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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
13 October 1995 - October 1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study was performed under GLP conditions and according to a protocol equivalent or similar to OECD guideline 414.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1996
Report date:
1996
Reference Type:
publication
Title:
Developmental toxicity study of orally administered resorcinol bis-diphenylphosphate (RDP) in rabbits
Author:
Ryan, B.M., Henrich, R., Mallett, E., Freudenthal, R.I.
Year:
2000
Bibliographic source:
International Journal of Toxicology, 19: 257-264

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
treatment period according to old guideline (exposure GD 6-29 in stead of complete gestation period)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction mass of 3-[(diphenoxyphosphoryl)oxy]phenyl triphenyl 1,3-phenylene bis(phosphate) and tetraphenyl 1,3-phenylene bis(phosphate)
EC Number:
701-337-2
Cas Number:
not available
Molecular formula:
C30H24O8P2
IUPAC Name:
Reaction mass of 3-[(diphenoxyphosphoryl)oxy]phenyl triphenyl 1,3-phenylene bis(phosphate) and tetraphenyl 1,3-phenylene bis(phosphate)
Details on test material:
- Name of test material (as cited in study report): Fyrolflex RDP
- Physical state: Liquid
- Analytical purity: Confidential information
- Impurities (identity and concentrations): Confidential information
- Purity test date: Confidential information
- Storage condition of test material: At room temperature

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products (HRP), Inc., Denver, PA
- Age at study initiation: approx. 4.5 months (females)
- Weight at study initiation: 2.92-3.44 kg (females)
- Housing: under standard conditions
- Diet (e.g. ad libitum): Ad libitum, 50:50 mixture of high fiber and rabbit chow
- Water (e.g. ad libitum): Ad libitum, municipal water
- Acclimation period: two weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-25
- Humidity (%): 30-69
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Doses of the test substance at 50, 200 and 1000 mg/kg bw/day were prepared in a corn oil vehicle at a constant dosing volume of 1.5 ml/kg bw. Individual doses were prepared daily, mixing the contents using a stopcock connector.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Not necessary, accepted vehicle
- Amount of vehicle (if gavage): 1.5 ml/kg
- Lot/batch no. (if required): 114H0275
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: not indicated
- Further matings after two unsuccessful attempts: no
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of gestation
- Any other deviations from standard protocol:
Duration of treatment / exposure:
23 days (gestation days 6 through 29)
Frequency of treatment:
Once daily
Duration of test:
29 days
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
50, 200, 1000 mg Fyrolflex RDP/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
31.5, 125.8, 629 mg RDP/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
27
Control animals:
yes, concurrent vehicle
Details on study design:
Not relevant

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice (weekdays) or once (weekends) daily
- Cage side observations: mortality

DETAILED CLINICAL OBSERVATIONS: Yes, clinical examinations
- Time schedule: Prior to randomization and study initiation

BODY WEIGHT: Yes
- Time schedule for examinations: at randomization, every two days during gestation, at study termination

FOOD CONSUMPTION:
- Food consumption recorded: Yes, but not corrected for spillage
- Time schedule: Day 0-29 (every 2 days) and at termination

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 29 (followed by gross necropsy)
- Organs examined: Liver, spleen, kidneys (histopathology)
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: one-third per litter
Statistics:
- Mean and standard deviation (all parameters)
- Multivariate analysis of variance
- One-way ANOVA
- Post-hoc comparisons: Dunnett's test (in presence of significant main effects)
- Chi-square and Fischer Exact test (malformation data)
Indices:
Not relevant
Historical control data:
Historical control values for anomalies in litter as published by the Middle Atlantic Reproduction and Teratology Association/Midwest Teratology Association (MARTA/MTA) were used.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
- No mortality related to treatment
- No dose-related clinical signs observed in any of the substance-treated groups
- No significant differences detected in body weight, uterus weight, corrected body weight or corrected body weight gain
- No biologically significant effect on food consumption
- No significant effects observed on mean liver, kidney and spleen weight
- No gross pathological abnormalities noted

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: No maternal toxicity up to the highest dose tested

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
- No statistically significant difference in number of live or total implants, resorptions, corpora lutea, or percent implantation loss
- No significant difference found in mean fetal weight
- No gross external malformations observed in the pups
- No dose related increase in incidence nor any clear pattern of visceral anomalies was noted. The fetal incidence is similar to or below the observed incidence for these anomalies as published by MARTA/MTA
- The incidence of cephalic anomalies was greatest in the high dose group, but is similar or well below the observed incidence for these anomalies as published by MARTA/MTA
- No skeletal anomalies were considered related to treatment. No skeletal anomalies were observed in the high dose group. The fetal incidence is similar to or below the observed incidence for these anomalies as published by MARTA/MTA

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Effects were not observed up to the highest dose tested.

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

RESULTS OF TEST DOSING GROUPS
Control (vehicle) Low (50 mg/kg bw/day) Medium (200 mg/kg bw/day) High (1000 mg/kg bw/day)
MATERNAL TOXIC EFFECTS BY DOSE LEVEL 
Number of animals 27 27 27 27
Mortality and day of death 0 0 0 0
Body weight x x x Day 16-18: Significant increase in body weight gain
Food consumption x x x Day 20: Significant increase in food consumption
Clinical signs x x x x
Number pregnant per dose level 26 27 25 26
Number aborting 0 0 0 0
Number of corpora lutea 238 231 241 254
Number of implantations 234 227 226 236
Number of resorptions early/late 14/3 5/7 9/2 7/10
Pre-implantation loss 4 4 15 18
Post-implantation loss 17 12 11 17
Duration of Pregnancy x 2 animals: Premature delivery 1 animal: Parturition on GD 29 x
Number of litters 25 25 25 26
Gross pathology incidence and severity 1 animal: mass on the left Fallopian tube, 1 animal: non-viable litter observed x x x
Organ weight changes (liver, kidney, spleen) x x x x
FETAL DATA 
Litter size (mean +/- SD) 8.35 +/- 2.23 8.60 +/- 1.91 8.60 +/- 1.85 8.42 +/- 1.70
Number viable 217 215 215 219
Litter weights x x x x
Postnatal survival x x x Higher incidence of deaths in one litter
Sex ratio (M/F) 1:1 0.9:1 0.9:1 1.3:1
Grossly external abnormalities 1 pup: abnormal hindlimb x x x
Visceral abnormalities 1 pup: short/absent innominate, 1 pup: abnormal branching of the subclavian 1 pup: common truncus, 1 pup: short/absent innominate, 2 pup of 1 litter: abnormal branching of the subclavian x 1 pup: short/absent innominate
Skeletal abnormalities 1 pup: fused ribs 1 fetus: fused sternebrae, 2 pups: fused or forked ribs 3 fetuses: fused sternebrae, 1 pup: unilateral absence of lumbar vertebral arch x
Cephalic abnormalities x 1 pup: slight hypoplasia of diencephalon 1 pup: unilateral dilatation of ventricle 3 pups of 2 litters: unilateral dilatation of ventricle, slight hypoplasia of diencephalon or ectopic lens and convoluted retina
x = no effects (as compared to control group)

Applicant's summary and conclusion

Conclusions:
Under the conditions of this study, exposure to Fyrolflex RDP by oral gavage up to 1000 mg/kg bw/day was found not to result in maternal and developmental toxicity in rabbits. Therefore, a NOAEL of 1000 mg/kg bw/day was established. As a result, the substance does not need to be classified as toxic to reproduction based on the criteria outlined in Annex I of 1272/2008/EC and Annex VI of 67/548/EEC.
Executive summary:

Pregnant rabbits were exposed to Fyrolflex RDP by oral gavage from gestation day 6 through 29 in a concentration of 0, 50, 200 and 1000 mg/kg bw/day. Throughout the gestation period the dams were observed for clinical signs and body weight, food consumption was recorded. On day 29 of gestation the dams were sacrificed and post-mortem the liver, spleen and kidneys were weighed and examined. Uteri and ovaria were examined: gravid uterus weight and number of corpora lutea, implantations and resorptions was recorded. Litter was examined for gross external, visceral, cephalic and skeletal anomalies.

No clinical signs of maternal toxicity were evident during the study or were apparent from gross necropsy observations. Mean body weights, body weight gains, food consumption, uterus weights and organ weights showed no test substance relaeted effects.

No significant differences in fetal (litter) body weights were observed between the test substance-treated groups and the vehicle control. Also, no significant increases in fetal deaths, resorptions, or malformations were observed between the test substance-treated groups and the control. The visceral, cephalic and skeletal malformations observed were low in incidence, sporadic in nature, and were not considered test substanc-related because no clear pattern or relationship between the affected structure and dose group could be established. All anomalies were similar to or below the historical control values for anomalies in litter as published by the Middle Atlantic Reproduction and Teratology Association/Midwest Teratology Association (MARTA/MTA).

Under the conditions of this study, exposure to Fyrolflex RDP by oral gavage up to 1000 mg/kg bw/day was found not to result in maternal and developmental toxicity in rats. Therefore, a NOAEL of 1000 mg/kg bw/day was established. As a result, the substance does not need to be classified as toxic to reproduction based on the criteria outlined in Annex I of 1272/2008/EC and Annex VI of 67/548/EEC.