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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

For the oral route, a dietary combined repeated dose toxicity study with reproduction/developmental screening test (OECD 422, GLP) is available for MPP. The no-observed-adverse-effect-level (NOAEL) for reproductive/developmental toxicity was considered to be 15000 ppm (854 mg/kg/d for males and 1049 to 1957 mg/kg/d for females, treatment before pairing through to lactation) . 

Link to relevant study records
Reference
Endpoint:
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:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: Males 70 to 77 days old; Females 63 to 70 days old.
- Weight at study initiation: Males 338 to 397 g; Females 214 to 261 g.
- Housing: Cages comprised of a polycarbonate body with a stainless steel mesh lid; changed at appropriate intervals. Solid bottom cages were used during the acclimatization,pre-pairing, gestation, littering and lactation periods, contained softwood based bark-free fiber bedding, which was changed at appropriate intervals each week. Grid bottomed cages were used during pairing. These were suspended above absorbent paper which was changed daily during pairing.
- Diet (e.g. ad libitum): Powdered diet. The diet contained no added antibiotic or other chemotherapeutic or prophylactic agent, non-restricted.
- Water (e.g. ad libitum): Potable water from the public supply via polycarbonate bottles with sipper tubes. Bottles were changed at appropriate intervals, non-restricted.
- Acclimation period: Five days before commencement of treatment.

DETAILS OF FOOD AND WATER QUALITY:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Monitored and maintained within the range of 20-24ºC.
- Humidity (%): Monitored and maintained within the range of 40-70%.
- Air changes: Filtered fresh air which was passed to atmosphere and not recirculated.
- Photoperiod (hrs dark / hrs light): Artificial lighting, 12 hours light : 12 hours dark.
Route of administration:
oral: feed
Vehicle:
other: Standard diet
Details on exposure:
Dosing was restricted to the F0 generation.
Males were treated continuously for two weeks before pairing, up to necropsy after a minimum of five consecutive weeks. Females were treated continuously for two weeks before pairing, throughout pairing, gestation and until Day 6 of lactation.
The F1 generation received no direct administration of the test item, MPP. Any exposure to the test item or metabolites was through the mother to the offspring in utero and/or through the milk.
Details on mating procedure:
Pairing commenced After a minimum of two weeks of treatment.
Male/female ratio 1:1 from within the same treatment groups.
Duration of pairing Up to two weeks.
Daily checks for evidence of mating
Ejected copulation plugs in cage tray and sperm in the vaginal smear.
Day 0 of gestation When positive evidence of mating was detected.
Male/female separation Day when mating evidence was detected.
Pre-coital interval Calculated for each female as the time between first pairing and evidence of mating.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Stability of a homogeneous formulation has been confirmedin both frozen and ambient conditions for 32 days at 100 ppm and 22 days at 20000 ppm.
Duration of treatment / exposure:
Males were treated continuously for two weeks before pairing, up to necropsy after a minimum of five consecutive weeks.
Females were treated continuously for two weeks before pairing, throughout pairing, gestation and until Day 6 of lactation.
Frequency of treatment:
Continuously.
Dose / conc.:
0 ppm
Remarks:
Control
Dose / conc.:
250 ppm
Remarks:
On F0.
Dose / conc.:
2 000 ppm
Remarks:
On F0.
Dose / conc.:
15 000 ppm
Remarks:
On F0.
No. of animals per sex per dose:
10
Control animals:
yes, plain diet
Details on study design:
The study consisted of one control and three treated groups. The F0 generation of the study was identified as follows:
Group Treatment Level (ppm) Number of animals : Male Female
1 Control 0 10 10
2 MPP 250 10 10
3 MPP 2000 10 10
4 MPP 15000 10 10
Parental animals: Observations and examinations:
Clinical and Behavioral Observations: at least twice daily
Cages were inspected daily
Detailed physical examination and arena observations: Before treatment commenced and during each week of treatment and on Days 0, 6, 13 and 20 after mating and Days 1 and 6 of lactation
Sensory reactivity and grip strength: during Week 5 on males, at Days 4-6 of lactation on females
Motor activity: During Week 5 of treatment for males and at Days 4-6 of lactation for females
Body Weight: males: Before treatment commenced (Day 1) and weekly thereafter. On the day of necropsy.
Body Weight: females: Before treatment commenced (Day 1) and weekly before pairing. Days 0, 6, 13 and 20 after mating. Day 1, 4, and 7 of lactation. On the day of necropsy.
Food Consumption: Weekly, from the day that treatment commenced. Males: Week 1, 2 and 4. Females: Days 0-5, 6-12 and 13-19 after mating, Days 1-3 and 4-6 of lactation.
Hematology (peripheral blood): Week 2 before pairing
Blood Chemistry: Week 2 before pairing
Estrus Cycles: After pairing until mating
Organ weight and macroscopic pathology and histopathology investigations were undertaken.
Oestrous cyclicity (parental animals):
Wet smears After pairing until mating, using pipette lavage.
Litter observations:
Clinical observations
Litter size
Sex ratio of each litter
Individual offspring body weights
Postmortem examinations (parental animals):
Females: Each uterine horn Number of implantation sites was counted and confirmed if none were visible at visual inspection.
Postmortem examinations (offspring):
Premature deaths: Where possible, a fresh macroscopic examination (external and internal) with an assessment of stomach for milk content was performed.
Offspring at scheduled termination: Examined externally, if found to be normal offspring were discarded without further examination. Any externally abnormal offspring were also examined internally. Abnormal tissues were retained in an appropriate fixative.
Statistics:
Bartlett's test for variance homogeneity.
- If not significant at the 1% level: a parametric analysis.
For pretreatment data (group differences): analysis of variance.
Inter group comparisons: t-tests, with the error mean square from the one-way analysis of variance.
For all other comparisons: F1 approximate test.
- If significant at the 1% level: a non-parametric analysis.
For pretreatment data: Kruskal-Wallis’ test.
Inter group comparisons: Wilcoxon rank sum tests.
For all other comparisons: H1 approximate test, non-parametric equivalent of the F1 test.
For grip strength, motor activity, clinical pathology, litter size and survival indices, if 75% of the data (across all groups) were the same value: Fisher’s exact tests.
Treatment groups: pairwise comparisons of each dose group against the control.
Sex ratio: generalized mixed linear model with binomial errors, a logit link function and litter as a random effect.
Treated group, compared to control: Wald chi-square test.
Gestation length: exact two-tailed Linear-by-linear test with equally spaced scores.
Organ weight data: analysis of covariance using terminal body weight as covariate.
For some parameters, including pre-coital interval and mating performance the similarity of the data was such that analyses were not considered to be necessary.
Significant differences between the groups compared were expressed at the 5% (p<0.05) or 1% (p<0.01) level.
Reproductive indices:
Wet smears; Pairing commenced; Male/female ratio; Duration of pairing; Daily checks for evidence of mating; Day 0 of gestation; Male/female separation; Pre-coital interval; Duration of gestation; Parturition observations; Clinical observations.
Offspring viability indices:
Litter size; Sex ratio of each litter.
Clinical signs:
no effects observed
Description (incidence and severity):
There were no clinical signs that were considered to indicate an immediate or delayed reaction to treatment.
Mortality:
no mortality observed
Description (incidence):
There were no unscheduled deaths.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There was no adverse effect of body weight gain in males throughout or females before pairing, during gestation and lactation.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There was no indication of a food consumption effect on either males throughout or females before pairing, during gestation or lactation.
Food efficiency:
no effects observed
Description (incidence and severity):
There was no indication of a food consumption effect on either males throughout or females before pairing, during gestation or lactation.
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
At haematology evaluation during Week 2 of study there were no statistical differences from the Control for males.
For females receiving 15000 ppm: - mean cell haemoglobin and mean cell haemoglobin concentration: statistically lower than Control
- red blood cell distribution width: statistically higher than Control
- No other parameters attained statistical differences to the Control.
- reticulocyte results: Due to these difficulties manual differential counts were performed, and subsequently it was considered that the original reticulocyte channel data was not reliable for these animals. There were no notable effects for males at any dose level or females at lower dose levels.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Urea concentration: males receiving MPP at 15000 ppm : statistically higher than Control
females receiving MPP at 15000 ppm : statistically lower than Control
Potassium concentration: males receiving MPP at 15000 ppm: statistically higher than Control
Calcium and phosphorus concentration: female receiving 15000 ppm or 2000 and 15000 ppm respectively: statistically lower than Control
All other differences from controls were attributed to normal biological variation
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
There were no effects on behavioral parameters.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
There were no indications of any adverse effects of MPP on sensory reactivity or grip strength assessments.
Motor activity was considered not to be adversely affected by the test material.
An isolated statistical significance of lower than control hind limb grip strength occurred for males receiving 250 ppm during week 5 of study, however, in the absence of any dose related trend or similar effect in females this was considered to have arisen by chance.
Males during Week 5 of treatment receiving 15000 ppm and females at Day 4-6 of lactation receiving 15000 ppm displayed statistically lower activity than Control low beam and for males only high beam activity during a single 6 minute interval this was not part of an extended trend and overall values were no significantly different to the control therefore this difference is not attributed to treatment. Also, females receiving 2000 ppm displayed statistically higher low beam activity than Control for a single 6 minute period this was not part of a dose related trend and no other period were significantly different to the control.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathological changes related to treatment with MPP were seen in males and in females administered 15000 ppm but not at 250 or 2000 ppm.
Effects of MPP were detected in the kidney of all males and in the majority of females at 15000 ppm (cf. Table 2). The changes seen in the kidneys at 15000 ppm were considered to be adverse.
All other histological changes were considered to be unrelated to treatment.
Reproductive performance:
no effects observed
Description (incidence and severity):
There was no effect on pre-coital interval, mating performance, fertility or gestation length or index.
Key result
Dose descriptor:
NOAEL
Remarks:
for reproductive/developmental toxicity
Effect level:
15 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
food consumption and compound intake
reproductive performance
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
15 000 ppm
System:
urinary
Organ:
kidney
Treatment related:
yes
Clinical signs:
no effects observed
Description (incidence and severity):
There were no clinical signs observed which were indicative of a reaction to MPP.
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Male and females: body weights and body weight gain offspring derived from females receiving 2000 or 15000 ppm were slightly lower than Control, this did not display a dose dependant trend. Although this may be attributable to treatment and/or the larger mean litter size in these groups compared with Controls, it is considered not to be adverse at the degree observed.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no offspring necropsy findings that were attributed to MPP.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
15 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
clinical signs
body weight and weight gain
gross pathology
histopathology: non-neoplastic
Mortality / viability:
no mortality observed
Reproductive effects observed:
no
Conclusions:
The no-observed-adverse-effect-level (NOAEL) for reproductive/developmental toxicity was considered to be 15000 ppm.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
854 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

For the oral route, a dietary combined repeated dose toxicity study with reproduction/developmental screening test (OECD 422, GLP) is available for MPP. The dietary administration of MPP to Sprague-Dawley rats receiving doses 250, 2000 or 15000 ppm for 5 weeks to males and females for 2 weeks before pairing, throughout gestation up to Day 7 of lactation was not associated with any effect on any of the reproductive parameters assessed. The no-observed-adverse-effect-level (NOAEL) for reproductive/developmental toxicity was considered to be 15000 ppm (854 mg/kg/d for males and 1049 to 1957 mg/kg/d for females, treatment before pairing through to lactation). 

Effects on developmental toxicity

Description of key information

For the oral route, a dietary combined repeated dose toxicity study with reproduction/developmental screening test (OECD 422, GLP) is available for MPP. See section above.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available (further information necessary)
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

These data suggest that, at non-toxic doses, MPP is not a reproductive or developmental toxicant.

Additional information