Registration Dossier

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:
key study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report date:
2018

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 (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
Diethyl ethylphosphonate
EC Number:
201-111-9
EC Name:
Diethyl ethylphosphonate
Cas Number:
78-38-6
Molecular formula:
C6H15O3P
IUPAC Name:
diethyl ethylphosphonate
Test material form:
liquid

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
At 8-12 weeks; female animals were non-pregnant and nulliparous
The animals were housed in plastic cages suspended on stainless steel racks in a room equipped with central air-conditioning. The room temperature was within the range of 22 ± 2°C; relative humidity was within the range of 55 ± 10 %. The light regimen was set to a 12-hour light / 12-hour dark cycle The sanitation was performed according to standard operation procedures.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
olive oil
Duration of treatment / exposure:
The animals were dosed daily for 7 days a week.
Frequency of treatment:
Once per day.
Females were treated during:
- 14-day pre-mating,
- 14-day mating (maximum)
- 22-day gestation (approximately)
- 13-day lactation
Males were treated during:
- 14-day pre-mating,
- 14-day mating (maximum)
The animals designated for post-treatment observation (5 animals per sex in control and high groups, respectively) remained untreated for subsequent 14 days.
Doses / concentrationsopen allclose all
Dose / conc.:
25 mg/kg bw/day
Remarks:
Low
Dose / conc.:
50 mg/kg bw/day
Remarks:
Mid
Dose / conc.:
150 mg/kg bw/day
Remarks:
High
Dose / conc.:
150 mg/kg bw/day
Remarks:
High satellite
Control animals:
yes, concurrent vehicle

Examinations

Statistics:
Individual data (five males and all pregnant females) of clinical chemistry, haematology, body
weight, relative weight of organs, and T4 levels obtained in the experiment were assessed applying
statistical software StatgraphicsTM Centurion. Kruskal-Wallis statistical procedure of multiple
comparison was adopted to test the null hypothesis that the medians among the dose groups
(control, low, mid, high) are the same. The p-value of 0.05 was considered as the level of statistical
significance. In the case of statistically significant outcome the Kruskal-Wallis was followed by
Mann-Whitney W test to determine which medians are different from which other. Basic
descriptive statistics (mean, SD) are reported as well.
Results of Tail flick test and Grip-strength test are presented as mean ± sd. Significance of the
difference between the results was determined using the ANOVA test. Difference between the
means of Low, Mid, High and Control group at the 0.05 significance level was considered
significant. The data were evaluated by statistical software StatgraphicsTM Centurion.
Reproduction/developmental and locomotor activity data were analysed using STATISTICA 7.0
(Statsoft, Inc. Tulsa, OK) software. The data are represented as mean ± S.E.M (and were analysed
by one-way analyses of variance (ANOVA) followed by Dunnet’s post-hoc test for a multiple
comparison procedure to compare each of a number of treatments with a single control. The p<0.05
value was considered statistically significant.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
Animals lived through the observation period without significant visible clinical signs. Daily clinical examination only tremor in one female (ID 99) of High dose was registered. No other signs were observed.
Mortality:
no mortality observed
Description (incidence):
The incidence of mortality in the animals of the High dose could be caused by the test item treatment. All other males and females at all dosage levels survived to the scheduled necropsy.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The body weight of males of all dose groups was mildly increasing during the study. No significant differences between control and dose groups were observed. The body weight of High dose satellite males was similar in comparison with recovery control males during the whole study.
The body weight of females of all dose groups was mildly increasing during the study. No significant differences between control and dose groups were observed. The body weight of recovery High dose females was similar in comparison with recovery control females during the whole study.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption of males of all dose groups was similar to the control males during the whole study. Food consumption of recovery treated males was similar in comparison with control group during the whole application and recovery period.
Food consumption of treated females was similar in comparison with control group during the whole application period. Food consumption of recovery treated females was similar in comparison with recovery control females for the whole study.
Organ weight findings including organ / body weight ratios:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive performance:
no effects observed
Description (incidence and severity):
In summary none of used doses significantly influenced length of pregnancy, number of implants, survival of pups, anogenital distance, or other variables.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
ca. 50 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
body weight and weight gain

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality 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
Gross pathological findings:
no effects observed

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 150 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
clinical signs

Overall reproductive toxicity

Reproductive effects observed:
no
Lowest effective dose / conc.:
150 mg/kg bw/day (nominal)
Treatment related:
no

Applicant's summary and conclusion