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Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
other justification
Justification for data waiving:
other:
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

In a study according to OECD 414 (2001) Himalayan rabbit was administered 3 dose levels by oral gavage during major organogenesis and foetal development. MMPP resulted in slight (200 mg/kg) to moderate (400 mg/kg) up to severe maternal toxicity at 600 mg/kg bw. Due to maternal toxicity, developmental effects were seen in fetuses from 400 mg/kg bw. onwards in form of increased resorption rates and concomitantly decreased number of fetuses. There was no indication that MMPP might be capable of inducing abnormalities or malformations in fetuses and thus MMPP is not teratogenic in rabbit fetuses.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2006
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
LPT Laboratory of Pharmacology and Toxicology GmbH & Co. KG, 22147 Hamburg, Germany
Limit test:
no
Species:
rabbit
Strain:
Himalayan
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Own bred
- Age at study initiation: 4 to 5 months at day 0 of gestation
- Weight at study initiation: 2.3 to 3.0 kg at day 0 of gestation
- Fasting period before study: not reported
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20+/-3
- Humidity (%): 55+/-15
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
Aqua ad iniectabilia
Details on mating procedure:
Until observation of copulation. Day of copulation was considered as Day 0 of pregnancy
Duration of treatment / exposure:
Day 6 – 28 of pregnancy
Frequency of treatment:
daily
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
60 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
Dose / conc.:
400 mg/kg bw/day (nominal)
Dose / conc.:
600 mg/kg bw/day (nominal)
No. of animals per sex per dose:
20 dams with litters in groups 0, 60 200 and 400
10 dams with litters in group 600
Control animals:
yes, concurrent vehicle
Maternal examinations:
Body weight Once daily from day 0 through 29; Data in report were given as mean values for days 0, 3, 6, 9, 12, 15, 18, 21, 24, 27 and 29 and as weight gains for three days intervals

Food consumption:Yes, once daily

Clinical signs: Yes – at least once daily

Ovaries and uterine content:
Gravid uterine weights, ovarian corpora lutea counted and uterine contents determined (number of implantation sites, dead or live fetuses, placentae, number and size of resorptions)
Fetal examinations:
General: Number of fetuses per litter, litter size, no. of dead fetuses, foetal weight, sex ratio, inspection for external malformations and variations
Skeletal: Yes, skeletal malformations and variations/retardations
Soft tissue: Yes, visceral malformations and variations
Statistics:
Yes
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
From the remaining 21 dams in the 600 mg dose group, two aborted. In three of the remaining 19 dams haemorrhagic faeces were noted over one to three days.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
At 400 mg/kg bw., one of 23 pregnant dams died prematurely with signs of gastric and pulmonal changes. The dose of 600 mg/kg induced two pre-terminal deaths (from 24 dams) and one further pre-terminal sacrifice in moribund condition. Macroscopic organ findings were gastric, spleenic and /or hepatic lesions. Signs preceding deaths were reduced motility and /or soft haemorrhagic faeces.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At 600 mg/kg bw., body weights were significantly reduced in phases (up to -8% from controls).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
At 200 and 400 mg/kg bw., both absolute and relative food consumption were distinctly reduced especially during the first three treatment days (with up to 44 or 72% below the control values) and for the relative food consumption on gestation days 7 to 9. At 600 mg/kg, absolute and relative food consumption were distinctly reduced especially during the first week of treatment.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Uterus weights: At 600 mg/kg, gravid uteri weights were reduced due to the decreased number of fetuses.
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Number of abortions:
no effects observed
Pre- and post-implantation loss:
effects observed, treatment-related
Description (incidence and severity):
A total post-implantation loss was noted in 2 of 22 surviving dams at 400 mg/kg and in 9 of 19 surviving dams at 600 mg/kg.
Total litter losses by resorption:
effects observed, treatment-related
Description (incidence and severity):
At 400 mg/kg and 600 mg/kg, the number of early and total resorptions was increased and the number of fetuses was decreased.
Key result
Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
food consumption and compound intake
Fetal body weight changes:
no effects observed
Changes in postnatal survival:
effects observed, treatment-related
Description (incidence and severity):
The foetal mortality during the incubator stay was increased, as 3 of 37 fetuses died within 6 to 24 hours after laparotomie.
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Variations: Skeletal examination revealed increased foetal incidences of fused sternebrae and/or total skeletal variations from 400 mg/kg bw. onwards. The incidences were, however, still within the historical background data of the laboratory.
Soft tissue examinations: No effects
Retardations: No effects
Key result
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: increased resorptions and decreased number of fetuses
Developmental effects observed:
no
Conclusions:
In a study according to OECD 414 (2001) Himalayan rabbit was administered 3 dose levels by oral gavage during major organogenesis and foetal development. MMPP resulted in slight (200 mg/kg) to moderate (400 mg/kg) up to severe maternal toxicity at 600 mg/kg bw. Due to maternal toxicity, developmental effects were seen in fetuses from 400 mg/kg bw. onwards in form of increased resorption rates and concomitantly decreased number of fetuses. There was no indication that MMPP might be capable of inducing abnormalities or malformations in fetuses and thus MMPP is not teratogenic in rabbit fetuses.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
60 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
Klimisch 1; guideline study
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Additional information

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