Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

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
Developmental toxicity study (exposure GD6-19): maternal and developmental NOAEL 3000 mg/kg bw.day (equivalent to OECD414)
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2 May 1979 - 30 January 1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to an equivalent of OECD guideline 41 and performed under GLP conditions. However the treatment period was shorter than required, as only exposure was from GD6-19 in stead of the during the entire gestation period.
Reason / purpose:
reference to other study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
exposure only during GD6-19, food consumption was not recorded
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: COBS CD
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Michigan
- Age at time of mating: Approx. 13 weeks
- Weight at study initiation: 251-255 (means per group)
- Housing: Individually
- Diet (e.g. ad libitum): Ad libitum, Purina Certified Rodent Chow
- Water (e.g. ad libitum): Ad libitum, tap water
- Acclimation period: At least 10 days

ENVIRONMENTAL CONDITIONS
Animals maintained in a temperature-, humidity- and light-controlled environment (photoperiod (hrs dark / hrs light): 12/12)
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Santicizer 148 was dispended daily, in dose volumes of 0.280, 0.932 and 2.796 ml/kg. The control group was given water at the highest dose volume.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
No data
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: No data
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
GD6-19
Frequency of treatment:
Daily
Duration of test:
Approximately 4 weeks
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
Dose / conc.:
3 000 mg/kg bw/day
No. of animals per sex per dose:
25 (females)
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: Based on a pilot teratology study (Rodwell, 1980)
- Rationale for animal assignment: Block design
Maternal examinations:
CAGE SIDE OBSERVATIONS:
- Time schedule: Daily
- Cage side observations: Mortality and clinical signs (including cause of death if necessary)

BODY WEIGHT:
- Time schedule for examinations: GD 0, 6, 9, 12, 16 and 20.

POST-MORTEM EXAMINATIONS:
- Sacrifice on gestation day #20
- Organs examined: Uterus, abdominal and thoracic cavities and their organs (unspecified)
- Tissues were preserved only as deemed necessary by gross findings
- Uteri from nongravid females were opened and placed in 10% ammonium sulfide for confirmation of pregnancy
Ovaries and uterine content:
The ovaries and uterine content was examined after termination for:
- Gravid uterus weight
- Number of corpora lutea
- Number of implantations
- Number of early resorptions
- Number of late resorptions
- Number and location of viable and nonviable fetuses
Fetal examinations:
- External examinations (incl. palate and eyes): All per litter
- Soft tissue examinations: Half per litter
- Skeletal examinations: Half per litter
Statistics:
- Chi-square test criterion with Yates' correction
- Fisher's exact probability test
- Mann-Whitney U-test
- Bartlett's test for homogeneity of variance
- T-test
Indices:
Not calculated
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Some effects were noted, but these were not considered toxicologically relevant
Mortality:
mortality observed, non-treatment-related
Description (incidence):
1 gravid dam of the low dose group died
Body weight and weight changes:
no effects observed
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
- Necropsy: Some effects were noted, but these were not considered to be related to treatment
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
- Mortality: 1 gravid dam of the low dose group died
- Clinical signs: Some effects were noted, but these were not considered toxicologically relevant
- Body weight: No effects observed
- Necropsy: Some effects were noted, but these were not considered to be related to treatment
Dose descriptor:
NOAEL
Effect level:
3 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The effects were not considered to be toxicologically relevant as these were also observed in historical controls.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The effects were not considered to be toxicologically relevant as these were also observed in historical controls.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The effects were not considered to be toxicologically relevant as these were also observed in historical controls.
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
- Increase in external malformations for the mid dose group, but no dose-related response was noted
- Increase in visceral malformations for the low dose group, but no dose-related response was noted
- Skeletal malformations were observed in the low and high dose group
The effects were not considered to be toxicologically relevant as these were also observed in historical controls.
Dose descriptor:
NOAEL
Effect level:
3 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: No treatment related or toxicologically relevant adverse effects
Abnormalities:
no effects observed
Developmental effects observed:
no

RESULTS OF TEST DOSING GROUPS
Control Low (300 mg/kg bw/day) Medium (1000 mg/kg bw/day) High (3000 mg/kg bw/day)
MATERNAL TOXIC EFFECTS BY DOSE LEVEL 
Number of animals 25 25 25 25
Mortality and day of death x 1 gravid female died (gavage error) x x
Clinical signs Soft stool and scabbing on the forelimbs, dry red matter around the mouth, nose and forelimbs Soft stool and scabbing on the forelimbs, dry red matter around the mouth, nose and forelimbs Soft stool and scabbing on the forelimbs, dry red matter around the mouth, nose and forelimbs, hair loss Soft stool and scabbing on the forelimbs, dry red matter around the mouth, nose and forelimbs, hair loss, matting and/or staining of anogenital haircoat
Body weight x x x x
Body weight gain x x x x
Number pregnant per dose level 24 21 24 23
Number of corpora lutea (mean/dam) 16.1 14.8 16 16.2
Number of implantations (mean/dam) 14 13.2 13.8 14.4
Post-implantation loss 0.8 0.5 0.5 1.1
Early resorptions (mean/dam) 0.8 0.5 0.5 1
Late resorptions (mean/dam) 0 0 0 0.1
Number of dams with only resorptions 1 0 0 0
Gross necropsy 1 dam with small cysts in cortex of kidney and 1 with bilateral hydrometra 1 dam(#) with dark red-brown mass on fatty tissue of right ovary and 1 with bilateral hydrometra 1 dam with bilateral hydrometra 1 dam with bilateral hydrometra
Histopathological examination 1 dam(#) with mass that was circumscribed focus of fat necrosis, surrounded by scanty to moderate fibrosis and few scattered acute inflammatory infiltrates
FETAL DATA
Number viable (mean/dam) 13.2 12.7 13.3 13.3
Sex ratio (M/F) 0.505 0.51 0.498 0.492
Litter weights (mean/fetus in gram) 3.6 3.8 3.7 3.8
Grossly external abnormalities (all per litter examined) x x 1 fetus with cleft palate, 8 with dwarfism (2 litters) x
Visceral abnormalities (half per litter examined) x 1 fetus with retro-ureter uterus 1 fetus with hydrocephaly and 2 with microphtalmia x
Skeletal abnormalities (half per litter examined) x 1 fetus with bent rib x 1 fetus with bent rib
x = no effects (as compared to control group)
# = same animal / same effect
Conclusions:
Under the conditions of this study, no significant or toxicologically relevant adverse effects were noted in the dams and fetuses. A NOAEL of 3000 mg/kg bw/day was established for both maternal and developmental toxicity.
Executive summary:

The study was performed according to an equivalent of OECD guideline 414, but the treatment period was shorter than required (GD6 -19 in stead of the entire gestation period). 25 female rats/group were treated with 0, 300, 1000 or 3000 mg/kg bw/day. Mortality, clinical signs and body weight of the dams were recorded, uterine examinations were performed to reveal effects on the development of fetuses.

One gravid dam died on GD17 due to hemorrhage in the stomach and was attributed to a gavage error. Some clinical signs were noted but these were not considered of toxicological relevance. No effect on body weight was observed. Necropsy revealed some effects, but these were not considered to be related to treatment. An increase in external malformations was noted for the mid dose group and an increase in visceral malformations for the low dose group, but no dose-related response was observed. Skeletal malformations were observed in the low and high dose group. The effects were not considered to be toxicologically relevant as these were also observed in historical controls.

Under the conditions of this study, no significant or toxicologically relevant adverse effects were noted in the dams and fetuses. A NOAEL of 3000 mg/kg bw/day was established for both maternal and developmental toxicity.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
3 000 mg/kg bw/day
Species:
rat
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

The key study was performed according to an equivalent of OECD guideline 414. 25 female rats/group were exposed to 0, 300, 1000, or 3000 mg/kg bw/day during gestation day (GD) 6 -19. Mortality, clinical signs and body weight of the dams were recorded, uterine examinations were performed to reveal effects on the development of fetuses.

One gravid dam died on GD17 due to hemorrhage in the stomach and was attributed to a gavage error. Some clinical signs were noted but these were not considered of toxicological relevance. No effect on body weight was observed. Necropsy revealed some effects, but these were not considered to be related to treatment. An increase in external malformations was noted for the mid dose group and an increase in visceral malformations for the low dose group, but no dose-related response was observed. Skeletal malformations were observed in the low and high dose group. The effects were not considered to be toxicologically relevant as these were also observed in historical controls.

Under the conditions of this study, no significant or toxicologically relevant adverse effects were noted in the dams and fetuses. A NOAEL of 3000 mg/kg bw/day was established for both maternal and developmental toxicity.

A supporting study is available which is the range-finding study for the key study. In this study, five pregnant female rats/dosing group were treated with 0, 250, 500, 1000, 2500 or 5000 mg/kg bw/day of Santicizer 148 (undiluted) from GD6 -19. A decrease in the mean number of viable fetuses in the 5000 mg/kg bw/day group as well as an increase in mean post-implantation loss (early and late) was considered an adverse effect of treatment, although not tested for significance. Based on these effects, a developmental NOAEL of 2500 mg/kg bw/day was established. No maternal toxicity was observed, indicating a maternal NOAEL of 5000 mg/kg bw/day. The dose levels of the key study were based on these findings.

Justification for classification or non-classification

Based on the available information, IDDPP does not need to be classified for toxicity to reproduction and development according to the criteria outlined in Annex I of 1272/2008/EC and Annex VI of 67/548/EEC