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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:
Sept-October 2009
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report Date:
2010

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Name: Uvasorb® HEB
Description: Whitish powder
Storage: RT, PL, with dessicant
Lot Number: 1508G21
Expiration Date: 29 JUL 2013

Test animals

Species:
rat
Strain:
CD-1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Portage, MI
- Age at study initiation: Approximate Age at Arrival 72 days for males and 66 days for females
- Weight at study initiation: Weight (g) on Day after Arrival (P) Males: 290 - 325 g; Females: 190 - 220 g; (F1) Males: 382 - 421 g; Females: 234 - 260 g
- Housing: Adult generation rats were individually housed in stainless steel, wire-bottomed cages, except during the cohabitation and postpartum periods. During cohabitation, each pair of rats was housed in the male rat's cage. Beginning no later than DG 20, female rats were individually housed in nesting boxes. Each dam and delivered litter was housed in a common nesting box during the postpartum period. All cage sizes and housing
conditions were in compliance with the Guide for the Care and Use of Laboratory Animals. Cages of adult rats were arranged to minimize possible effects due to cage placement by vertical distribution of dosage groups in the cage racks.
- Diet :. ad libitum
- Water : ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): (18°C to 26°C
- Humidity (%): 30% to 70%
- Air changes (per hr): minimum of ten changes per hour of 100% fresh air that had been passed through 99.97% HEPA filters
- Photoperiod (hrs dark / hrs light): An automatically controlled 12-hours light:12-hours dark fluorescent light cycle was maintained. Each dark period began at 1900 hours (± 30 minutes).

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on mating procedure:
Within each dosage group, consecutive order was used to assign rats to cohabitation, one male rat per female rat. The cohabitation period consisted of a maximum of 14 days.
Female rats with spermatozoa observed in a smear of the vaginal contents and/or a copulatory plug observed in situ were considered to be at DG 0 and assigned to individual housing. One female rat with no confirmed date of mating after completion of the 14-day cohabitation period was removed from cohabitation and assigned to individual housing.
Duration of treatment / exposure:
Male rats were administered the test substance and/or the vehicle once daily beginning 14 days before cohabitation, through the cohabitation period (maximum 14 days) and continuing through the day before sacrifice (at least 14 days after the completion of cohabitation).
Female rats were given the test substance and/or the vehicle once daily beginning 14 days before cohabitation, through the cohabitation period (maximum 14 days) and continuing through day 4 postpartum. Any dam in the process of parturition was not given the test substance and/or vehicle until the following work day. Such events were noted and tabulated. No dam missed more than one daily dosage.
Dosages were adjusted daily for body weight changes and given at approximately the same time each day. Prepared formulations were stirred continuously during dosage administration.
Pups were not directly given the test substance and/or the vehicle but may have been exposed to the test substance and/or the vehicle in utero during gestation or via maternal milk during the lactation period.
Frequency of treatment:
once daily
given at approximately the same time each day.
Doses / concentrations
Remarks:
Doses / Concentrations:

Basis:
nominal conc.
250, 500 and 1000 mg/kg/day. The dosage volume was 5 mL/kg
No. of animals per sex per dose:
Forty male and forty female Crl:CD(SD) rats were assigned to four dosage groups (Groups I through IV; 10 rats per sex per group).

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:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

Male Rats
One male rat in the 1000 mg/kg/day dosage group was euthanized on day 22 of study (DS 22) because of adverse clinical signs. This early death was presumed related to administration of Uvasorb® HEB. All other male rats survived until scheduled sacrifice.
Clinical signs attributed to Uvasorb® HEB generally were limited to the 1000 mg/kg/day dosage group, and included reduced grooming (i.e., fecal staining in the anogenital region, ungroomed coat), signs of respiratory distress (i.e., rales and hyperpnea), mild to moderate dehydration (based on skin turgor), hunched posture, red and/or brown perioral substance, scant feces and piloerection. Low incidences of gasping, thin body condition,
pale ears, ptosis, dyspnea, tachypnea, red perinasal substance, pale extremities, decreased motor activity, teeth grinding, bradypnea, fecal staining in the urogenital region, mucoid or black feces, paws cold to touch and tip-toe walk also occurred at 1000 mg/kg/day and were attributed to Uvasorb® HEB.
At 1000 mg/kg/day, body weight gains were significantly reduced during the first two weeks of the dosage period, with the most pronounced effects occurring on DSs 8 to 14, and again on DSs 14 to 22. Thereafter, body weight gains for male rats treated with 1000 mg/kg/day Uvasorb® HEB were generally increased (except DSs 36 to 43) as compared to the vehicle control group values. Despite these increases, body weight gains in the 1000 mg/kg/day dosage group were reduced by 22% for the entire dosage period when compared to the vehicle control group value. Reflecting the reduced body weight gains, the average body weight in the 1000 mg/kg/day dosage group was significantly reduced on DSs 14 and 22, in comparison to the vehicle control group values.
Corresponding to the reductions in body weight gain, absolute feed consumption values at 1000 mg/kg/day were lower than the vehicle control group value on DSs 1 to 14 (7% lower than the vehicle control group value). Thereafter, absolute feed consumption values were comparable to the vehicle control group values.
There were no effects on mating and fertility, terminal body weights or male reproductive organ weights at any dosage level tested. In addition, there were no treatment-related gross lesions or microscopic observations at any dosage level tested.

Female Rats
One female rat in the 1000 mg/kg/day dosage group was euthanized on day 9 of gestation (DG 9) because of adverse clinical signs. This early death was presumed related to administration of Uvasorb® HEB. All other female rats survived until scheduled sacrifice.
Gasping occurred in a significantly increased number of female rats in the 1000 mg/kg/day dosage group, in comparison to the vehicle control group value. This observation occurred in each rat (N=3) on one occasion during the premating period, and was also observed in male rats in this same dosage group. Further, rales, urine-stained abdominal fur, white or red perioral substance, fecal staining in the anogenital region, decreased motor activity, dyspnea, open mouth breathing, pale extremities and ears, hunched posture and moderate excess salivation occurred in one or two rats on at least one occasion during the premating period. Most of these clinical signs occurred in the female rat that was euthanized during the gestation period.
A net loss in body weight occurred in female rats at 1000 mg/kg/day during the second week of the premating dosage period (DSs 8 to 14; -1.0 g loss vs. a gain of 6.9 g in controls), which resulted in an overall reduction in body weight gains for the entire premating dosage period (DSs 1 to 14; 35% of the vehicle control group value).
Body weights and body weight gains of the gestating and lactating female rats were unaffected by dosages of Uvasorb® HEB as high as 1000 mg/kg/day. In addition, absolute and relative feed consumption values during the premating, gestation and lactation periods were also unaffected at any dosage level tested.
Uvasorb® HEB did not affect estrous cycling, mating or fertility, natural delivery or litter observations or female reproductive organ weights at any dosage level tested. All pregnant rats (10, 10, 10 and 8 rats in the four respective dosage groups) delivered a litter.
No gross lesions were identified at necropsy examination, and there were no microscopic observations related to Uvasorb® HEB.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Remarks:
for general toxicity
Effect level:
500 mg/kg bw/day
Sex:
male/female
Dose descriptor:
NOAEL
Remarks:
for reproductive toxicity
Effect level:
> 1 000 mg/kg bw/day
Sex:
male/female

Results: F1 generation

General toxicity (F1)

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

Details on results (F1)

In the F1 generation pups, there were no apparent effects on clinical or necropsy observations following paternal or maternal treatment.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Little to no information currently exists on the reproductive effects of Uvasorb® HEB in Sprague-Dawley rats. Therefore, the purpose of this screening study was to provide preliminary information concerning the effects of Uvasorb® HEB on male and female rat reproductive performance.

Based on the results of this study, the no-observable-adverse-effect-level (NOAEL) for general toxicity for Uvasorb® HEB is 500 mg/kg/day. Mortality was observed in both sexes at 1000 mg/kg/day, in addition to adverse clinical signs, reductions in body weight gain and/or net losses in body weight.
Uvasorb® HEB did not affect the ability of male and female rats to mate and produce viable litters at any dosage level tested. In addition, there were no microscopic changes in the testes of male rats that would indicate that Uvasorb® HEB should be considered a reproductive toxicant at dosages as high as 1000 mg/kg/day. Therefore, the NOAEL for reproductive toxicity is greater than 1000 mg/kg/day.