Reaction products of tetrabromophthalic anhydride with 2,2'-oxydiethanol and methyloxirane

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

various

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Adequate data on structural analogues is available. See Section 7.12. "Additional Toxicological Data".Read across, rather than actual data, was used for this endpoint. The studies cited in Section 7.12 were previously screened in the OECD SIDS or U.S. National Institute of Health program,s and/or performed by the U.S. National Cancer Institute or U.S. National Toxicology Program or available in the open literature.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Tetrabromophthalic anhydride [CASRN 632-79-1] Review of the toxicological literature,

Author:

Tice

Year:

1999

Bibliographic source:

http://ntp.niehs.nih.gov/ntp/htdocs/Chem_Background/ExSumPdf/Tetrabromophthalic.pdf, pp. 1-15 (See Appendix 6.2).

Reference 2

Reference Type:

publication

Title:

Bioassay of phthalic anhydride for possible carcinogenicity CAS No. 85-44-9

Author:

Anonymous

Year:

1979

Bibliographic source:

National Cancer Institute, Carcinogenesis, Technical Report Series No. 159, pp. 1-107 (See Appendix 6.3)

Reference 3

Reference Type:

publication

Title:

Toxicokinetics of phthalic acid: the common final metabolite of phthalic acid esters in rats,

Author:

Lim et al

Year:

2007

Bibliographic source:

JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH, PART A, Vol. 70, pp. 1344-1349.

Reference 4

Reference Type:

publication

Title:

NTP Technical Report on the Toxicology and Carcinogenesis Studies of Diallylphthalate (CAS No. 131-17-9) in F344/N Rats (Gavage Studies),

Author:

Anonymous

Year:

1985

Bibliographic source:

NATIONAL TOXICOLOGY PROGRAM TECHNICAL REPORT SERIES NO. 284, pp. 1-154 (See Appendix 6.4).

Reference 5

Reference Type:

other: OECD SIDS

Title:

OECD SIDS 1,2-Dihydroxypropane CAS: 57-55-6,

Author:

Anonymous

Year:

2001

Bibliographic source:

UNEP PUBLICATIONS, pp. 1-166, at p. 4 (See Appendix 6.5).

Reference 6

Reference Type:

other: OECD SIDS

Title:

OECD SIDS Initial Assessment Profile for Ethylene Glycols Category, pp. 1-4,

Author:

Anonymous

Year:

2004

Bibliographic source:

http://cs3-hq.oecd.org/scripts/hpv/ChemGroup.asp

Reference 7

Reference Type:

other: ATSDR

Title:

Toxicological profile for di(2-ethylhexyl) phthalate,

Author:

Anonymous

Year:

2002

Bibliographic source:

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, PUBLIC HEALTH SERVICE, AGENCY FOR TOXIC SUBSTANCES AND DISEASE REGISTRY, pp. 1-291

Reference 8

Reference Type:

other: EPA science policy

Title:

Proposed OPPTS science policy: PPARa-mediated hepatocarcinogenesis in rodents and relevance to human health risk assessments,

Author:

anonymous

Year:

2003

Bibliographic source:

OFFICE OF PREVENTION, PESTICIDES & TOXIC SUBSTANCES, U.S. ENVIRONMENTAL PROTECTION AGENCY, Washington, D.C. 20460, pp. 1-39.

Reference 9

Reference Type:

other: IARC

Title:

Peroxisome proliferation and its role in carcinogenesis: Views and expert opinions of an IARC working group, Lyon, 7-11 December 1994

Author:

Anonymous

Year:

1994

Bibliographic source:

IARC TECHNICAL PUBLICATION NO. 24, http://monographs.iarc.fr/ENG/Publications/techrep24/IARCrep24.pdf

Reference 10

Reference Type:

other: OECD SIDS

Title:

OECD SIDS Initial Assessment Profile for High Molecular Weight Phthalate Esters (HMWPE) Category, pp. 1-6,

Author:

anonymous

Year:

2004

Bibliographic source:

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Bis(2-ethylhexyl) tetrabromophthalate

EC Number:

247-426-5

EC Name:

Bis(2-ethylhexyl) tetrabromophthalate

Cas Number:

26040-51-7

IUPAC Name:

bis(2-ethylhexyl) 3,4,5,6-tetrabromophthalate

Test animals

Species:

rat

Strain:

not specified

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

28 d

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 200, 2000, 20000 ppm diet
Basis:
nominal in diet

No. of animals per sex per dose:

10/sex/dose

Control animals:

yes, concurrent no treatment

Positive control:

Di(2-ethylhexyl)phthalate at a dose of 15000 ppm was included as a positive control (rats 5/sex/group)

Results and discussion

Effect levels

Dose descriptor:

NOAEL

Effect level:

2 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see below

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

see below

Applicant's summary and conclusion

Conclusions:

The NOEL in this 28 d rat study was 2000 ppm in the diet.

Executive summary:

Di(2-ethylhexyl)-3,4,5,6-tetrabromophalate (DEHTBP) is a brominated form of di(2-ethylhexyl)phthalate. DEHTBP has been evaluated in a 28-day dietary feeding study (rats 10/sex/dose group for DEHTBP) with dose levels of 0, 200, 2000, or 20000 ppm.Di(2-ethylhexyl)phthalate at a dose of 15000 ppm was included as a positive control (rats 5/sex/group) to evaluate the potential of DEHTBP to induce reproductive toxicity. The study was conducted in accordance with international guidance for performing 28-day repeated dose studies and was compliant with Good Laboratory Practice standards. Slight body weight decreases was observed in high dose DEHTBP females (91% of controls), along with a decrease in alanine aminotransferase activity (p<0.05). Also observed in high dose females were decreased calcium and phosphorous levels. There were no other adverse effects observed for hematology, clinical chemistry, urinalysis, organ weights, gross or microscopic analyses in male or female rats. Electron microscopy of livers from DEHTBP-treated animals was negative for peroxisome proliferation, a marker of PPARa. The positive control produced marked signs of toxicity in stark contrast to the negative control and DEHTBP test groups. The study authors reported a no-observed-adverse-effect level of 2000 ppm.

The above study with DEHTBP demonstrates that bromination of di(2-ethylhexyl)phthalate at the 3, 4, 5, and 6 position prevents the reproductive toxicity observed with di(2-ethylhexyl)phthalate in rodents. There are several possible explanations for this including: 1) DEHTBP may be poorly absorbed compared to di(2-ethylhexyl)phthalate; 2) if absorbed, DEHTBP or its metabolites may not act as an PPARaagonists; or 3) if absorbed, DEHTBP may not cross the blood:testes barrier. Regardless, DEHTBP provides a worse case scenario of the potential for an esterified form of 3,4,5,6-tetrabromophthalic acid to induce reproductive toxicity. These findingsare important for a structure activity comparison to the Reference Substance and the UVCB product because they demonstrate that bromination of a chemical shown to cause reproductive toxicity in rodents (i.e., di(2-ethylhexyl)phthalate) prevents that outcome. Because the reproductive toxicity of phthalate esters are associated with molecules that contain a 4 to 6 carbon linear or branched backbone,the absence of reproductive toxicity findings with DEHTBP, as well as, the absence of 4 to 6 carbon linear or branched aliphatic side chains in the Reference Substance and the UVCB product support that neither is a candidate for inducing reproductive toxicity.