]-1-cyclopentyl-3-phenylurea
EC Number:
266-096-3
EC Name:
1-[(4-chlorophenyl)methyl]-1-cyclopentyl-3-phenylurea
Cas Number:
66063-05-6
Molecular formula:
C19H21ClN2O
IUPAC Name:
1-[(4-chlorophenyl)methyl]-1-cyclopentyl-3-phenylurea

Test animals

Species:
rat
Strain:
Wistar
Remarks:
SPF animal
Details on species / strain selection:
Standard laboratory species/strain with background data available.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 5 wks
- Weight at study initiation: Males: 50-80 g; Females: 45-75 g.
- Housing: Animals were housed in a barrier-sustained animal room.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 8 days.

ENVIRONMENTAL CONDITIONS
- Temperature: 22-26°C
- Humidity: 45-65%
- Air changes (per hr): 12
- Photoperiod: lighted 14 hours per day.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Remarks:
For each dose level, pencycuron was weighed and mixed with basal diet to obtain the prescribed concentration.
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
For each dose level, pencycuron was weighed and mixed with basal diet to obtain the prescribed concentration. The mixture was stirred by a SS-501 mixer.

DIET PREPARATION
- Rate of preparation of diet (frequency): once every 2 weeks
Details on mating procedure:
- M/F ratio per cage: 1/1
- Proof of pregnancy: existence of plugs or sperms in vaginal smear referred to as day 0 of pregnancy.
- After successful mating each pregnant female was caged: Maternal animals were housed individually in polypropylene cages with appropriate bedding.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Before the start of study, stability (for 4 weeks) and homogeneity of pencycuron in diet were confirmed by analysis. A part of the test diet of each dose level, sampled every 3 months, was analyzed for concentration of pencycuron. The results of the chemical analyses of the test diets used in the present study were satisfactory, indicating that there were no abnormal values influencing the evaluation of this study.
Duration of treatment / exposure:
The test diet or basal diet (controls) was administered for the entire study period. Male and female animals were treated for at least 10 weeks prior to mating and throughout mating. Females were treated during gestation and lactation. Offspring were treated from weaning.
Frequency of treatment:
Continuously via dietary administration
Details on study schedule:
- F1 parental animals not mated until 13 weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were 5 weeks of age.
- Age at mating of the mated animals in the study: 13 weeks
Doses / concentrationsopen allclose all
Dose / conc.:
0 ppm
Remarks:
Control
Dose / conc.:
50 ppm
Dose / conc.:
500 ppm
Dose / conc.:
10 000 ppm
No. of animals per sex per dose:
27/sex/group
Control animals:
yes
Details on study design:
- Dose selection rationale: Dose levels and group size were determined based on the information of preliminary toxicological studies.

Examinations

Parental animals: Observations and examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: All animals were observed daily for general condition and appearance. Any abnormalities were recorded individually with their onset, duration and severity when necessary.
Dead animal was autopsied upon discovery so as to examine the cause of the death.

BODY WEIGHT: Yes
- Time schedule for examinations: Males and females were weighed once a week until termination of study. Maternal animals were weighed on days 0, 7, 14 and 21 of gestation, and on days 0 (day of delivery), 4, 7, 14 and 21 of lactation.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food intake of males and females were individually measured once a week for all cages except for mating period. Mean food intakes (g/day /rat) were individually calculated by dividing total intake by the days between measurement points.

Intake of pencycuron (mg/kg/day) for a cage or an animal was calculated as follows:
Test substance intake= Concentration(ppm) in diet X Mean food intake (g/day/rat)/ Mean body weight(g) between measurement points.

OTHER:
Observations during reproductive period:
- Pre-mating period: Vaginal smear was examined daily using Giemsa-stain method from 2 weeks before mating to day 0 of gestation or to the termination of mating period.
- Perinatal period: Abortion, premature birth and dystocia were checked.
- At birth: Duration of gestation was calculated. Number of live and dead newborns, their sex, and their external abnormalities were observed. The pups were skin or hair-dyed with methylviolett for individual identification.
- Nursing period: Nursing conditions of dams and mortalities of pups were observed every day.
- Body weight of pups: Individual body weight of pups per dam for each sex was measured on days 0, 4, 7, 14 and 21 post partum, and mean pups body weight for each sex was calculated.
Postmortem examinations (parental animals):
- Autopsy: For all the parental animals (sacrificed to schedule as well as found dead), complete gross examination was done.
- Period of autopsy:
Parental females: Day of weaning.
Parental males: After parental female's 2nd delivery.
- Organ weights: For all the parental animals of P and F1 generations following organs were weighed. liver, kidneys, spleen, ovaries, testes
- Fixation of organs: Following organs of all the parental animals of P and F1 generations were fixed and preserved in 10% buffered formalin solution.
liver, kidneys, spleen, brain, pituitary, vagina, uterus, mammary gland, ovaries, epididymis, seminal vesicle, prostate, testes and organs or tissues with gross lesion.
- Histopathological examinations were performed for all fixed specimens of P and F1 parental animals of control and the highest dose group and of non-copulated or non-pregnant animals in the low and medium dose groups. The specimens were processed to obtain ordinary hematoxylineosin-stained sections for microscopic examination. Further, livers in the 50 ppm and 500 ppm groups were also examined microscopically, because changes in the liver were found in the highest dose group, it seemed that the changes were caused by treatment of pencycuron.
Postmortem examinations (offspring):
Pathological examinations:
- Autopsy: For all weanlings, complete gross examination was done.
- Period of autopsy:
Weanlings: Day of weaning.
Surplus pups at culling: Day 4 of lactation.
Statistics:
The significance of differences between the control and each dose group was analyzed by Student's t-test (the Aspin-Welch's modification was used if homogeneity of variance is not obtained by F-test), chi-square test, Wilcoxon's rank-sum test and Fisher's exact fit test. Difference of P<0.05 was considered significant.

The statistical tests applied are as follows:
Student's t-test: Body weight of parental animal, food intake, organ weight(absolute and relative), number of newborn, pup's body weight; Chi-square test: Sex ratio, mating index, gestation index, birth index, duration of gestation; Wilcoxon's rank-sum test: Day 4 and 21 survival indices of pups; Fisher's exact fit test: Incidence of organs or tissues with abnormality and of newborns with external abnormality.
Reproductive indices:
Mating index = (number of animals copulated/ number of animals cohabited) x 100
Gestation index = (number of pregnants/ number of females copulated) x 100
Birth index = (number of dams with live newborns/ number of pregnants) x 100
Sex ratio = number of live male newborns/ number of live female newborns
Offspring viability indices:
Day 4 survival rate = (number of live pups on day 4/ number of live newborns )x 100
Day 21 survival rate= (number of live pups on day 21/ number of pups after culling on day 4) x 100

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
Throughout the study, neither toxic signs nor changes in general conditions attributable to pencycuron were observed in both sexes.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
In the 10,000 ppm group of the P generation, one dam (F213) died due to foreign body pneumonia resulting from inhaling food and nesting material.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In the 10,000 ppm group, body weights of both sexes of the P generation showed significantly lower gain as compared with those in control group. Significantly lower values were found at the following intervals: in males of the P generation, during weeks 1-13 and 15-19 of treatment; in females of the P generation, during weeks 1-11 of treatment and most part of the generation and lactation period.

In the 500 ppm group, significantly lower body weights were also observed in both sexes of the P generation at the following intervals; during weeks 1-3 of treatment in males; and during weeks 1-4 of treatment and on day 21 of lactation of 1st and 2nd parity in females. In the 50 ppm group, although statistically significant changes were sporadically found at some intervals, but there were no dose-response relationships.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
In the 10,000 ppm group, significant decreases of food intakes was observed in both sexes of the P generation at the following intervals: in the P generation, during weeks 0-3 of treatment in males; during weeks of treatment 0-1 and periods of 1st lactation and 2nd gestation. In the 500 ppm group, significantly lower food intakes were observed in animals of the P generation at the following intervals: during weeks 0-2 of the treatment in males of the P generation. In the 50 ppm group, significant differences were sporadically found at some intervals in both sexes. However, these changes were considered to be unrelated to pencycuron treatment, because there were no dose-response relationships and these changes were transient.

The mean intakes of pencycuron were : 3.2-3.4 mg/kg/day in males and 4.6-4.9 mg/kg/day in females of 50 ppm group; 32.7-34.0 mg/kg/day in males and 48.7 mg/kg/day in females of 500 ppm group ; and 676.4-704.3 mg/kg/day in males and 998.5-1000.6 mg/kg/day in females of 10000 ppm group.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
In the 10,000 ppm group, centrilobular hepatocellular swellings were observed in both sexes of the P generation. No such changes were detected in any animal of the 500 ppm and 50 ppm groups. With respect to other organs, sporadic and slight findings were observed in both sexes. However, there were no significant differences in incidence between the control and treated groups. As to the infertile animals, no histopathological abnormalities were detected in their reproductive organs.
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
No abnormality in regularity of the oestrous cycle was observed.
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
No abnormality was observed, and indices of mating and fertility in any treated groups were comparable to those in the control group. With respect to the data on parturition, stillbirth was noted in one dam in control group of the P generation, and 4 dams in control , 2 dams in 500 ppm. There were no dose-response relationships. And the duration of gestation in the treated groups of any generations and parities as comparable to that in the control group. In all treated groups, when the mean number of live pups, sex ratio and survival index on the day of delivery were compared to those in the control group, no significant differences attributable to pencycuron were obtained.

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
500 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
organ weights and organ / body weight ratios
Remarks on result:
other: Equivalent dose levels for males (3.2-3.4 mg/kg/day), females (4.6-4.9 mg/kg/day)

Target system / organ toxicity (P0)

Key result
Critical effects observed:
no

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
no effects observed
Description (incidence and severity):
Throughout the study, neither toxic signs nor changes in general conditions attributable to pencycuron were observed in both sexes.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
There were no deaths attributable to treatment
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In the 10,000 ppm group, body weights of both sexes of F1 generation showed significantly lower gain as compared with those in control group. Significantly lower values were found at the following intervals: F1 males , during weeks 0-15 of treatment; in F1 females, during weeks 0-6 of treatment, on days 4,7 and 14 lactation of the 1st parity , on days 7 and 14 of lactation of the 2nd parity.

In the 500 ppm group, the body weights of F1 animals of both sexes in the 500 ppm group were comparable to those in the control group.

In the 50 ppm group, although statistically significant changes were sporadically found at some intervals, there were no dose-response relationships.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
In the 10,000 ppm group, significant decreases of food intakes was observed in F1 generation at the following intervals: in F1 generation, during weeks 0-7 of treatment in males; during the gestation and lactation periods of the 1st litter and the lactation period of the 2nd litter in females. In the 500 ppm group, significantly lower food intakes were observed in animals of the F1 generation at the following intervals: during the gestation periods of 1st and 2nd parity in F1 females. In the 50 ppm group, significant differences were sporadically found at some intervals in both sexes. However, these changes were considered to be unrelated to the pencycuron treatment, because there were no dose-response relationships and these changes were transient.

The mean intakes of pencycuron: 3.2-3.4 mg/kg/day in males and 4.6-4.9 mg/kg/day in females of 50 ppm group; 32.7-34.0 mg/kg/day in males and 48.7 mg/kg/day in females of 500 ppm group; and 676.4-704.3 mg/kg/day in males and 998.5-1000.6 mg/kg/day in females of 10,000 ppm group.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Absolute and relative liver weights of both sexes in the 10,000 ppm group were significantly higher than those in the control group. And the absolute and relative spleen weights in both sexes treated with 10,000 ppm were significantly lower. In the 500 ppm group, the absolute and /or relative liver weights were likewise higher in both sexes of F1 females. In the 50 ppm group, liver and spleen weights were comparable to those in the control values. With respect to the other organs, the following changes were sporadically observed: in the 50 ppm group, an increase in the spleen (absolute and relative) and kidneys (absolute) in F1 males. However, there were no dose- response and consistent tendencies.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
As a sporadic change, slight abnormalities in some organs of a few animals in any generations were observed, however , there were no significant differences in incidence between the control and treated groups.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
In the 10,000 ppm group, centrilobular hepatocellular swellings were observed in both sexes of F1 generation. No such changes were detected in any animal of the 500 ppm and 50 ppm groups.
With respect to other organs, sporadic and slight findings were observed in both sexes. However, there were no significant differences in incidence between the control and treated groups. As to the infertile animals, no histopathological abnormalities were detected in their reproductive organs.
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
No abnormality in regularity of sexual cycle was observed, and indices of mating and fertility in any treated groups were comparable to those in the control group. With respect to the data on parturition, stillbirth was noted in one dam in control group of the P generation, and 4 dams in control , 2 dams in 500 ppm. There were no dose-response relationships. And the duration of gestation in the treated groups of any generations and litters was comparable to that in the control group. In all treated groups, when the mean number of live pups, sex ratio and survival index on the day of delivery were compared to those in the control group, no significant differences attributable to pencycuron were obtained.

Effect levels (P1)

Key result
Dose descriptor:
NOAEL
Effect level:
500 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
organ weights and organ / body weight ratios
Remarks on result:
other: Equivalent dose levels for males (3.2-3.4 mg/kg/day), females (4.6-4.9 mg/kg/day)

Target system / organ toxicity (P1)

Key result
Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Description (incidence and severity):
Throughout the study, neither toxic signs nor changes in general conditions attributable to pencycuron were observed in both sexes.
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
Significantly lower values of F1A pup survival rate were observed on day 4 of 1st lactation in the 500 and 10000 ppm groups. However , this change was evaluated to be incidental, since the values for the F1B litters were comparable to those in the control group.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In the 10,000 ppm group, body weights of both sexes of F1 generation showed significantly lower gain as compared with those in control group. Significantly lower values were found at the following intervals: F1 males , during weeks 0-15 of treatment; in F1 females, during weeks 0-6 of treatment.

In the 500 ppm group, the body weights of F1 animals of both sexes in the 500 ppm group were comparable to those in the control group.

In the 50 ppm group, although statistically significant changes were sporadically found at some intervals, there were no dose-response relationships.

With respect to the pup's body weights, significantly lower values were observed in F1a and F1b offspring in the 10,000 ppm group.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Anogenital distance (AGD):
not examined
Nipple retention in male pups:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
In the weanlings, the following findings were observed: in the control group , one case of absent in kidney and uterine horn (F1a female) and one case of absent in kidney (F1b male); in the 50 ppm group, one case of hydronephrosis (F1a male); in the 500 ppm group, 5 cases of hydronephrosis (F1a male: 1 case) and one case of hypoplasia in kidney (F1a female). However, there was no dose-response relationship in incidence.
Histopathological findings:
not examined
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
As an external abnormality of newborns, one F1a pup with short tail in control group, one F1b pup with tailless in 500 ppm group were observed, but the incidences were very low in each case.

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
500 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain

Results: F2 generation

General toxicity (F2)

Clinical signs:
no effects observed
Description (incidence and severity):
Throughout the study, neither toxic signs nor changes in general conditions attributable to pencycuron were observed in both sexes.
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
Significantly lower values of pup's survival rate were observed on day 4 of 1st lactation (F2a) in the 500 and 10000 ppm groups. However, this change was evaluated to be incidental, since the values of 2nd parity (F2b) were comparable to those in the control group.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
With respect to the pup's body weights, significantly lower values were observed in F2a and F2b offspring in the 10,000 ppm group. In the 500 ppm group, similar lower changes were also observed in F2a and F2b offspring.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Anogenital distance (AGD):
not examined
Nipple retention in male pups:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, non-treatment-related
Histopathological findings:
not examined
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
As an external abnormality of newborns, one F2b pup with manus valga in 10,000 ppm group was observed, but the incidences were very low in each case.

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not examined

Effect levels (F2)

Key result
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
500 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain

Target system / organ toxicity (F2)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
Pencycuron did not influence the reproductive performance of the animals at dietary concentrations of up to and including 10,000 ppm (676.4-704.3 mg/kg/day in males and 998.5-1000.6 mg/kg/day in females).
Executive summary:

To investigate the potential effects of pencycuron on reproductive performance and growth of offspring, doses of 0, 50, 500 and 10,000 ppm owere administered to two successive generations of Wistar rats. Mating was performed 2 times for both the P (F0) and F1 generation; F1 parental animals were selected from the F1b offspring.  At 10,000 ppm, food intake and bodyweights of the parental groups were decreased. Body weights of the P generation at 500 ppm were also significantly decreased (by up to 5%) within the first week of treatment; findings are considered to be due to poor palatability.  Similarly, The F1 generation at 500 ppm initially had slightly lower body weights than the controls but compensated later.  Body weight gain of of the F0 generation at 500 ppm was reduced after the first two weeks (by up to 10%), but thereafter the animals gained weight comparable to controls and largely compensated the initial body weight reduction. In a parallel feeding test, food consumption was reduced up to 6% at the start of treatment. Overall it is concluded that changes in body weight (gain) and food consumption are considered to be due to palatability effects and are not considered toxicologically relevant.  The liver of rats of both generations and sexes was the organ which was influenced by pencycuron on both, microscopical and macroscopical level. At 10000 ppm pencycuron, significantly increased absolute and relative liver weight and an increased incidence of centrilobular hepatocellular hypertrophy were identified.  At 500 ppm, liver weight was increased for females in both generations and male animals of the F0 generation. The increase in absolute (5%) and relative (5%) mean liver weight in F0 males was only slight (5 and 6% of controls, respectively). In females, the increase in absolute and relative liver weight in F1 females was 11%, while the relative liver weight was increased only 7%. Changes are considered to be partly due to high variations in absolute liver weights in both control groups (F0 and F1), whereas body weights were comparable.  No macroscopic or histopathological correlates for liver effects up to and including 500 ppm were noted.  The body weight of pups was decreased in the highest dosing groups for both generations and at the 500 ppm dosing group for the F2-pups. However, body weights of F2a and F2b pups were within the normal range, but were lower than the unusually high control pup weights. These were mainly caused by smaller litter sizes, complete loss of potentially weak pups, and/or selection of the smallest pups for culling in the control groups. Observed changes in pup body weight at 500 ppm were therefore not considered toxicologically relevant.  Pencycuron did not influence the reproductive performance of the animals; the reproductive NOAEL is therefore 10,000 ppm. Based on, respectively, decreased body weight of the pups, and on decreased body weight and increased liver weight in the parents at the next higher dose, a dose of 500 ppm pencycuronis the NOAEL for parental and offspring effects.