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Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
The substance has a low Toxicologic activity.and none of the available test supply evidence of toxicity, However relevant data are available
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
structural similarity assessed by QSAR Toolbox v 3.4.0
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
The substance has a low Toxicologic activity.and none of the available test supply evidence of toxicity, However relevant data are available
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Species:
rat
Strain:
other: Crj:CD(sd)IGS
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
corn oil
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: no adverse effects on the estrous cycle, mating index, fertility index, gestation index, gestation length, number of corpora lutea, number and rate of implantations, and delivery index.
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
sexual maturation
clinical signs
body weight and weight gain
Reproductive effects observed:
no

<Reproductive and developmental toxicity>

There were no adverse effects on the estrous cycle, mating index, fertility index, gestation index, gestation length, number of corpora lutea, number and rate of implantations, and delivery index. Observations of pups revealed no effects of the compound on viability, sex ratio and body weight. There were no abnormalities in morphology of pups related to dosing.

<No observed adverse effect level(NOAEL)>

From these results, under the conditions of this study, the NOAEL, both for repeated dose toxicity and reproductive and developmental toxicity, is considered to be 1000 mg/kg/day.      

Conclusions:


From these results, under the conditions of this study, the NOAEL, both for repeated dose toxicity and reproductive and developmental toxicity, is considered to be 1000 mg/kg/day.
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1986
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
The substance has a low Toxicologic activity.and none of the available test supply evidence of toxicity, However relevant data are available
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
other: EPA Proposed guidelines for health assessment of suspect developmental toxicants. Federal Register 49 (227) p.46325
GLP compliance:
no
Species:
rat
Strain:
Sprague-Dawley
Remarks:
(approximately 9 weeks old)
Sex:
male/female
Route of administration:
dermal
Vehicle:
unchanged (no vehicle)
Duration of treatment / exposure:
20 Day
Frequency of treatment:
daily
Remarks:
0.0, 800.0 or 2000.0 mg/kg/day
No. of animals per sex per dose:
20
Details on study design:
No. of animals: Three groups of 15 presumed-pregnant rats: Six groups of 10 males and 10 females Group 1 (control); Group 2 (800 mg/kg); and Group 3 (2000 mg/kg) Control: 15 Females for Group 1

During the mating period female rats which had not previously borne pups were placed Conditions with male rats in a ratio of 1:1 and observed daily for evidence of having engaged ir breeding activity.

Presumed-pregnant rats were distributed among three experimental groups: one dermal control, and two exposed groups. At the start of the dosing phase of the study, all of the experimental groups contained 15 presumed-pregnant females. All treatments for Groups l-3 were preformed on each of gestation days 0-19, where designation as gestation day 0 followed detection of a vaginal plug (in situ or expelled) and spermatozoa in the vaginal lavage fluid.

Test article was applied once daily to the clipped, intact dorsal skin of the rat. In no case were the application sites covered. To minimize ingestion of the test material, the rats were fitted with cardboard Elizabethan-style collars.
All animals were monitored throughout gestation until sacrifice for
1.) changes in appearance, behavior, and excretory function, and
2.) signs of ill-health, mortality, or abortion. A pre-partum investigation on a variety of fetal and maternal parameters foi each of the groups was undertaken to assess the influence of test article on reproductive performance.
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
2 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
Reproductive effects observed:
no

Administration of test article to the uncovered skin of collared rats at doses of 800 or 2000 mg/kg/day produced slight skin irritation (erythema and flaking) at the site of application. Neither maternal parameters (food consumption, body weight gain: monitored throughout gestation (days O-19) nor reproductive parameters (number ol implants, resorptions, or viable fetuses) were adversely affected at either of the dose levels tested. No evidence of teratogenicity (abnormal development) was observec during external examination of fetuses from pregnant dams exposed to test article. Mean fetal body weights and crown-rump distances were similar in all of the experimental groups.    

Conclusions:
Dermal administration of test article did not adversely affect parameters of reproductiw performance during gestation, nor did it adversely affect in utero survival and development of concepti.

Data source

Reference
Reference Type:
publication
Title:
Pentaerythritol tetra(2-ethylhexanoate) Repeated dose and Reproductive/developmental toxicity
Year:
2005
Bibliographic source:
http://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF7299-99-2d.pdf

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes

Test material

1
Reference substance name:
Reference substance 001
Cas Number:
7299-99-2

Test animals

Species:
rat
Strain:
other: Crj:CD(sd)IGS
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: no adverse effects on the estrous cycle, mating index, fertility index, gestation index, gestation length, number of corpora lutea, number and rate of implantations, and delivery index.
Remarks on result:
not determinable due to absence of adverse toxic effects

Results: F1 generation

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
sexual maturation
clinical signs
body weight and weight gain

Overall reproductive toxicity

Reproductive effects observed:
no

Any other information on results incl. tables

<Reproductive and developmental toxicity>

There were no adverse effects on the estrous cycle, mating index, fertility index, gestation index, gestation length, number of corpora lutea, number and rate of implantations, and delivery index. Observations of pups revealed no effects of the compound on viability, sex ratio and body weight. There were no abnormalities in morphology of pups related to dosing.

<No observed adverse effect level(NOAEL)>

From these results, under the conditions of this study, the NOAEL, both for repeated dose toxicity and reproductive and developmental toxicity, is considered to be 1000 mg/kg/day.      

Applicant's summary and conclusion

Conclusions:


From these results, under the conditions of this study, the NOAEL, both for repeated dose toxicity and reproductive and developmental toxicity, is considered to be 1000 mg/kg/day.