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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

OECD 421, GLP Study (2021) :

NOAEL parental toxicity = 638.8 mg/kg bw/d

NOAEL reproductive toxicity =638.8 mg/kg bw /d

NOAEL neonatal toxicity = 638.8 mg/kg bw/d

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2020-2021
Reliability:
1 (reliable without restriction)
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
OECD Guideline for the Testing of Chemicals: Guideline 421, Reproduction/Development Toxicity Screening Test, 29 Jul 2016
GLP compliance:
yes
Limit test:
no
Justification for study design:
according to OECD Guideline for the Testing of Chemicals: Guideline 421, Reproduction/Development Toxicity Screening Test, 29 Jul 2016
The route of administration was oral (dietary) because this is a potential route of exposure for humans. Historically, this route has been used extensively for studies of this nature.
Dietary concentrations for this study were determined based on results from a repeated dose toxicity study.
Tested substance was well tolerated in males and females up to 10,000 ppm. Adverse effects were limited to microscopic findings for
males at 10,000 ppm, which included microtubular degeneration, papillary cysts, tubular dilation, and hyperplasia of the pelvic urothelium in the kidneys; these findings did not show signs of recovery following a 14-day treatment-free (recovery) period. A dietary concentration of 10,000 ppm corresponded to calculated mean test substance consumption values of 1011 and 944 mg/kg/day for males and females, respectively. Based on these results, dietary
concentrations of 2300, 4750, and 10,000 ppm (target dose levels of 150, 300, and 600 mg/kg/day) were selected for the current OECD 421 study. These dietary concentrations were derived from the current Testing Facility experience and historical control data and took into consideration differences noted in the animal housing and consequent growth rates in the United States versus Europe where the 28-day study was conducted. The high-concentration was
expected to produce some toxicity, but not excessive lethality that would prevent meaningful evaluation. The mid-concentration was expected to produce minimal toxic effects. The low-concentration was expected to produce no observable indications of toxicity.
Species:
rat
Strain:
Wistar
Remarks:
Wistar Han Rats
Details on species / strain selection:
This species and strain of rat is recognized as appropriate for reproduction studies. Tested laboratory has reproductive historical control data in this species from the same strain and source. This animal model has been proven to be susceptible to the effects of reproductive toxicants. Furthermore, this species and strain of rat has been used in a previous study with this test substance.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
On 04 and 20 Aug 2020, female and male Crl:WI(Han) rats were received from Charles River Laboratories, Inc., Raleigh, NC. The animals were approximately 10 to 11 weeks old and weighed between 154 and 260 g at the initiation of dosing.
Water: Municipal tap water, treated by reverse osmosis and ultraviolet irradiation, is available ad libitum during the study.
Diet: PMI Nutrition International, LLC Certified Rodent LabDiet® 5002 meal
Housing: All animals housed in groups of 2-3 by sex following receipt and throughout acclimation and the pre-mating period in clean, solid-bottom cages with bedding material (Bed O’Cobs® or other suitable material) in an environmentally controlled room.
During cohabitation, the females are paired (1:1) with a male from the same strain and source in solid-bottom cages for mating (home cage of the male). Following positive signs of mating or the end of the mating period, each female is individually housed in clean, solid-bottom cages with bedding material (Bed O’Cobs® or other suitable material) in an environmentally controlled room and remain in these cages with their litter until euthanasia. Upon completion of
successful mating, or at the end of the mating period, all adult males remain individually housed until euthanasia.
Animals were maintained in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, 2011).

ENVIRONMENTAL CONDITIONS
Controls will be set to maintain temperature at 73 ± 5°F (23 ± 3°C) and relative humidity at 50 ± 20%. Temperature and relative humidity will be monitored continuously. Data for these 2 parameters will be scheduled for automatic collection on an hourly basis. Fluorescent lighting controlled by light timers will provide illumination for a 12-hour light/dark photoperiod. Overhead lights in the study room will not be illuminated during the dark portion of the light/dark photoperiod, unless approved by the Study Director. Functions performed during the dark portion of the light/dark photoperiod will be performed with the use of lamps and/or flashlights.
The cages will be subjected to routine cleaning at a frequency consistent with maintaining good animal health and Charles River Standard Operating Procedures.
Route of administration:
oral: feed
Vehicle:
other: PMI Nutrition International, LLC Certified Rodent LabDiet® 5002
Details on study schedule:
Study Initiation Date: 28 Jul 2020
Experimental Starting Date: 26 Aug 2020
Initiation of Exposure: 26 Aug 2020
Completion of In-life: 19 Oct 2020
Dose / conc.:
150 mg/kg bw/day (nominal)
Remarks:
mean test substance consumption:
Males: 155mg/kg/day // Females: 215.1mg/kg/day (prior to mating); 156.6mg/kg/day (gestation); 314.4mg/kg/day (lactation)
Dose / conc.:
300 mg/kg bw/day (nominal)
Remarks:
mean test substance consumption:
Males: 320.1mg/kg/day // Females: 451.9mg/kg/day (prior to mating); 307.7mg/kg/day (gestation); 702.5mg/kg/day (lactation)
Dose / conc.:
600 mg/kg bw/day (nominal)
Remarks:
mean test substance consumption:
Males: 667.5mg/kg/day // Females: 937.2mg/kg/day (prior to mating); 693.3mg/kg/day (gestation); 1399.3mg/kg/day (lactation)
No. of animals per sex per dose:
10 males and 10 females per group.
Control animals:
yes
Positive control:
None
Clinical signs:
no effects observed
Description (incidence and severity):
All F0 males and females in the control, 2300, 4750, and 10,000 ppm groups survived to the
scheduled necropsy. No test substance-related clinical observations were noted at the daily
examinations at any dietary concentration. Observations noted in the test substance-exposed groups were noted infrequently, similarly in the control group, and/or in a manner that was not
concentration related.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean body weights and body weight gains in the 2300, 4750, and 10,000 ppm (achieved doses of 155.0, 320.1, and 667.5 mg/kg/day, respectively) group males were unaffected by tessubstance exposure throughout the study. Differences from the control group were slight, not statistically significant, and/or not noted in a concentration-related manner.

Mean body weights and body weight gains in the 2300, 4750, and 10,000 ppm (achieved doses of 215.1, 451.9, and 937.2 mg/kg/day, respectively) group females were unaffected by test substance exposure during the premating period. None of the differences from the control group were statistically significant. In the 10,000 ppm group, slightly lower mean body weight gains were occasionally noted duringthe gestation, resulting in a statistically significantly lower mean body weight gain when the entire gestation exposure period (Gestation Days 0–20) was evaluated compared to the control
group. Consequently, mean absolute body weight at 10,000 ppm was 5.7% lower (not statistically significant) than the control group on Gestation Day 20. The effects on mean body
weight and body weight gains at 10,000 ppm (achieved dose of 693.3 mg/kg/day) were considered test substance-related, but not adverse, due to the minimal impact on mean absolute
body weight.
Mean body weights and body weight gains in the 2300 and 4750 ppm groups (achieved doses of 156.6 and 307.7 mg/kg/day, respectively) were unaffected by test substance exposure during
gestation. None of the differences from the control group were statistically significant.

Mean body weights and body weight gains in the 2300, 4750, and 10,000 ppm (achieved doses of 314.4, 702.5, and 1399.3 mg/kg/day, respectively) groups were unaffected by test substance
exposure during lactation. None of the differences from the control group were statistically significant
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Mean food consumption, evaluated as g/animal/day, and food utilization in the 2300, 4750, and
10,000 ppm group males (achieved doses of 155.0, 320.1, and 667.5 mg/kg/day, respectively)
was unaffected by test substance exposure. Statistically significant differences in food
consumption were noted in all test substance-exposed groups sporadically throughout the
premating period (Study Days 0–14). However, these differences had no effect on mean absolute
body weights or body weight gains at any dietary concentration, and therefore were not
considered test substance-related.

Mean food consumption, evaluated as g/animal/day, and food utilization in the 2300, 4750, and
10,000 ppm groups (achieved doses of 215.1, 451.9, and 937.2 mg/kg/day, respectively) was
unaffected by test substance exposure during the premating period. Any statistically significant
differences in the test substance-exposed groups were transient in nature, were not noted in a
concentration-related manner, and/or had no effect on mean absolute body weights and body
weight gains during the premating period, and therefore were not considered test
substance-related.

Mean maternal food consumption, evaluated as g/animal/day, in the 10,000 ppm (achieved dose
of 693.3 mg/kg/day) group was generally lower than the control group throughout gestation and
when the entire gestation period (Gestation Days 0–20) was evaluated; the difference was
statistically significant only on Gestation Day 6–7. Lower (not statistically significant) mean
food utilization was also noted in the 10,000 ppm group throughout gestation. The lower mean
food consumption corresponded with the lower mean body weight gains noted in this group and
were considered test substance-related, but without toxicological significance or relevance, based
on the minimal impact on mean absolute body weight.
In the 2300 and 4750 ppm (achieved doses of 156.6 and 307.7 mg/kg/day, respectively) groups,
mean maternal food consumption and food utilization were generally lower than the control
group throughout gestation; differences were occasionally statistically significant and not noted
in a clear concentration-related manner. The effects on maternal food consumption at 2300 and
4750 ppm were considered test substance-related, but without toxicological significance or
relevance, based on the lack of effects on mean absolute body weights and body weight gains in
these groups.

Mean maternal food consumption, evaluated as g/animal/day, and utilization in the 2300, 4750,
and 10,000 ppm groups (achieved doses of 314.4, 702.5, and 1399.3 mg/kg/day, respectively)
was unaffected by test substance during lactation. None of the differences from the control group
were statistically significant
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:
effects observed, non-treatment-related
Description (incidence and severity):
In the 2300, 4750, and 10,000 ppm group F0 males (achieved doses of 155.0, 320.1, and
667.5 mg/kg/day groups, respectively), lower (8.7%, 15.7%, and 50.7%, respectively) mean T4
concentrations were noted compared to the control group; the differences were statistically
significant at 4750 and 10,000 ppm. The lower mean T4 concentrations were considered test
substance-related based on the magnitude of change and the concentration-related manner in
which the differences were observed. However, the lower T4 concentrations noted for F0 males
were considered nonadverse, based on the lack of corresponding effects on mean thyroid gland
weights or histopathologic findings, the inherent biological variability of this hormone in the
male rat, and the lack of evidence of endocrine disruption at any dietary concentration. In
addition, changes in thyroid hormone levels in the plasma is not necessarily an indication of a
toxic effect of the test substance, but rather can be affected by the strain, sex, and age of the rat,
as well as the handling of the individual anima
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No test substance-related microscopic findings were noted. The microscopic findings observed
were considered incidental, of the nature commonly observed in this strain and age of rats,
and/or were of similar incidence and severity in control and treated animals and, therefore, were
considered unrelated to exposure of the test substance
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
Mean gestation lengths in the 2300, 4750, and 10,000 groups were similar to those in the control
group. No statistically significant differences were noted. No signs of dystocia were noted in
these groups.
The mean numbers of implantation sites, mean postimplantation loss, and live birth and gestation
indices in the 2300, 4750, and 10,000 ppm groups were similar to the control group values.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
No test substance-related effects on reproductive performance were observed at any exposure
concentration. No statistically significant differences were noted between the control and test
Reproductive performance:
no effects observed
Description (incidence and severity):
No test substance-related effects on reproductive performance were observed at any exposure
concentration. No statistically significant differences were noted between the control and test
No test substance-related effects on reproductive performance were observed at any exposure
concentration. The mean numbers of days between pairing and coitus in the test substance-exposed groups were
similar to the control group value. The mean lengths of estrous cycles in these groups were also
similar to the control group value. None of these differences were statistically significant.
Key result
Dose descriptor:
NOAEL
Effect level:
> 638.8 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
female lowest result (period gestation)
Key result
Dose descriptor:
NOAEL
Effect level:
> 667.5 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: based on the absence of any adverse effects at all dietary concentrations tested
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Critical effects observed:
no
Clinical signs:
no effects observed
Description (incidence and severity):
The general physical condition (defined as the occurrence and severity of clinical observations)
of all F1 pups in this study was unaffected by test substance exposure.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Two (1), 1(1), and 2(1) pups (litters) in the control, 2300, and 4750 ppm groups, respectively, were found dead.
Two (2) and 11(3) pups (litters) in the 2300 and 4750 ppm groups, respectively, were missing.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In the 10,000 ppm (achieved dose of 1399.3 mg/kg/day for F0 females) group, mean F1 male and
female birth (PND 1) weights were 8.30% and 9.20% lower, respectively, than the control group;
differences were not statistically significant. Lower (not statistically significant) mean body
weight gains were noted for F1 males and females at 10,000 ppm during PND 1–7 compared to
the control group, resulting in mean F1 male and female absolute body weights that were 12.49%
to 14.25% and 11.47% to 14.98% lower, respectively, than the control group during PND 4–10;
the difference was statistically significant for F1 females on PND 7. Mean body weight gains for
F1 males and females in the 10,000 ppm group were similar to or higher than the control group
during PND 7–13, resulting in mean absolute body weights that were 7.08% and 5.46% lower,
respectively, than the control group on PND 13; none of the differences were statistically
significant. The effects on mean absolute body weights and body weight gains following birth
(PND 1–7) in the 10,000 ppm group were considered test substance-related, but not adverse,
based on the similar body weights and body weight gains to the control group during the latter
portion (PND 7–13) and at the end of the postnatal period (recovery), and the absence of any
other evidence of developmental toxicity (live birth index, pup birth weights, number of pups
born, pup postnatal survival, etc.) at this concentration.
Mean male and female pup body weights and body weight changes in the 2300 and 4750 ppm
groups were unaffected by parental exposure of the test substance throughout the postnatal
period. No statistically significant differences from the control group were noted and were
considered minimal.
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
Endocrine findings:
no effects observed
Description (incidence and severity):
There were no test substance-related effects on thyroid hormone values in the F1 males and
females at any dietary concentration on PND 13. Differences from the control group slight, not
statistically significant, and/or were not noted in a concentration-related manner.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Mean thyroid/parathyroid weights for F1 males and females in 2300, 4750, and 10,000 ppm
groups was unaffected by parental exposure of the test substance. Differences from the control
group were slight, not statistically significant, and/or not noted in a concentration-related
manner.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Two (1), 1(1), and 2(1) pups (litters) in the control, 2300, and 4750 ppm groups, respectively,
were found dead. No internal findings that could be attributed to parental test substance exposure
were noted at the necropsies of pups that were found dead. Aside from the presence or absence
of milk in the stomach, no other internal findings were noted.
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Mortality / viability:
not examined
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
.
Mean male and female pup body weights and body weight changes in the 2300 and 4750 ppm
groups were unaffected by parental exposure of the test substance throughout the postnatal
period. No statistically significant differences from the control group were noted and were
considered minimal.
Anogenital distance (AGD):
no effects observed
Description (incidence and severity):
The anogenital distances (absolute and relative to the cube root of pup body weight) in the 2300,
4750, and 10,000 ppm groups were similar to the control group values when evaluated on PND 1
and 4. Differences from the control group were slight and not statistically significant
Nipple retention in male pups:
no effects observed
Description (incidence and severity):
Areolae/nipple anlagen in the F1 male pups was unaffected by parental exposure of the test
substance when evaluated on PND 13. No retained nipples were noted for male pups at any
exposure level.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Mean thyroid/parathyroid weights for F1 males and females in 2300, 4750, and 10,000 ppm
groups was unaffected by parental exposure of the test substance. Differences from the control
group were slight, not statistically significant, and/or not noted in a concentration-related
manner.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Two (1), 1(1), and 2(1) pups (litters) in the control, 2300, and 4750 ppm groups, respectively,
were found dead. No internal findings that could be attributed to parental test substance exposure
were noted at the necropsies of pups that were found dead. Aside from the presence or absence
of milk in the stomach, no other internal findings were noted.
Remarks on result:
other: Awaiting test results
Key result
Reproductive effects observed:
no
Lowest effective dose / conc.:
638.8 mg/kg bw/day (actual dose received)
Treatment related:
no
Conclusions:
Under the conditions of this screening study, based on the absence of any adverse effects at all dietary concentrations tested, a concentration of 10,000 ppm (the highest dietary concentration tested; achieved doses of 667.5 mg/kg/day [F0 males] and 638.8，693.3, and 1399.3 mg/kg/day [F0 females during premating, gestation, and lactation, respectively]) was considered to be the no-observed-adverse-effect level (NOAEL) for F0 systemic toxicity, F0 reproductive toxicity, and F1 neonatal toxicity of Rosyfolia when administered continuously in the diet to Crl:WI(Han) rats.
Executive summary:

The objective of this study was to provide preliminary information on the potential adverse effects of the test substance on male and female reproduction within the scope of a screening study. This encompassed gonadal function, mating behavior, conception, parturition, and lactation of the parental generation and the development of offspring from conception through Day 13 or postnatal life.

Animals were exposed to the test substance continuously in the diet. Males were exposed for 14 days prior to mating and continuing through euthanasia (Study Days 0–27). Females were exposed for 14 days prior to mating and continuing through Lactation Day 13. The following parameters and end points were evaluated in this study: clinical signs, body weights, body weight gains, food consumption, estrous cycles, reproductive performance, parturition, litter viability and survival, anogenital distance, areolae/nipple anlagen retention, thyroid hormones, gross necropsy findings, organ weights, and histopathologic examinations.

All F0 males and females in the control, 2300, 4750, and 10,000 ppm groups survived to the scheduled necropsy. No test substance-related clinical observations were noted at any dietary concentration.

In the 10,000 ppm group, lower mean body weight gains, with corresponding lower mean food consumption and food utilization, were noted for F0 females throughout gestation (GestationDays 0–20) compared to the control group, resulting in a mean absolute body weight in this group that was 5.7% lower than the control group on Gestation Day 20. The effects on body weight gain and food consumption for F0 females at 10,000 ppm (achieved dose of 693.3 mg/kg/day) during gestation were considered test substance-related, but not adverse, based on the relatively small magnitude of change for mean absolute body weights and the lack of

other signs of maternal toxicity. Lower mean food consumption and food utilization were also noted for F0 females in the 2300 and 4750 ppm groups generally throughout gestation (Gestation Days 0–20) compared to the control group. The effects on mean food consumption for F0 females at 2300 and 4750 ppm (achieved doses of 156.6 and 307.7 mg/kg/day, respectively) during gestation were considered test substance-related, but without toxicological significance or relevance, based on the lack of effects on mean body weights and body weight gains in these groups. Mean absolute body weights, body weight gains, food consumption, and food utilization for F0 females (during the premating and lactation periods) and for F0 males (throughout the dosing period) were unaffected by test substance exposure at all dietary concentrations.

There were no test substance-related effects on F0 reproductive performance (mating, fertility, and pregnancy indices), estrous cyclicity, precoital intervals, or delivery observations (including gestation length, gestation index, and implantation sites) at any dietary concentration. Lower (8.7% to 50.7%) mean T4 concentrations were noted for F0 males in the 2300, 4750, and 10,000 ppm groups (achieved doses of 155.0, 320.1, and 667.5 mg/kg/day, respectively) compared to the control group. These differences were considered test substance-related based on the magnitude of change and the concentration-related manner in which the differences were

observed. However, the lower T4 concentrations noted for F0 males were considered nonadverse, based on the lack of corresponding effects on mean thyroid gland weights or histopathologic findings, the inherent biological variability of this hormone in the male rat, and the lack of evidence of endocrine disruption at any dietary concentration. In addition, changes in thyroid hormone levels in the plasma is not necessarily an indication of a toxic effect of the test substance, but rather can be affected by the strain, sex, and age of the rat, as well as the handling of the individual animal (Dohler et al, 1979).

Test substance-related higher mean kidney weights (relative to terminal body weight) were noted in the 2300, 4750, and 10,000 ppm group F0 males (achieved doses of 155.0, 320.1, and 667.5 mg/kg/day, respectively), and a higher mean kidney weight (relative to brain weight) was noted in the 10,000 ppm group F0 males (achieved dose of 667.5 mg/kg/day). These findings were within the range of the historical control database values, had no microscopic correlates, and were considered nonadverse. There were no other test substance-related effects in F0 male and female gross observations, organ weights, or histopathology.

The mean number of F1 pups born (including number of live newborn pups), percentage of males at birth, postnatal survival (including live birth, viability, and survival indices), clinical conditions of the pups, absolute and relative anogenital distance, and areola/nipple retention (males) in the 2300, 4750, and 10,000 ppm groups were unaffected by parental test substance exposure.

In the 10,000 ppm group (achieved dose of 1399.3 mg/kg/day for F0 females), mean F1 male and female pup birth weight (PND 1) were 8.30% and 9.20% lower, respectively, than the control group. Lower mean body weight gains were noted for F1 male and female pups at 10,000 ppm during PND 1–7 compared to the control group, resulting in mean absolute body weights that were up to 14.25% and 14.98% lower, respectively, than the control group during PND 4–10.

Mean body weight gains for F1 male and female pups in this group were similar to or higher than the control group during PND 7–13, resulting in mean absolute body weights that were similar to the control group on PND 13. The initial effects on F1 pup body weights and body weight gains during PND 1–7 at 10,000 ppm were considered test substance-related, but not adverse, because mean F1 male and female pup body weights in this group were similar to the control group

during the latter portion (PND 7–13) and at the end of the postnatal evaluation period. Mean F1 pup body weights and body weight gains in the 2300 and 4750 ppm groups were unaffected by parental exposure to the test substance.

There were no test substance-related macroscopic findings noted in F1 pups that were found dead or at the scheduled necropsy on PND 13. There were no test substance-related effects on serum T4 concentration or thyroid/parathyroid weights in the F1 pups at any dietary concentration on PND 13.

In conclusion, under the conditions of this screening study, based on the absence of any adverse effects at all dietary concentrations tested, a concentration of 10,000 ppm (the highest dietary concentration tested; achieved doses of 667.5 mg/kg/day [F0 males] and 937.2, 693.3, and 1399.3 mg/kg/day [F0 females during premating, gestation, and lactation, respectively]) was considered to be the no-observed-adverse-effect level (NOAEL) for F0 systemic toxicity, F0 reproductive toxicity, and F1 neonatal toxicity of Rosyfolia when administered continuously in the diet to Crl:WI(Han) rats.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
638.8 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
638.8 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP
Additional information

The lowest NOAEL of 638.8 mg/kg/day is selected given the different animals were exposed on diet with dose level of the 1000 ppm up to 1399.3 mg/kg/day during lactation period.

Justification for classification or non-classification

As there is no toxicity was identified up to the top dose in male and female prior to mating, gestation and lactation periods, and also systemic toxicity identified as well. Thus non-classification is selected for this endpoint.

Additional information