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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Remarks:
Supporting study to exclude teratogenic effects, specifically related to levocardia, in rat offspring following exposure to synthetic esters
Adequacy of study:
supporting study
Study period:
1990
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Remarks:
acceptable restrictions include nonstandard dermal exposure, only a single dose group (2000 mg/kg/day), and administration on gestation days 0-19

Data source

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

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
nonstandard dermal exposure, only a single dose (2000 mg/kg/day) in addition to sham controls, exposure on day 0-19 of gestation, limited details on exposure
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS:
Number of female Sprague-Dawley rats: 170
Number of male Sprague-Dawley rats: 50
Age at study initiation: approx. 9 weeks
Source: Charles River Laboratories, Portage, MI
Acclimation period: 2 weeks
Diet: Purina Certified Rodent Chow #5002 (meal), ad libitum
Water: tap water, ad libitum

ENVIRONMENTAL CONDITIONS:
Temperture (degrees Celsius): air-conditioned rooms set to 20-22 C
Relative humidity: 40-60%
Photoperiod (hrs dark/ hrs light): 12/12

Administration / exposure

Route of administration:
dermal
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Type of wrap if used: open exposure, no wrap
- Time intervals for shavings or clippings: animals were clipped/collared on gestation day 0, clipped once weekly thereafter, collars were replaced as necessary
- Exposure adminstered on clipped, intact skin
- Site: Dorsal
- Controls: The rats of the control group were clipped and collared as treated animals. The intact dorsal skin of each rat was stroked with the tip of a syringe, but no test material was applied
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused, M/F ratio per cage: 1/1
- Proof of pregnancy: vaginal plug/ sperm in vaginal smear referred to a day 0 of pregnancy
Duration of treatment / exposure:
gestation days 0-19
Frequency of treatment:
daily
Duration of test:
Animals were sacrificed on day 20 of gestation
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Sham Control
Dose / conc.:
2 000 mg/kg bw/day (nominal)
Remarks:
Stock 103
Dose / conc.:
2 000 mg/kg bw/day (nominal)
Remarks:
Stock 461 (Negative Control)
No. of animals per sex per dose:
25 presumed-pregnant females
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Doses for Stock 103 were based on results of a 13-week dermal study prreviously conducted with the same material (Study #61923), Stock 461 was selected as the negative control based on the fact thaat it is also a base stock that has been demonstrated to be non-teratogenic in a previously conducted developmental toxicity study (# 40922)

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
Time schedule: At least once daily
Cage side observations checked: signs of pathosis, abortion, premature delivery, and death

DETAILED CLINICAL OBSERVATIONS: no data

BODY WEIGHT: yes
Time schedule: days 0, 6, 10, 16, and 20 of gestation

FOOD CONSUMPTION AND COMPOUND INTAKE: no
WATER CONSUMPTION AND COMPOUND INTAKE: no
POST-MORTEM EXAMINATIONS: yes
Sacrifice: On day 20 of gestation
Examination: Thoracic and abdominal cavities were exposed and the reproductive organs were examined grossly for evidence of pathosis
Ovaries and uterine content:
Ovaries and uterine content were examined after sacrifice: yes
Examinations included:
- Gravid uterus weight: yes
- Number of corpora lutea per ovary of each pregnant female: yes
- Number and location of implantations: Yes
- Early resorptions: Yes
- Late resorptions: Yes
- Live and dead fetuses: Yes
- Other: ovaries of nonpregnant females were grossly examined and then discarded
Fetal examinations:
- External examinations: yes - all per litter
- Visceral anomalies: yes - all per litter
- Skeletal examinations: No
- Head examinations: No
Statistics:
- Analyses of variances and group comparison of maternal biophase, caesarean section, and fetal data were conducted using Fisher's Exact or Dunnett's test
- ANOVA followed by group comparisons using Bartlett's Test was applied to evaluate fetal visceral data
- Differences between control and treated groups were considered statistically significant if the probability of the difference being due to chance was less than 5% (p<0.05)

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
- Non-treatment related effects (often observed in collared animals): red nasal exudate, chromodacryorrhea, red vaginal discharge (previously noted in control females at this study facility).
- Treatment-related effects: decreased amount of stool and perineal staining. Transient (gestation day 3-7) "hunched" posture, decreased amount of stool, and soft stool with subsequent perineal staining was observed in a single female.


Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
- Non-treatment related effects (often observed in collared animals): neck lesions
- Treatment-related effects: skin irritation, including erythema, edema, flaking, and scabbing, skin stiffening and cracking (stock 461 exposed mice only),
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Stock 103 and Stock 461-exposed groups gained significantly less weight compared to control animals. Mean carcass weight and overall net body weight gain were significantly reduced.
Food consumption and compound intake (if feeding study):
not examined
Description (incidence and severity):
food was provided to animals ad libitum
Food efficiency:
not examined
Description (incidence and severity):
food was provided to animals ad libitum
Water consumption and compound intake (if drinking water study):
not examined
Description (incidence and severity):
water was provided to animals ad libitum
Ophthalmological findings:
no effects observed
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Only uterine weights were examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed

Effect levels (maternal animals)

open allclose all
Dose descriptor:
LOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
dermal irritation
Remarks on result:
other: skin irritation (erythema, flaking, scabbing)
Remarks:
skin irritation (erythema, flaking, scabbing)
Dose descriptor:
LOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
maternal abnormalities
number of abortions
pre and post implantation loss
total litter losses by resorption
effects on pregnancy duration
early or late resorptions
dead fetuses
changes in pregnancy duration
changes in number of pregnant
necropsy findings

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Description (incidence and severity):
Observations considered not to be treatment-related: One fetus in the control group and one fetus exposed to Stock 103 were born with microphthalmia (left eye only). One Stock 461-exposed fetus was edematous and had anophthalmia (left eye) and brachdactyly (bilateral hindpaws). A second fetus exposed to Stock 461 had a shortened and filamentous tail.
Skeletal malformations:
not examined
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
- One fetus (stock 103-treated) had moderate dilation of the renal pelvis
- One fetus (stock 461-treated) had a common truncus arteriosus (common aortic and pulmonary trunk)
- One fetus (stock 461-treated) had situs inversus of the heart, vessels, lungs, and stomach
- Anomalies observed at the time of visceral examination by sectioning included dilation of the lateral ventricles of the brain (control group only), anophthalmia (control group only), microphthalmia (control group only), dilation of the renal pelvis (stock 103-treated group only)
Other effects:
no effects observed

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
external malformations
visceral malformations
Remarks on result:
not determinable due to absence of adverse toxic effects

Applicant's summary and conclusion

Conclusions:
Stock 103 and Stock 461 (negative control) were adminstered once daily using dermal application to presumed pregnant rats at dose levels of 0 and 2000 mg/kg/day. All animals were exposed omn gestation days 1-19 and sacrificed on day 20.

Both materials produced slight to moderate skin irritation at the dosing site. A decrease in net body weight gain was the only sign of maternal toxicity observed in exposed animals. No adverse effects were noted for any of the reproductive parameters evaluated. Fetal development, specifically heart development, was unaffected by Stock 103 and Stock 461 treatment.