Isodecyl diphenyl phosphate

Endpoint summary

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 for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

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 or test system 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