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https://ntp.niehs.nih.gov/go/dart01abs

Abstract for DART-01

Prenatal Development Studies of Tris(chloropropyl) Phosphate in Sprague Dawley (Hsd:Sprague Dawley SD) Rats (Gavage Studies)

CASRN: 13674-84-5
Chemical Formula: C9H18Cl3O4P
Molecular Weight: 327.57
Synonyms/Common Names: 2-Propanol, 1-chloro-, phosphate (3:1); tris(2-chloroisopropyl)phosphate
Report Date: June 2020

FULL REPORT PDF

Abstract

Tris(chloropropyl) phosphate (TCPP) is used as a flame retardant in textiles, furniture (flexible polyurethane foam), and other related products. In addition, it is manufactured for use in construction materials (rigid polyurethane foam), electronic products, paints, coatings, and adhesives. Several flame retardants have been removed from products in commerce because of toxicity concerns, and TCPP has been considered as a replacement flame retardant for use in these products. Because of concerns for increased use, and thus increased human exposure, the Consumer Product Safety Commission nominated TCPP for toxicological testing by the National Toxicology Program. Additional information on the evaluation of the potential toxicity of TCPP is available at the Program’s website. The purpose of this report is to summarize and discuss TCPP effects on prenatal development. In these studies, time-mated female Sprague Dawley (Hsd:Sprague Dawley SD) rats received TCPP (95.7–97% pure) in 0.5% methylcellulose by gavage from implantation on gestation day (GD) 6 to the day before expected parturition (GD 20). Evidence of TCPP-related maternal and fetal toxicity was examined in the dose range-finding study followed by the standard prenatal developmental toxicity study.

Dose range-finding prenatal developmental toxicity study

Groups of 11 time-mated female rats were administered 0, 300, 650, or 1,000 mg TCPP/kg body weight per day (mg/kg/day) in 0.5% aqueous methylcellulose by gavage from GD 6 to GD 20. Vehicle control (0 mg/kg) animals received aqueous methylcellulose.

Maternal toxicity was observed in the 1,000 mg/kg group as evidenced by 7 of 11 dams being either found dead or euthanized moribund. Associated clinical observations in the 1,000 mg/kg group included convulsion, tremors, prone, gasping, hypoactivity, hunched posture, nasal discharge, stained fur, piloerection, salivation, and rooting (pre- and postdosing), which occurred throughout gestation. One female in the 650 mg/kg group was euthanized moribund on GD 16 with associated clinical observations including cold to touch, hypoactivity, paleness, ataxia, and labored breathing, which may have been related to TCPP exposure. All vehicle control and 300 mg/kg animals survived to study termination. No TCPP-related effects were found on maternal body weights, body weight gain, or feed consumption from GD 6 to GD 20. Additionally, there were no significant exposure-related effects on postimplantation loss, fetal body weights, or fetal sex ratio, although limited litters were available for assessment in the 1,000 mg/kg TCPP group because of maternal toxicity. Finally, there were no significant exposure-related external fetal findings (including examination of the palate).

Prenatal developmental toxicity study

Because of the maternal toxicity observed at 1,000 mg/kg in the dose ranging-finding study, groups of 25 time-mated female rats were administered 0 (n = 50), 162.5, 325, or 650 mg TCPP/kg/ body weight per day in 0.5% aqueous methylcellulose by gavage from GD 6 to GD 20. Vehicle control (0 m/kg) animals received aqueous methylcellulose. Animals were added to the vehicle control group to obtain historical control data for both maternal and fetal findings in this strain of rat. In this study, TCPP was well tolerated and no exposure-related effects occurred on mortality, maternal body weights, body weight gains, or feed consumption during gestation. Low incidences of clinical observations including nasal discharge, salivation, twitches, ataxia, piloerection, audible respiratory sounds, and hyperactivity were observed in the 650 mg/kg group. Adverse clinical observations were not observed in other groups exposed to TCPP. There were no notable placental or other maternal gross observations at necropsy except for dose-related increases in absolute (9%, 16%, and 26% at 162.5, 325, and 650 mg/kg, respectively) and relative liver weights.

No significant effects of TCPP were observed on postimplantation loss, mean fetal body weights, or fetal sex ratio. Likewise, no biologically relevant exposure-related malformations were found in external, visceral, and skeletal fetal exams of groups exposed to TCPP.

Conclusions

Under the conditions of the prenatal study, no evidence of developmental toxicity of TCPP was found in Hsd:Sprague Dawley SD rats administered 162.5, 325, or 650 mg/kg in the absence of overt maternal toxicity.

National Toxicology Program (NTP). 2020. NTP developmental and reproductive toxicity technical report on the prenatal development studies of tris(chloropropyl) phosphate (CASRN 13674‑84-5) in Sprague Dawley (Hsd:Sprague Dawley SD) rats (gavage studies). Research Triangle Park, NC: National Toxicology Program. DART Report 01. https://doi.org/10.22427/NTP-DART-01

Studies

Summary of Exposure-related Findings in Rats in the Prenatal Developmental Toxicity Gavage Study of Tris(chloropropyl) Phosphate

    0 mg/kg [a]

    162.5 mg/kg

    325 mg/kg

    650 mg/kg

Maternal parameters

Animals on study

50

25

25

25

Number pregnant

44

21

21

20

Number died or euthanized moribund

0

0

0

0

Clinical observations

None

None

None

Ataxia, audible respiratory sounds, hyperactivity, nasal discharge, piloerection, salivation, and twitches

Body weight and feed consumption[b]

Necropsy body weight

382.3 ± 3.1

386.3 ± 4.2

384.3 ± 5.1

379.4 ± 8.2

Body weight change GD 6 to 21

139.6 ± 2.5

143.6 ± 3.0

139.9 ± 3.8

137.6 ± 6.3

Feed consumption GD 6 to 21

22.8 ± 0.23

22.5 ± 0.33

22.9 ± 0.33

22.2 ± 0.42

Necropsy observations

Organ weights

None

9% ↑ in absolute liver weight

16% ↑ in absolute liver weight

26% ↑ in absolute liver weight

Developmental/Fetal parameters

Number of litters examined

44

21

21

20

Number of live fetuses evaluated

599

300

270

259

Number of live fetuses per litter[c]

13.61 ± 0.30

14.29 ± 0.37

12.86 ± 0.62

12.95 ± 0.91

Number of early resorptions[d]

22

11

11

15

Number of late resorptions[d]

2

0

0

0

Number of dead fetuses[d]

1

0

2

0

Number of whole litter resorptions

0

0

0

0

Percent postimplantation loss[c]

3.81 ± 1.13

3.42 ± 0.99

4.33 ± 1.19

7.17 ± 4.50

Fetal body weight per litter[b]

5.29 ± 0.04

5.22 ± 0.06

5.42 ± 0.08

5.22 ± 0.07

Male fetal weight per litter

5.42 ± 0.05

5.35 ± 0.06

5.47 ± 0.06

5.34 ± 0.06

Female fetal weight per litter

5.17 ± 0.04

5.08 ± 0.06

5.30 ± 0.09

5.09 ± 0.07

Gravid uterine weight[b]

98.89 ± 1.93

101.98 ± 2.23

95.76 ± 4.06

91.78 ± 5.91

External findings

None

None

None

None

Visceral findings

None

None

None

None

Skeletal findings

None

None

None

None


Level of evidence of developmental toxicity: No evidence


GD = gestation day.
[a] This study had two vehicle control groups. Data from both vehicle control groups were combined and are presented here.
[b] Results given in grams. Data are displayed as mean ± standard error.
[c] Data are displayed as mean ± standard error.
[d] No statistical analyses were performed on number of early resorptions, number of late resorptions, or number of dead fetuses.