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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: According to or similar to guideline study OECD 422:GLP
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
read-across: supporting information
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:
1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: According to or similar to guideline study OECD 422:GLP
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
reference to same study
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
No deaths or clinical signs of toxicity or behavioral changes were noted. No significant differences in body weights or feed consumption were observed. Startle reflex, open field test, and forelimb grip reflex performance data also revealed no treatment-related findings in the parental animals. There were also no treatment-related changes in hematology or blood chemistry parameters, organ weights or gross pathology. An apparent treatment-related, slight to moderate hyperplasia of the non-glandular mucosa of the stomach, associated with degeneration, hyperkeratosis and submucosal subacute inflammation and, in a few cases, with erosion, was seen in animals of all treated groups. This effect was considered an artifact of the dosing method and not directly related to the toxicity of the test material. No other treatment related histological changes were observed.

There were no treatment-related effects at any dose level on any of the reproductive parameters evaluated in this study. These included measures of reproductive performance (mating, conception, gestation length, litter size), offspring survival (gestation and postnatal survival indices, percent pre- and post-implantation loss). The mean mating time of the 1000 mg/kg/day groups was slightly longer than of the control, however, the increase was not statistically significant and within the normal range of variability for this strain of rats. There was a, non dose-related, decrease in fertility (decreased fertility index) was observed in all treated groups (not statistically significant) compared to controls. However, this effect took place in the absence of any adverse effects on reproductive organs and may have resulted from changes in mating behavior due related to stomach irritation experienced by the treated animals.
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: No effects noted at highest dose tested.
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not specified
There were no treatment-related effects at any dose level on any of the reproductive parameters evaluated in this study including offspring survival (gestation and postnatal survival indices, percent pre- and post-implantation loss), pup body weight and pup sex ratio. There were also no treatment-related effects on any of the developmental parameters evaluated including external abnormalities, number of live and still births, mortality, sex determination and weights of pups.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: No effects noted at highest dose tested.
Reproductive effects observed:
not specified
Conclusions:
Oral dosing of Linpar 10 to male and female Sprague Dawley rats at levels of 0, 25, 150, or 1000 mg/kg body weight /day produced no evidence of developmental toxicity or teratogenicity and no statistically significant treatment-related effects on any of the reproductive parameters evaluated in this study. Based on these data, the no-observable-adverse effect level (NOAEL) for developmental toxicity was 1000 mg/kg/day and the NOAEL for reproductive toxicity was 1000 mg/kg/day, the highest dose tested.
Executive summary:

This data is being read across from the source study that tested decane based on analogue read across.

Groups of 10 male and 10 female Sprague Dawley rats were dosed with Linpar 10 daily by gavage at exposure levels of 0, 25, 150, or 1000 mg/kg/day Males were dosed from the 14th day prior to mating, during mating until the end of the mating period. Females were dosed from the 14th day prior to the start of the mating phase to day 4 of lactation.  There were no treatment-related effects at any dose level on any of the reproductive parameters evaluated in this study.  These included measures of reproductive performance (mating, conception, gestation length, litter size), offspring survival (gestation and postnatal survival indices, percent pre- and post-implantation loss), pup body weight and pup sex ratio. There were no treatment-related effects at any dose level on any of the developmental paramters evaluated in this study including external abnormalities of pups, number of live and still births, mortality, sex determination, and weights of pups.  Based on these data, the no-observable-adverse-effect level (NOAEL) for developmental toxicity was 1000 mg/kg/day and the NOAEL for reproductive toxicity was 1000 mg/kg/day.

Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report date:
1995

Materials and methods

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

Test material

Constituent 1
Chemical structure
Reference substance name:
Decane
EC Number:
204-686-4
EC Name:
Decane
Cas Number:
124-18-5
Molecular formula:
C10H22
IUPAC Name:
decane
Details on test material:
LINPAR 10 (commercial Decane)
approx. composition: 97% 1-decane

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
not specified
Details on exposure:
Males were treated from day 14 prior to the mating phase until the end of the mating phase and then killed, Females were treated from day 14 prior to mating, through day 4 of lactation and then killed.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Males were dosed from the 14th day prior to mating, during mating until the end of the mating period. Females were dosed from the 14th day prior to the start of the mating phase to day 4 of lactation.
Frequency of treatment:
Single daily dose 7days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 25, 150, or 1000 mg/kg/day (10 ml/kg dosing volume)
Basis:
other: gavage
No. of animals per sex per dose:
10 male, 10 female per group
Control group: 10 male, 10 female, 0.5% methylcellulose
Control animals:
yes

Examinations

Parental animals: Observations and examinations:
Effects on general toxicity, neurobehavioral activity, clinical chemistry, and hematology were evaluated. Gross necropsies and histopathologic examination of tissues were conducted with emphasis on the male reproductive tract.
Reproductive assessment included mating, conception and fertility indices, reproductive organ weights and gross and histologic examination of the reproductive tract (special emphasis on stages of spermatogenesis in male gonads and interstitial testicular cell structure).
Sperm parameters (parental animals):
stages of spermatogenesis in male gonads and interstitial testicular cell structure
Litter observations:
Developmental toxicity assessment included, observations of external abnormalities, number of live and still births, mortality, sex determination and weights of pups.
Statistics:
Adult body weights and feed consumption, maternal body weight gains, gestation length and pup body weights were analyzed by ANOVA. Mean mating time was analyzed via the Kaplan Meier method. Pregnancy rates and mating, conception, viability index, post implantation losses, fertility and gestation indices were analyzed by the trend test, Chi-square 2XN and Fisher's exact test (all one tailed). The probability of survival per group was calculated by the product-limit procedure of Kaplan-Meier. Both a trend test and a log-rank test were used to analyze differences in survival among groups.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

No deaths or clinical signs of toxicity or behavioral changes were noted. No significant differences in body weights or feed consumption were observed. Startle reflex, open field test, and forelimb grip reflex performance data also revealed no treatment-related findings in the parental animals. There were also no treatment-related changes in hematology or blood chemistry parameters, organ weights or gross pathology. An apparent treatment-related, slight to moderate hyperplasia of the non-glandular mucosa of the stomach, associated with degeneration, hyperkeratosis and submucosal subacute inflammation and, in a few cases, with erosion, was seen in animals of all treated groups. This effect was considered an artifact of the dosing method and not directly related to the toxicity of the test material. No other treatment related histological changes were observed.

There were no treatment-related effects at any dose level on any of the reproductive parameters evaluated in this study. These included measures of reproductive performance (mating, conception, gestation length, litter size), offspring survival (gestation and postnatal survival indices, percent pre- and post-implantation loss). The mean mating time of the 1000 mg/kg/day groups was slightly longer than of the control, however, the increase was not statistically significant and within the normal range of variability for this strain of rats. There was a, non dose-related, decrease in fertility (decreased fertility index) was observed in all treated groups (not statistically significant) compared to controls. However, this effect took place in the absence of any adverse effects on reproductive organs and may have resulted from changes in mating behavior due related to stomach irritation experienced by the treated animals.

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: No effects noted at highest dose tested.

Results: F1 generation

General toxicity (F1)

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

Details on results (F1)

There were no treatment-related effects at any dose level on any of the reproductive parameters evaluated in this study including offspring survival (gestation and postnatal survival indices, percent pre- and post-implantation loss), pup body weight and pup sex ratio. There were also no treatment-related effects on any of the developmental parameters evaluated including external abnormalities, number of live and still births, mortality, sex determination and weights of pups.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: No effects noted at highest dose tested.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Oral dosing of Linpar 10 to male and female Sprague Dawley rats at levels of 0, 25, 150, or 1000 mg/kg body weight /day produced no evidence of developmental toxicity or teratogenicity and no statistically significant treatment-related effects on any of the reproductive parameters evaluated in this study. Based on these data, the no-observable-adverse effect level (NOAEL) for developmental toxicity was 1000 mg/kg/day and the NOAEL for reproductive toxicity was 1000 mg/kg/day, the highest dose tested.
Executive summary:

Groups of 10 male and 10 female Sprague Dawley rats were dosed with Linpar 10 daily by gavage at exposure levels of 0, 25, 150, or 1000 mg/kg/day Males were dosed from the 14th day prior to mating, during mating until the end of the mating period. Females were dosed from the 14th day prior to the start of the mating phase to day 4 of lactation.  There were no treatment-related effects at any dose level on any of the reproductive parameters evaluated in this study.  These included measures of reproductive performance (mating, conception, gestation length, litter size), offspring survival (gestation and postnatal survival indices, percent pre- and post-implantation loss), pup body weight and pup sex ratio. There were no treatment-related effects at any dose level on any of the developmental paramters evaluated in this study including external abnormalities of pups, number of live and still births, mortality, sex determination, and weights of pups.  Based on these data, the no-observable-adverse-effect level (NOAEL) for developmental toxicity was 1000 mg/kg/day and the NOAEL for reproductive toxicity was 1000 mg/kg/day.

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