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EC number: 284-895-5
CAS number: 84989-06-0
The fraction of tar acids, rich in 2,4- and 2,5-dimethylphenol, recovered by distillation of low-temperature coal tar crude tar acids.
In absence of experimental data on Tar acids, Xylenol fraction (CAS
84989-06-0) an analogue read-across approach was conducted:
WoE - m/p-cresols (RL2; similar to OECD 451 and under GLP, female
mouse): NOAEL(carcinogenicity): 300 mg/kg bw/day;
WoE - m/p-cresols (RL2; similar to OECD 451 and under GLP, male rat):
NOAEL(carcinogenicity): 230 mg/kg bw/day;
Under the conditions of this 2-year study (oral feed, 0,100, 3000, 10000
ppm = equivalent to avaraged daily doses of approx. 0, 100, 300 , or
1040 mg/kg bw/day), there was some evidence of carcinogenic activity of
60 : 40 m/p-cresol in female B6C3F1 mice based on the increased
incidence of forestomach squamous cell papilloma. The LOAEL (f) is
therefore 1040 mg/kg bw/day.
Under the conditions of these 2-year studies
(OECD TG 451, oral feed, 0.1500, 5000 or 1500 ppm), there was equivocal
evidence of carcinogenetic activity of 60:40 m/p-cresol in male F344/N
rats based on the marginally increased incidence of renal tubule
adenoma. The LOAEL(male rats) is therefore 720 mg/kg bw/day.
The available data on m/p cresol does not meet the criteria for
classification for carcinogenicity of Tar acids, Xylenol fraction (CAS
84989-06-0) according to Annex VI of Regulation (EC) No 1272/2008.
However, Tar acids, Xylenol fraction (CAS 84989-06-0) has a harmonized
classification for Carcinogenicity (Carc. 1B, H350) according to Annex
VI of Regulation (EC) No 1272/2008 under the following criteria: The
classification as a carcinogen or mutagen need not apply if it can be
shown that the substance contains less than 0.1% benzene and/or 0.005%
Justification for read-across
There are no data for carcinogenicity available for Tar acids, Xylenol
fraction (CAS 84989-06-0). Read-across from appropriate substances is
conducted in accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5.
According to Article 13 (1) of Regulation (EC) No 1907/2006,
"information on intrinsic properties of substances may be generated by
means other than tests, provided that the conditions set out in Annex XI
are met”. In particular for human toxicity, information shall be
generated whenever possible by means other than vertebrate animal tests,
which includes the use of information from structurally related
substances (grouping or read-across) “to avoid the need to test every
substance for every endpoint”.
Tar acids, Xylenol fraction (CAS 84989-06-0) is an UVCB substance
comprised of tthe main constituents xylenols (all isomers in total >
60%; 2,4- and 2,5-xylenol > 40%), ethyl phenols (< 30%) and cresols (<
25%). The read-across approach is therefore based on the main
constituents of Tar acids, Xylenol fraction (CAS 84989-06-0), given
common functional groups, common precursors and the likelihood of common
breakdown products via biological processes. For further details on the
read-across approach, please refer to the analogue justification in
section 13 of the technical dossier.
For carcinogenicity read-across from reliable data on the analogue
substance m/p-cresol was conducted.
The following discussion below has been taken from the NTP technical
report on Cresols.
In 2007, US Health and Human Services published a Toxicity and
Carcinogenicity Study in which only male rats or only female mice were
fed m/p-cresol mixture over a period of two years without interim kill
(similar to OECD 451 and under GLP). Neither absolute/relative organ
weights nor blood biochemistry data were reported. The report contains
only histopathological data.
The NTP generated carcinogenicity data has been discussed below in light
of the NTP technical Report on cresols (2008).
Male F344/N rats received in feed 0, 1500, 5000 and 15000 ppm (=
equivalent to daily doses of approx. 0, 70, 230 or 720 mg/kg bw/day)
daily for 105 weeks. Under the condition of these 2 -year studies, there
was equivocal evidence of carcinogenic activity on m/p-cresol based on
the 4/50 male rats with renal tubular adenomas. The incidence of these
neoplasms was not significant but exceeded the historical control data
of the laboratory (1/297[feed studies]). In NTP studies the kidney is
the second most commonly affected site for chemically induced neoplasms
in the male rat and these are most adenomas (NTP, 2006). In this study
it could be speculated that the increased incidence of adenoma in the
15000 ppm group arose by mechanisms of action similar to that proposed
for hydroquinone. Hydroquinone markedly increases the number of renal
tubular cell adenomas when administered to F344/N male (but not female)
rats at nephrotoxic doses. There is speculation that this is attributed
to a minor metabolite 2,3,5 -tris(glutathione-S-yl)hydroquinone a potent
toxic and redox-active species. The formation of benzoquinones from m-
and p-cresol and quinone methide from p-cresol is inferred from
identification of specific glutathione conjugates formed in rat and
human liver microsomal incubations. In rats, cresols are detoxicated
primarily by conjugation to glucuronic acid of sulphate. It is likely
that minor amounts of cresol-derived glutathione conjugates are also
formed in vivo. However the potential for formation of quinone like
reactive metabolites from cresols should be much lower than from
hydroquinone itself. Therefore the potential non-neoplastic response in
the kidney should be much weaker in cresol-exposed rats than in rats
exposed to similar doses of hydroquinone. No increased incidences of
other neoplasms were observed in any other tissues of cresol exposed
rats. However, due to the presence of renal tubule adenomas in the high
exposure concentration group the evidence of carcinogenicity in rats in
the NTP study was considered equivocal.
Female B6C3F1 mice received in feed 0, 1000, 3000, 10000 ppm for 106-107
weeks (= equivalent to daily doses of approx. 0, 100, 300 or 1040 mg/kg
bw/day). Under the conditions of these 2-year studies there was some
evidence of carcinogenic activity of m/p-cresol mixture based on the
increased incidence of forestomach squamous cell papillomas. However,
there is no human counterpart for the rodent forestomach. Therefore, the
forestomach squamous cell papillomas are of minor significance for the
human situation. In addition, due to the corrosive property of the test
substance, chronic irritation is expected to be the mode of action.
Significantly increased incidences of respiratory epithelial hyperplasia
of the nose were significantly increased in the 3000 and 10000 ppm
groups. However cresols have been shown to be respiratory irritants in
humans and animals following inhalation exposure. The non-neoplastic
lesions were most likely due to inhalation exposure of the p-isomer
volatising from the feed during consumption and not from direct systemic
exposure following oral absorption. Such lesions are considered to be an
adaptive response and are among those commonly observed in NTP
inhalation studies of chemicals that are known irritants (NTP, 2000).
Under the conditions of these 2 year studies, there was equivocal
evidence of carcinogenic activity of m/p cresol in male F344/N rats
based on the marginally increased incidence of renal tubule adenoma.
There was some evidence of carcinogenic activity of m/p cresol in female
B6C3F1 mice based on the increased incidence of forestomach squamous
The available data on m/p cresol show no clear evidence that m/p cresol
is carcinogenic. Therefore, Tar acids, Xylenol fraction (CAS 84989-06-0)
is not classified for Carcinogenicity according to Annex VI of
Regulation (EC) 1272/2008.
National Toxicology Program (NTP, 2000). NTP Technical report on the
toxicology and carcinogenesis studies of napthalene (CAS no. 91 -20 -3)
in F344/N rats (inhalation studies). Technical report series No. 500.
NIH publication No. 01 -4434. National Institutes of Health, Public
Health Services, US Department of Health and Human Services, Research
Triangle Park, NC.
National Toxicology Program (NTP, 2006). NTP Technical report on the
toxicology and carcinogenesis studies of benzophenone (CAS no. 119 -61
-9) in F344/N rats and B6C3F1 mice (feed studies). Technical report
series No. 533. NIH publication No. 06 -4469. National Institutes of
Health, Public Health Services, US Department of Health and Human
Services, Research Triangle Park, NC.
National Toxicology Program (NTP, 2008). NTP Technical report on the
toxicology and carcinogenesis studies of cresols (CAS No. 1319 -77 -3)
on male Fe44/N rats and female B6C3F1 mice (feed studies). Technical
report series No. 550. NIH publication No. 08 -5891. National Institutes
of Health, Public Health Services, US Department of Health and Human
Services, Research Triangle Park, NC.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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