Tar acids, xylenol fraction

Carcinogenicity

Description of key information

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;

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: only female mice in test; due to the design of the study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

yes

Remarks:

only female mice in test

GLP compliance:

yes

Species:

mouse

Strain:

B6C3F1

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic Laboratory Animals and Sevices, Germantown, NY
- Age at study initiation: 6 weeks
- Housing: 2-3 rats/cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 12 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72
- Humidity (%): 50
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

DIIET PREPARATION
- Rate of preparation of diet (frequency): monthly
- Mixing appropriate amounts with NTP-2000 food
- Storage temperature of food: at 25°C in the dark

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Periodic analyses of the dose formulations were conducted by the study laboratory usinng GC. The dose formulations were analyzed approximately every 3 months. All of the dose formulations analyzed for rats were within 10% of the target concentration.

Duration of treatment / exposure:

106 - 107 weeks

Frequency of treatment:

daily

Post exposure period:

no

Dose / conc.:

1 000 ppm (nominal)

Remarks:

100 mg/kg bw/day (actual ingested)

Dose / conc.:

3 000 ppm (nominal)

Remarks:

300 mg/kg bw/day (actual ingested)

Dose / conc.:

10 000 ppm (nominal)

Remarks:

1040 mg/kg bw/day (actual ingested)

No. of animals per sex per dose:

50 female mice per dose

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: the highest exposure concentrations was based on the minimal toxicity observed at this level in a 13 week study with m/p-cresol mixture

Positive control:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: yes
- Time schedule: Clinical findings were recorded during week 5 of the study, at 4 week intervalls thereafter and at termination

BODY WEIGHT: Yes
- Time schedule for examinations: at the beginning of the study weekly for the first 13 weeks, at 4 week intervals thereafter and at study termination

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined: Yes; at the beginning of the study weekly for the first 13 weeks, at 4 week intervals thereafter
- Compound consumption calculated as mean mg/kg bw/day

OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes; was performed on all mice
HISTOPATHOLOGY: Yes; complete histopathology was performed on all mice. In additon to gross lesions and tissue masses , the following tissues were examined:
adrenal gland, bone with marrow, brain, clitoral gland, esophagus, eye, gall bladder, hardrian gland, heart and aorta, large intestine, small intestine, kidney, liver, lung, mainstem bronchi, lymph nodes (mandibular and mesenteric), mammary gland, nose, ovarties, pancreas, parathyroid gland, pituitary gland, salivary gland, skin, spleen, stomach (forestomach and glandular), thymus, thyroid gland, trachea and urinary bladder and uterus

For all paired organs samples from each organ were examined.

Other examinations:

no

Statistics:

Kaplan Meier, Cox-method, Tarone's life-table test, Poly-k-test

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Other effects:

not specified

Details on results:

see section "remarks on results"

Survival rates: 41/50, 43/50, 44/50, 42/50

Mean body weight of the 3000 ppm and 10000 ppm groups were less than those of the control group after weeks 12 and 9, respectively, and decreased to 88% and 75% that of the control group, respectively, by the end of the study.

There were no clinical findings related to exposure to cresols.

Nonneoplastic effects
----Lung: bronchiole, hyperplasia (0/50, 42/50, 44/49, 47/50)
----Nose: respiratory epithelium, hyperplasia (0/50, 0/50, 28/49, 45/49)
----Thyroid gland: follicular degeneration (7/48, 24/48, 24/49, 21/50)
----Liver: eosinophilic focus (1/50, 0/50, 2/49, 12/50)

Neoplastic effects
---- Forestomach: squamous cell papilloma : 0/50, 1/50, 1/49, 10/50 (20%)

The incidence of squamous cell papillomas was significantly greater in the 10000 ppm group than in the control group. One mouse in the 10000 ppm group had multiple squamous cell papillomas. The incidence increased the overall historical incidence range of 0-4%.

Equivocal findings
- None

Level of evidence of carcinogenic activity: some evidence

Key result

Dose descriptor:

LOAEL

Effect level:

1 040 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

histopathology: neoplastic

Key result

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Critical effects observed:

not specified

Conclusions:

Under the conditions of this 2 -year study (OECD TG 451, oral feed, 0,100, 3000, 10000 ppm), 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 celll papilloma. However, there is no human counterpart for the rodent forestomach (Proctor et al., Toxicol Sci 98, 313 -326, 2007). Therefore, the forestomach squamous cell paplillomas 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. Due to the design of the study, NOAEL could be determined. Increased incidences of non-neoplastic lesions were observed in the respiratory tract (hyperplasia in the nose and lung), thyroid gland (follicular degeneration), and liver (eosinophilic focus) of mice exposed to m/p-cresol.

Executive summary:

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.

Reference 2

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: only male rats in test

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

yes

Remarks:

only male rats tested

GLP compliance:

yes

Species:

rat

Strain:

other: Fisher 344/N

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic Laboratory Animals and Sevices, Germantown, NY
- Age at study initiation: 6 weeks
- Housing: 2-3 rats/cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 11 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72
- Humidity (%): 50
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): monthly
- Mixing appropriate amounts with NTP-2000 food
- Storage temperature of food: at 25°C in the dark

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Periodic analyses of the dose formulations were conducted by the study laboratory usinng GC. The dose formulations were analyzed approximately every 3 months. All of the dose formulations analyzed for rats were within 10% of the target concentration.

Duration of treatment / exposure:

105 weeks

Frequency of treatment:

daily

Post exposure period:

no

Dose / conc.:

1 500 ppm (nominal)

Remarks:

70 mg/kg bw/day (actual ingested)

Dose / conc.:

5 000 ppm (nominal)

Remarks:

230 mg/kg bw/day (actual ingested)

Dose / conc.:

15 000 ppm (nominal)

Remarks:

720 mg/kg bw/day (actual ingested)

No. of animals per sex per dose:

50 male rats per dose

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: the highest exposure concentrations was based on the minimal toxicity observed at this level in a 13 week study with m/p-cresol mixture

Positive control:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: yes
- Time schedule: Clinical findings were recorded during week 5 of the study, at 4 week intervalls thereafter and at termination

BODY WEIGHT: Yes
- Time schedule for examinations: at the beginning of the study weekly for the first 13 weeks, at 4 week intervals thereafter and at study termination

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined: Yes
at the beginning of the study weekly for the first 13 weeks, at 4 week intervals thereafter
- Compound consumption calculated as mean mg/kg bw/day

OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes; was performed on all rats
HISTOPATHOLOGY: Yes; complete histopathology was performed on all rats. In additon to gross lesions and tissue masses, the following tissues were examined:
adrenal gland, none with marrow, brain, esophagus, eye, hardrian gland, heart and aorta, large intestine, small intestine, kidney, liver, lung, mainstem bronchi, lymph nodes (mandibular and mesenteric), mammary gland, nose, pancreas, parathyroid gland,
pituitary gland, preputial gland, prostate gland, salivary gland, skin, spleen, stomach (forestomach and glandular), testis with epididymis and seminal vesicle, thymus, thyroid gland, trachea and urinary bladder

For all paired organs samples from each organ were examined

For extended evaulation of renal proliferation lesions, additional sections of both kidneys from the residual formalin-fixed wet tissues were obtained for each male rat. 3 sections of the left kidney and 4 sections of the right kidney were examined for
each rat.

Other examinations:

no

Statistics:

Kaplan Meier, Cox-method, Tarone's life-table test, Poly-k-test

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Other effects:

not specified

Details on results:

mean body weights of the 15000 ppm group were less than those of the controls throughout the study and decreased to 15% less than that of the controls by the end of the study
Survival rates: 33/50, 34/50, 33/50, 31/50
There were no clinical findings related to exposure to cresols.
Equivocal finding :
The incidence of renal tubule adenomas was increased in the 15000 ppm group and the incidence exceeded the historical range for controls in feed studies (0-2%)

Nonneoplastic effects
----Kidney
pelvis, transitional epithelium, hyperplasia (0/50, 0/50, 2/50, 8/50);
severity of nephropathy (1.4, 1.4, 1.7, 2.1)

----Nose:
goblet cell, hyperplasia (23/50, 40/50, 42/50, 47/50);
respiratory epithelium, hyperplasia (3/50, 17/50, 31/50, 47/50)
respiratory epithelium, metaplasia, squamous (0/50, 1/50, 8/50, 40/50);
inflammation (17/50, 19/50, 19/50, 28/50)

----Liver:
eosinophilic focus (14/50, 14/50, 13/50, 23/50)

Neoplastic effects
-----None

Equivocal findings:
---- Kidney:
renal tubule adenoma
--standard evaluation - 0/50, 0/50, 0/50, 3/50;
--standard and extended evaluations combined - 0/50, 0/50, 0/50, 4/50 (8%)

Level of evidence of carcinogenic activity : equivocal evidence

Key result

Dose descriptor:

NOAEL

Effect level:

230 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Key result

Dose descriptor:

LOAEL

Effect level:

720 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Under the conditions of these 2-year studies, there was equivocal evidence of carcinogenic activity of 60:40 m-/p-cresol in male F344/N rats based on the marginally increased incidence of renal tubule adenoma.

Critical effects observed:

not specified

Conclusions:

Under the conditions of this 2-year study (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 incidence of these neoplasms was not significant but exceeded the historical control data of the laboratory (1/297[feed studies]). Exposure to 60:40 m-/p-cresol resulted in increased incidences of non-neoplastic lesions in the kidney (hyperplasia), nose (inflammation, hyperplasia, and metaplasia), and liver (eosinophilic focus) of rats.

Executive summary:

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.

Reference 3

Endpoint:

carcinogenicity: oral

Type of information:

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

Remarks:

Summary of available data used for the endpoint assessment of the target substance

Adequacy of study:

key study

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

mouse

Effect level:

300 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Remarks on result:

other: Source, m/p-cresol, NTP, 2007

Key result

Dose descriptor:

LOAEL

Remarks:

mouse

Effect level:

1 040 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

histopathology: neoplastic

Remarks on result:

other: Source, m/p-cresol, NTP, 2007

Key result

Dose descriptor:

NOAEL

Remarks:

rat

Effect level:

230 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Remarks on result:

other: Source, m/p-cresol, NTP, 2007

Key result

Dose descriptor:

LOAEL

Remarks:

rat

Effect level:

720 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Under the conditions of these 2-year studies, there was equivocal evidence of carcinogenic activity of 60:40 m-/p-cresol in male F344/N rats based on the marginally increased incidence of renal tubule adenoma.

Remarks on result:

other: Source, m/p-cresol, NTP, 2007

Critical effects observed:

not specified

Conclusions:

The available data on m/p cresol give equivocal evidence on carcinogenicity of Tar acids, Xylenol fraction (CAS 84989-06-0). The incidences of neoplasms were either non-significant but exceeded the historical control data of the laboratory (rat) or were based on forestomach squamous cell papillomas which are not directly relevant for humans.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

230 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2) studies from surrogate substances, i.e. constituents, and therefore considerd to have similar structure. This is why read-across is justified based on data on the constituents of Tar acids, xylenol fraction (CAS 84989-06-0) (refer to endpoint discussion for further details).
Taken together, the information from these independent sources is consistent and provides sufficient weight-of-evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex X, 8.9, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

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% benzo[a]-pyrene.

Additional information

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.

m/p-cresol:

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).

Rat study

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.

Mouse study

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 cell papilloma.

Conclusion:

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.

References:

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.