Registration Dossier

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

Referenceopen allclose all

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 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 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 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 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 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 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 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 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 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:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

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.