Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication report which meets basic scientific principles.
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Studies on the Toxicity of Insecticides and Food Additives in Pregnant Rats- (5) Foetal Toxicity of Tris-(Chloropropyl) Phosphate.
Author:
Kawasaki, H. et al.
Year:
1982
Bibliographic source:
Oyo Yakuri 24(5):697–702

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
the group sizes were smaller than stipulated under guideline and postnatal study was conducted also.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Purity: Not reported. Test material was a commercial tris chloropropyl phosphate flame retardant from Tokyo Kasei Kogyo K.K. containing: tris(2-chloroisopropyl) phosphate; bis (1-chloromethyl)(2-chloropropyl) phosphate; and bis (2-chloropropyl) (1-chloromethyl) phosphate
as confirmed by gas chromatography. The test substance may have been essentially the same as that used by Nakamura et al. (1979) (reviewed in the genotoxicity section).

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
Not specified

Administration / exposure

Route of administration:
oral: feed
Vehicle:
olive oil
Details on exposure:
20 gestational days, ad lib
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Not specified
Details on mating procedure:
no data
Duration of treatment / exposure:
20 gestational days for prenatal study. weaned at day 21 and 4 additional weeks for postnatal study.
Frequency of treatment:
Diet
Duration of test:
70 days
Doses / concentrations
Remarks:
Doses / Concentrations:
0.01, 0.1, or 1.0 % tris(2-chloroisopropyl) phosphate
Basis:
nominal in diet
No. of animals per sex per dose:
11-14 pregnant females/dose for prenatal test; 5-7 pregnant females/dose for postnatal test
Control animals:
not specified
Details on study design:
not specified

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
POST-MORTEM EXAMINATIONS: Yes



Ovaries and uterine content:
yes
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes: [30% per litter ]
- Skeletal examinations: Yes: [60% per litter ]
- Head examinations: No data
Statistics:
no data
Indices:
live born index was examined
Historical control data:
no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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

Details on maternal toxic effects:
Exposure had no effect on feed consumption or body weight gain.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: other:

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
There were no fetal deaths or gross external abnormalities in any group; treatment had no effect on fetal weights or the incidence of implantations and resorptions. There were no dose-related visceral abnormalities. The incidence of skeletal abnormalities was not statistically different from controls, but a few instances of cervical ribs and missing 13th ribs were observed in treated groups but not controls.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

There were no gross abnormalities observed at the birth in any group and there was no difference in the birth rate between the test and control groups.There were no differences between the test and control groups for the weaning rate at three weeks with no abnormalities observed.

Skeletal examination was performed on foetuses from the control and treatment groups. Cervical ribs and missing 13th ribs were encountered in all treatment groups,but not in the control group.65 control foetuses were examined and none showed cervical ribs.

In the 0.01%,0.1%and 1%treatment groups,77,73 and 64 foetuses were examined and 1,1,and 3 of them showed cervical ribs,respectively.No control foetuses demonstrated missing 13th rib, while 1,2 and 5 foetuses treated with 0.01%,0.1%and 1%TCPP showed missing 13th ribs. The incidence of cervical ribs and missing 13th ribs was not reported on a per litter basis and therefore,it is not possible to determine whether the increase in the incidence of these effects was seen only in one litter or spread across a number of litters.Also,due to the relatively lownumber of foetuses examined,it is difficult to conclude on the dose-dependence and therefore,the significance of the increase in missing 13th rib.Historical control data on the incidence of missing 13th rib was also not available.

Delayed ossification of the sternebrae was seen in 2 foetuses in the control group compared to 3,7 and 1 foetuses in the 0.01%,0.1%and 1.0%treatment groups.The authors of the report concluded that these effects were not significant.Following visceral examination of the foetuses only one case of dilatation of the renal pelvis was noted in the 0.1%treatment group. There were no other instances of abnormalities observed in any group following visceral examination.Weaning rate and rearing condition were unaffected by treatment and there was no evidence of any abnormality.

Table 1 Effects of TCPP on foetuses and dams fed from day 0 to day 20 of gestation

 Dose (%)   0   0.01   0.1   1.0 
 No. of animals(dams)   11   13   12   14 
 No. of implants   124   135   132   158 
 No. of resorptions   12   5   6   8 
 No. of dead foetuses   0   0   0   0 
 Live foetuses:   Male/Female   Male/Female   Male/Female   Male/Female 
 No.   56/56   63/67   52/74   77/73 
 Weight   (grams)   4.3/4.1   4.4/4.2   4.3/4.1   4.3/4.1 
 No. of foetuses with ext. malformations   0/0   0/0   0/0   0/0 

Table 2 Effects of TCPP on neonatal growth

 Dose (%)   0   0.01   0.1   1.0 
 No. of litters   5   6   7   6 
 At birth:         
 No. of live neonates   47   60   74   61 
 No. of dead neonates   1   3   0   3 
 Live birth index (%)   89.1   89.4   96   93 
 Abnormality of neonates   0   0   0   0 
 At weaning:         
 No. of dead neonates         
 Male:   1   1   1   0 
 Female:   1   0   0   1 
 No. of weanlings   38   47   55   47 
 Weanling rate (%)   95.0   97.9   98.2   97.9 
Abnormality of neonates    0   0   0   0 

Applicant's summary and conclusion

Conclusions:
The highest dose in this study, 1000 mg/kg/day, was a NOAEL for maternal, fetal, and postnatal toxicity.
Executive summary:

The rib count undertaken as part of the two generation reproductive toxicity study(TNO Quality of Life,2007)described above did not reveal any increase in missing 13th ribs or cervical ribs.Therefore,it is considered that this finding is not toxicologically significant.

Both prenatal and postnatal toxicity were well investigated for TCPP and suggesting that the chemical is not expected to be a developmental toxin.