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Effects on fertility

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Endpoint:
screening for reproductive / developmental toxicity
Remarks:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Remarks:
Study performed according to currently valid guidelines without restriction.
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
higher animal number was used to give 20 males and 20 females per group
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
the aniamls were 6-8 weeks of age at begining of the study and were maintained according to current recommendations at 64 - 79°F and 30-70% humidity, housed individually in steel wire mesh cages. Fluorescent lightning was provided for 12 hours per day.
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Concentration, stability, and homogeneity of the test stubstance in vehicle was analytically verified, the formulations in vehicle were prepared weekly, dose levels of 0, 750, 1,500, and 5,000 mg/kg bw were administered daily by gavage
Details on mating procedure:
Mating was performed by housing one female and one male of the same treatment group together for 14 days, evidence of copulation was verified by the presence of a copulatory plug in the vagina or by vaginal lavage with the presence of sperm, the day of copulation was considered gestational day 0.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Homogeneity, stability, and concentration of test substance in vehicle were analytically verified by the sponsor, the results are reported separately.
Duration of treatment / exposure:
Males were treated for at least 63 days with 21 days premating, 14 days of mating, and 28 days after mating. Females were treated for up to 64 days with 21 days premating, 14 days of mating, and throughout gestation. Half of the pregnant females were killed on gestational day 20, the other half was further treated and killed on day 3 of lactation.
Frequency of treatment:
once daily
Details on study schedule:
Groups of 20 males and 20 females were administered the test substance at dose levels of 0, 750, 1,500, or 5,000 mg/kg bw once daily orally by gavage for 21 days before mating and throughout mating and gestation up to 28 days after mating for males, up to day 20 of gestation for 10 females, and up to day 3 of lactation for the remaining 10 females.
Dose / conc.:
0.75 mg/kg bw/day (nominal)
Dose / conc.:
1 500 mg/kg bw/day (nominal)
Dose / conc.:
5 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
20 males and 20 females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
Half of the pregant females was killed at the end of gestation, the other half was allowed to give birth and the females and the pups were killed on day 3 of lactation.
Positive control:
none
Parental animals: Observations and examinations:
Mortality and clinical signs of toxicity twice daily, detailed clinical observation daily, bodyweights every 3-4 days, food consumption weekly, oestrus cycle determination before successful copulation daily, evidence of copulation during mating daily, signs of parturition twice daily at the end of gestation, abnormalities at parturition, litter size, number of stillborn and liveborn pups, pup sex, pup bodyweights and gross malformations and variations as soon as possible after parturition, pup behaviour daily, pup bodyweight and survival on day 4 post partum, the females killed on gestational day 20 were examined at necropsy for location of viable and nonviable foetuses, early and late resorptions, number of corpora lutea, gravid uterine weight, placenta morpholy, foetal sex and weight, gross and visceral malformations and variations, all parental males and females underwent macroscopic pathology examination, the organ weights of epididymides and testes were determined. Pups were killed on day 4 of lactation and examined for gross malformations and variations.
Oestrous cyclicity (parental animals):
recorded during mating until successful copulation, no changes detected
Sperm parameters (parental animals):
not examined
Litter observations:
Pup behaviour, bodyweights, and survival was recorded until necropsy on lactational day 4, the pups were examined for gross malformations and variations, the sex was determined.
Postmortem examinations (parental animals):
All parental animals, males and females, were subjected to full necropsy with macroscopic pathological examination, the weight of epididymidis and testes was determined.
Postmortem examinations (offspring):
Pups killed on lactational day 4 were examined for gross malformations, foetuses of females killed on gestational day 20 were examined for number of live and dead foetuses, early and late resorptions, sex and bodyweight, gross and visceral malformations and variations.
Statistics:
Levene's / ANOVA- Dunnett's / Welch's, Aresin-Square-Root Transformation followed by group pair-wise comparison, Fisher's exact test, Covariate Analysis.
Reproductive indices:
Number of viable and nonviable foetuses, number of early and late resorptions, number of corpora lutea, bodyweights and sex of foetuses, gross and visceral malformations and variations.
Offspring viability indices:
Litter size, number of stillborn and liveborn pups, sex, bodyweights, gross malformations and variations, behaviour daily, and survival up to postnatal day 4.
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:
not examined
Other effects:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
No effects at all were observed.
Key result
Dose descriptor:
NOEL
Effect level:
>= 5 000 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
clinical signs
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios
gross pathology
reproductive function (oestrous cycle)
reproductive function (sperm measures)
reproductive performance
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
No treatment-related effects were observed with respect to viability, sex distribution, bodyweights, gross and visceral malformations and variations, and behaviour up to day 4 after birth.
Key result
Dose descriptor:
NOEL
Generation:
F1
Effect level:
>= 5 000 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: No treatment related effect at all was observed in any sex in any group at any dose level in all parameters examined.
Reproductive effects observed:
not specified
Conclusions:
Dechlorane Plus was essentially nontoxic to reproduction in males and females and did not affect embryofoetal and postnatal development of offspring up to a dose level of 5,000 mg/kg bw per day.
Executive summary:

The NOEL for effects on parental animals (males and females) and on embryofoetal and postnatal development was determined at or above the highest dose level of 5,000 mg/kg bw per day.

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the extended one-generation reproductive toxicity study does not need to be conducted because there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity
other:
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
5 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Study of very good quality using high numbers of animals and high dose levels, extensive examinations.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Dechlorane Plus was administered to male and female rats at dose levels up to 5,000 mg/kg bw before, during, and after mating up to the end of gestation or to day 3 of lactation and did not cause any effect on male and female fertility examined as numbers of live and dead foetuses and pups, numbers of implantations and resorptions, numbers of corpora lutea and postimplantation loss.

Short description of key information:

No effects on male and female fertility at dose levels up to 5,000 mg/kg bw

Justification for selection of Effect on fertility via oral route:

Study with good quality, no other study on reproduction toxicity available.

Effects on developmental toxicity

Description of key information

In OECD 422 test no adverse effects on embryofetal development and no teratogenic effect was observed upon oral administration of Dechlorane Plus to rats throughout the whole gestation period.

An OECD 414 study on detailed prenatal development was not performed by the lead registrant based on exposure related waiving in accordance to REACH Annex XI, 3. For application of Dechlorane Plus in cables and adhesives both used for aircraft sector no significant emissions to environment or workers through the whole substance life cycle are expected. Only one consumer use exists where the substanceis tightly bound in the article matrix and no exposure is expected.  

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Data waiving:
exposure considerations
Justification for data waiving:
the study does not need to be conducted because relevant human exposure can be excluded as demonstrated in the relevant exposure assessment
Abnormalities:
not specified
Developmental effects observed:
not specified
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
5 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Study of very good quality, no other study on effects on reproduction available.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Dechlorane Plus was administered orally to groups of 20 male and 20 female rats at dose levels up to 5,000 mg/kg bw before mating, during mating, and throughout gestation until the end of gestation or until day 3 of lactation. No effects on the numbers of live and dead foetuses and pups, the numbers of corpora lutea, implantations and resorptions, on postimplantation loss, on fetal bodyweight and sex distribution, on pup viability and bodyweights, and on the numbers of gross, skeletal, and visceral malformations and variations were seen.

Toxicity to reproduction: other studies

Additional information

Dechlorane Plus did not affect male and female fertility, embryofetal development, pup viability and development, and parturition and was not teratogenic at oral dose levels up to 5,000 mg/kg bw administered before mating, throughout mating, throughout gestation and up to day 3 of lactation.

Justification for classification or non-classification

No effects on reproduction were observed at high dose levels up to 5,000 mg/kg bw.