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Toxicological information

Toxicity to reproduction: other studies

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Administrative data

Endpoint:
toxicity to reproduction: other studies
Remarks:
developmental neurotoxicant ? - in vitro study
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2011

Materials and methods

Principles of method if other than guideline:
Principle of test: This study evaluated the neurotoxicity of tris (1,3-dichloro-2-propyl) phosphate (TDCPP) compared to the organophosphate pesticide, chlorpyrifos (CPF), a known dev
elopmental neurotoxicant. We also tested the neurotoxicity of three structurally similar OPFRs, tris (2- chloroethyl) phosphate (TCEP), tris (1-chloropropyl) phosphate (TCPP), and tris (1,3- dibromopropyl) ph osphate (TDBPP), and 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), a major component of PentaBDE. Us ing undifferentiated and differentiating PC12 cells, changes in DNA synthesis, oxidative stress, differentia tion into dopaminergic or cholinergic neurophenotypes, cell number, cell growth and neurite growth were
assessed.
- Short description of test conditions: PC12 cells were exposed in the undifferentiated and differentiated
state.
- Parameters analysed / observed: cell proliferation, viability and differentation pathway
GLP compliance:
no
Type of method:
in vitro

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Test materials used are (14)C-TDCP, (14)C-TCPP and (14)C-TCEP
Radiochemical purity : 99.9%
Specific actiity: 78 mCi/mmol ; 6.7 MBq/mg
Specific details on test material used for the study:
10, 20, or 50 μM TDCPP (99% purity as measured by GC-ECNI-MS; Chem Service

Test animals

Species:
other:

Administration / exposure

Details on study design:
For TDCPP experiments assessing changes in DNA synthesis (24 hour exposure), cell number, cell growt h, neurite growth, oxidative stress, cell viability (4 day exposure), and phenotypic differentiation (6 day exposure), measurements were performed on 8–10 cultures for each treatment, using one to two separa te cell batches. For TDCPP experiments assessing changes in cell number, cell growth, and neurite g rowth (6 day exposure), measurements were performed on 15–23 cultures for each treatment, using thr ee separate cell batches. We evaluated two analysis of variance (ANOVA) factors (treatment x cell b atch) and found that the results did not vary significantly between different cell batches; therefore, results
across different batches were normalized and combined for presentation. Comparisons between OPFRs
were performed on 4–5 separate cultures from a single cell batch. BDE-47 studies were performed on 8– 10 cultures for each treatment, using a single cell batch. The results are presented as the mean ± SEM. Comparisons between treatments were carried out by ANOVA followed by a post hoc Fisher’s protected
least significant difference. Significance was assumed at p < 0.05 (two-tailed).
Statistics:
The results are presented as the mean ± SEM. Comparisons between treatments were carried out by ANOVA followed by a post hoc Fisher’s protected least significant difference. Significance was assumed
at p < 0.05 (two-tailed).

Results and discussion

Applicant's summary and conclusion

Conclusions:
Profound effects on neural cell replication and neurodifferentiation, processes that are critical to early n eurodevelopment were observed.
Executive summary:

Organophosphate flame retardants (OPFRs) are used as replacements for the commercial PentaBDE mixture that was phased out in 2004. OPFRs are ubiquitous in the environment and detected at high concentrations in residential dust, suggesting widespread human exposure. OPFRs are structurally similar to neurotoxic organophosphate pesticides, raising concerns about exposure and toxicity to humans. This study evaluated the neurotoxicity of tris (1,3-dichloro-2-propyl) phosphate (TDCPP) compared to the organophosphate pesticide, chlorpyrifos (CPF), a known developmental neurotoxicant. We also tested the neurotoxicity of three structurally similar OPFRs, tris (2-chloroethyl) phosphate (TCEP), tris (1-chloropropyl) phosphate (TCPP), and tris (1,3- dibromopropyl) phosphate (TDBPP), and 2,2′,4,4′- tetrabromodiphenyl ether (BDE-47), a major component of PentaBDE. Using undifferentiated and differentiating PC12 cells, changes in DNA synthesis, oxidative stress, differentiation into dopaminergic or cholinergic neurophenotypes, cell number, cell growth and neurite growth were assessed. TDCPP displayed concentration-dependent neurotoxicity, often with effects equivalent to or greater than equimolar concentrations of CPF. TDCPP inhibited DNA synthesis, and all OPFRs decreased cell number, and altered neurodifferentiation. Although TDCPP elevated oxidative stress, there was no adverse effect on cell viability or growth. TDCPP and TDBPP promoted differentiation into both neuronal phenotypes, while TCEP and TCPP promoted only the cholinergic phenotype. BDE-47 had no effect on cell number, cell growth or neurite growth. Our results demonstrate that different OPFRs show divergent effects on neurodifferentiation, suggesting the participation of multiple mechanisms of toxicity. Additionally, these data suggest that OPFRs may affect neurodevelopment with similar or greater potency compared to known and suspected neurotoxicants.