Distillates (coal tar), heavy oils

Carcinogenicity

Description of key information

After oral ingestion (feed) of coal tar, the target organs of tumorigenicity in particular included lung and liver.
Following inhalation, no exposure-related tumours were observed in organs other than the lung of rats exposed to coal-tar pitch fumes (aerosol) derived from heated pitch material (750 °C) for 43 or 86 weeks, 17 h/d, 5 d/wk.
Dermal exposure of mice with creosote resulted in development of malignant skin tumours in ca 26 % of the treated mice. A T25 value of ca. 60 ng BaP/cm² treated skin can be estimated based on the dose-response relationship of the experimental data.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

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

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

yes

Remarks:

only female animals used

Qualifier:

no guideline available

Principles of method if other than guideline:

Part of a comprehensive test programme in which the tumor profiles and DNA-adduct distribution after tar and BaP administration were compared.
For comparison, single i.p. injection into infant male and female mice of two strains (B6C3F1 and A/J) and after feeding to A/J female mice were included (see results Attached background material)
(not reviewed in this summary, only Overall Summary Table attached: see Attached background material).

GLP compliance:

not specified

Species:

mouse

Strain:

B6C3F1

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: National Center for Toxicological Research
- Age at study initiation: 5 weeks
- Weight at study initiation: 15 - 16 g (estimated from Culp et al. 1998, Fig. 1)
- Fasting period before study:
- Housing: 4/cage
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.8 +-0.4
- Humidity (%): 51.7 +-1.4
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

oral: feed

Details on exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): no data
- Mixing appropriate amounts with (Type of food): Coal tar frozen in liquid N2 was blended with the appropriate amount of NIH-31 meal,
- Storage temperature of food: no data

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Homogeneity was verified by BaP measurement by HPLC with fluorescence detection.

Duration of treatment / exposure:

2 years

Frequency of treatment:

continuous

Remarks:

Doses / Concentrations:
0.01, 0.03, 0.1, 0.3, 0.6, and 1.0 % (= 0.22, 0.66, 2.2, 6.6, 13.4, and 22.0 mg BaP/kg diet)
Basis:
nominal in diet
CTM 1

Remarks:

Doses / Concentrations:
12, 36, 120, 360, 720, and 1200 mg/(kg bw*d)
Basis:
actual ingested
CTM1: estimated from food consumption and bw development

Remarks:

Doses / Concentrations:
0.03, 0.1, and 0.3 % (= 1.1, 3.7, and 11.1 mg BaP/kg diet)
Basis:
nominal in diet
CTM 2

Remarks:

Doses / Concentrations:
36, 120, and 360 mg/(kg bw*d)
Basis:
actual ingested
CTM 2: estimated from food consumption and bw development

No. of animals per sex per dose:

48

Control animals:

yes, concurrent no treatment

yes, concurrent vehicle

Positive control:

BaP added in acetone (vehicle) to the diet: 0.0005, 0.0025, and 0.01 % (= 5, 25, and 100 mg BaP/kg diet) /
estimated from food consumption and bw development: 0.6, 3, and 12 mg BaP/(kg bw*d)

Sacrifice and pathology:

GROSS PATHOLOGY: Yes: all mice
HISTOPATHOLOGY: Yes: liver, lungs, small intestine, stomach, tongue, and esophagus
(All mice of CTM 1 groups 0.1, 0.3, 0.6 and 1.0% / all mice of the CTM 2 and BaP groups)

Other examinations:

DNA adducts in lung, liver and forestomach, using 32P-postlabelling

Statistics:

Dunnett´s test applied on means of daily food consumption and organ weights including one-way analysis of variance, Kruskal-Wallis one-way analysis or Dunn´s method for comparison of organ weights of test groups vs. control group.
Survival as function of the dose was calculated from the Kaplan-Meier survival curve.
Tumour incidences were evaluated using methods described by Korell et al. 1983 and modified Bonferonni procedure.

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

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

CLINICAL SIGNS AND MORTALITY (Culp et al 1998, Fig 2, not shown)
Significantly lower survival in mice exposed to both coal tar mixtures at doses of >= 0.3 % in diet [360 mg/(kg bw*d) and higher],
and in mice exposed to BaP of >=22 mg/kg diet [3 mg/(kg bw*d) and higher]

BODY WEIGHT AND WEIGHT GAIN
Significantly lower body weights in mice exposed to 0.6 % and 1.0 % CTM 1 [>= 720 mg/(kg bw*d)] and to 0.3 % CTM 2 [360 mg/(kg bw*d)],
and in mice exposed to BaP of 100 mg/kg diet [12 mg/(kg bw*d)]

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
CTM 1: ~25 - 30 % less at 0.6 and 1.0 %, resprectively
CTM 2: ~20 % at 0.3 %

ORGAN WEIGHTS
Liver weights of mice fed 360 mg/(kg bw*d) CTM 1or CTM 2 (0.3 % in diet) were significantly increased, approximately 40% vs control group.
Corresponding BaP doses were 0.8 and 1.1 mg/(kgbw*d), whereas treatment with 3 mg BaP/(kg bw*d) did not result in increased liver weights
(Note: Liver weights of higher exposed animals not determined due to tumour development accompanied by decreases
in body weights.)


HISTOPATHOLOGY: NEOPLASTIC (see Attached background material, from Culp et al 1998, Tab. III)

CTM 1: >=0.1 % [120 mg/(kg bw'd)], no significant increases in any tumor rate
>=0.3 % [360 mg/(kg bw'd)], significant and rapid increases in tumor rates (liver, lung, forestomach, hemangiosarcomas
histiocytic sarcomas and sarcomas in various tissues), no increase in small intestine at 0.3 %,

CTM 2: >=0.1 % [120 mg/(kg bw'd)], significant increase in lung tumor rate, but not in other tissues
>=0.3 % [360 mg/(kg bw'd)], significant and rapid increases in tumor rates (liver, forestomach, hemangiosarcomas
histiocytic sarcomas and sarcomas in various tissues), no increase in adenosarcomas in small intestine.
>=0.6 % [720 mg/(kg bw'd)], increase in adenosarcomas in small intestine

The dose-related trends were statistically highly significant.


HISTOPATHOLOGY: NEOPLASTIC (see Attached background material, from Culp et al 1998, Tab. IV)

BaP: at 5 mg/(kg bw*d), no significant increase in any tumour rate
>=25 mg/(kg bw*d), significant increase in the tumour rate of the forestomach (papillomas and/or carcinomas)
at 100 mg/(kg bw*d), additionally significant increase in the tumour rates of the tongue and esophagus, insignificant of the larynx
No increases in liver, lung, and other tissues.

Dose descriptor:

T25

Effect level:

>= 30 mg/kg bw/day

Based on:

test mat.

Remarks:

coal tar

Sex:

female

Basis for effect level:

other: Histopathology: liver and lung cancer

Remarks on result:

not determinable

Remarks:

no T25 identified. Effect type:carcinogenicity (migrated information)

Dose descriptor:

NOAEL

Remarks:

(= 0.01 % in diet)

Effect level:

ca. 12 mg/kg bw/day (actual dose received)

Sex:

female

Basis for effect level:

other: histopathology (liver tumors)

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

LOAEC

Remarks:

(= 0.03 % in diet)

Effect level:

ca. 36 mg/kg bw/day (actual dose received)

Sex:

female

Basis for effect level:

other: histopathology (liver tumors)

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Target organs of tumorigenicity of coal tar after oral ingestion are various organs distant from the first contact point,

in particular lung and liver, while BaP-induced tumors primarily emerged in tissue of local contact.

Hence, the data indicate significant differences for tumor induction by coal tar compared to BaP

(see Goldstein et al 1998, Tab. 2, see Attached background material):

(1) Both BaP and coal tar induced forestomach tumors in the 2y feeding study.

BaP, but not coal tar, induced also tumors at two other sites, tongue and esophagus.

Coal tar, but not BaP, induced tumors in lung, small intestine, and liver, as well as sarcomas, hemagiosarcomas,

and histiocytic sarcomas in several sites.

[Note: This statement is valid for B6C3F1 mice, since BaP also induced lung tumors in A/J mice, the most sensitive strain

(see Goldstein et al., Tab. 2, see Attached background material)]

(2) Intraperitoneal single doses of 125, 250, or 375 µg BaP alone or coal tar containing 3.7 and 14.7 µg BaP induced

liver tumors in infant (15 -day old) male B6C3F1 mice, but not in females.

Lower doses of BaP (31.5 or 62.5 µg) administered i.p. alone did not induce liver tumors.

(3) Tumorigenicity in 15 -day maleB6C3F1 mice by coal tar could not be recapitulated by a reconstituted mixture based on component concentrations. No tumors were found when 125 µg BaP was administered as part of the reconstituted mixture,

even though BaP administered alone at 125 µg/mouse induced tumors.

(4) Ingested coal tar induced lung tumors at high incidence and high multiplicity in A/J mice.

Also high oral doses of pure BaP resulted in a limited lung tumor yield in this sensitive strain,

but much less as compared to the coal tar potency.

---------------------------

Overall, BaP is at best a weak lung carcinogen when ingested, and therefore may not be a particularly good surrogate

for the use in human health risk assessments of coal tar.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

12 mg/kg bw/day

Study duration:

chronic

Species:

other: rat) (related to tar material

Carcinogenicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: inhalation

Type of information:

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

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Studies based on accepted scientific principles and methods, summarised in EU 2008: Risk Assessment Report on Pitch, Coal Tar, high temp.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

GLP compliance:

no

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

--

Route of administration:

inhalation: aerosol

Type of inhalation exposure (if applicable):

nose only

Vehicle:

other: clean air

Details on exposure:

The aerosol was generated by heating coal-tar pitch to 750°C under nitrogen atmosphere and diluting the high temperature tar/pitch vapour with 12°C clean air.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

43 and 86 wk

Frequency of treatment:

17 h/d, 5 d/wk

Post exposure period:

recovery period: 86 and 43 wk without exposure

Remarks:

Doses / Concentrations:
0, 1.1, or 2.6 mg/m3 of a CTPHT aerosol
Basis:
analytical conc.
coal tar pitch, high temperature, vapour/aerosol, MMAD = 0.5 µm, ca. 20 and 46 µg BaP/m3, resp.

No. of animals per sex per dose:

72

Control animals:

yes, concurrent no treatment

Histopathological findings: neoplastic:

effects observed, treatment-related

Dose descriptor:

T25

Remarks:

stated 33 % tumour-bearing animals

Effect level:

1.1 mg/m³ air (analytical)

Based on:

test mat.

Remarks:

coal-tar pitch vapour/aerosol

Sex:

female

Basis for effect level:

other: Histopathology: lung tumours

Remarks on result:

not determinable

Remarks:

no T25 identified. Effect type:carcinogenicity (migrated information)

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

1.1 mg/m³

Study duration:

chronic

Species:

other: rat) (related to pitch aerosol

Carcinogenicity: via dermal route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: dermal

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study, but test design shows shortcomings in test conditions reflected in the impairment and even destruction of the cutaneous barrier. This condition does not represent realistic exposure situations for humans.

Qualifier:

according to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

yes

Remarks:

see below

Principles of method if other than guideline:

The deviations were as follows:
• Only male mice were used
• Treatment: only 2x/week without cover on treated area
• Food consumption: not obtained
• Ophthalmology: not performed
• Hematology: only differential WBC count done
• Clinical chemistry: limited parameters examined
• Urinalysis: not performed
• Organ weights: only of liver and kidney
• Histopathology: only treated skin area

The limited test protocol is consistent with earlier studies on coal tar products (IARC Monographs Volumes 32, 33, 34, 35, 45). The skin carcinogenicity of tar oil and tar derivatives is established with no sex differences observed.

Alterations had to be made during the progress of the study: The introduction of further test groups with concurrent controls improved the quality of the study.

GLP compliance:

yes

Species:

mouse

Strain:

CD-1

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga, Sulzfeld, Germany
- Age at study initiation: ca. 4 weeks
- Weight at study initiation: ca. 32 g
- Fasting period before study: no
- Housing:
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):

Route of administration:

dermal

Vehicle:

other: toluene

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The test solutions were freshly prepared 1x/2 weeks and stored in closed bottles at 18-25°C protected from light and air by filling the bottles with nitrogen before preparing the solutions.

VEHICLE
- Justification for use and choice of vehicle (if other than water): solubility
- Concentration in vehicle: 4, 12, 40, 120, and 360 mg creosote oil per ml toluene
- Amount of vehicle (dermal exposure): 25 µl per treatment

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Measured concentrations were within ±10-% limits of nominal concentrations (p. 21, Tab. 12/12a, p. 72/73 of report).

Duration of treatment / exposure:

78 wk

Frequency of treatment:

2x/wk

Post exposure period:

none

Remarks:

Doses / Concentrations:
CTP 1: 0.3, 1, 3, and 9 mg oil per treatment in 25 µl toluene equivalent to 0.003, 0.01, 0.03, and 0.09 µg Benzo(a)pyrene; CTP 2: 0.1, 0.3, 1, 3, and 9 mg oil per treatment in 25 µl toluene equivalent to 0.027, 0.08, 0.27, 0.81, 2.43 µg Benzo(a)pyrene
Basis:
nominal conc.

No. of animals per sex per dose:

62

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: none

Positive control:

yes, animals dosed with 7.5 µg Benz(a)pyrene

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

CLINICAL SIGNS: Yes
- Time schedule:

DERMAL IRRITATION (if dermal study): Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION: No

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 12 and 18 months of treatment (end of study)
- Animals fasted: no data
- How many animals: all animals
- Parameters: differential leukocyte/blood count

CLINICAL CHEMISTRY: Yes, but only for controls and one CTP 2 group (group 8, dose 9 mg)
- Time schedule for collection of blood: after 269 days (unschelduled termination of group 08)
- Animals fasted: No data
- How many animals: 10 per group
- Parameters: total bilirubin, albumin, alanine aminotransferase, glutamate pyruvic aminotransferase, alkaline phosphatase, glutamate oxaloacetic aminotransferase

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
- Parameters: Treated skin area (microscopic), other organs (macroscopic, isolated cases microscopic)

HISTOPATHOLOGY: Yes
- How many animals: all surviving animals from all dose groups and animals of interim and terminal sacrifice
- Organs: treated skin area, organs other than skin only in some animals which died or were killed at an early stage of the study.

Statistics:

Haematology and clinical chemistry: variance analysis (ANOVA): two-tailed Dunnett´s test
Frequency data: chi-square contingency and Fisher test
Survival data: Kaplan-Meier analysis using the Lifespan program of SAS Inst. and logrank test (acc. to Mantel)

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

Result (carcinogenicity): ambiguous

CLINICAL SIGNS AND MORTALITY
- No specific effects related to test substance, but there was a strong irritancy of the solvent.

BODY WEIGHT AND WEIGHT GAIN
- No statistically significant differences in mean body weight (incl. terminal one) were observed compared to solvent controls in any surviving animals of the treated groups (Tab. 2/2a, p. 32/33 of report).

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
- not examined

FOOD EFFICIENCY
- not examined

WATER CONSUMPTION
-- not examined

OPHTHALMOSCOPIC EXAMINATION
- not examined

HAEMATOLOGY
- No significant effects were observed (see Report, Tab. 6a, p. 41-42).

CLINICAL CHEMISTRY
- For examined animals of the high dose CTP 2 group (group 08), no effects were observed.

URINALYSIS
- not examined

NEUROBEHAVIOUR
- not examined

ORGAN WEIGHTS
- No significant effects were found for the organs examined (liver and kidney).

GROSS PATHOLOGY
- No evidence of systemic effects due to treatment, except an increase in dead or moribund animals with enlarged spleen and enlarged lymph nodes in all treated groups as compared to the control. These effects were attributed to infections subsequent to skin ulcerations (p. 23).

HISTOPATHOLOGY: NON-NEOPLASTIC
- Treatment-related inflammatory changes of the skin were observed in all groups. They consisted either of slight to severe ulcerative dermatitis (ulceration) or superficial purulent dermatitis, epidermal erosion and inclusion cysts.
More than 70 % of the solvent control and oil-treated animals suffered from dermatitis:
In the solvent control, ulcerative dermatitis was noted in 27/62 mice, purulent dermatitis in 25/62 mice, and skin erosion in 9/62 animals.
In all CTP-1 dose groups, the frequency of ulcerative dermatitis was comparable to that of the negative control group (27/62, 23/62, 21/62, 28/62 and 31/62 mice in controls, 0.3, 1, 3 and 9 mg dose groups, respectively).
The incidence of epidermal hyperplasia without cellular atypia occurred in almost all animals of the solvent control and all CTP-1 treated groups in dose-related grade from very slight to severe (Report p. 25, Tab. 9/9a, p. 62-64 and 66/67).

HISTOPATHOLOGY: PRE-NEOPLASTIC
- The incidence of epidermal skin hyperplasia with cellular atypia occurred incidentally in the solvent control (1/62) and CTP-1 groups (1/62 and 2/62 at 1, 3, and 9 mg, respectively), but to a significantly higher extent in the CTP-2 treated groups (3 mg: 11/62; 9 mg: 13/62) in moderate to severe grade (Report p. 25).
Nodules (“apparent papillomas”) were macroscopically identified in CTP-1 groups (1/62; 2/62; and 4/62 in the 1, 3, and 9-mg group, respectively). No statistical significance was given for this change (p. 22).

HISTOPATHOLOGY: NEOPLASTIC
- see below Summary table and Report, p. 24/25, Tab. 10/11, p. 69-71.
- in the CTP-1 treated mice, 1/62 solitary squamous cell carcinoma was observed in the 3-mg group, while 2/62 squamous cell papillomas were seen in the 9-mg group. No skin tumour was found in the 0.3- and 1 mg CTP1 groups (Report, p. 24).
In the solvent controls, apart from the occurrence of one haemangioma (1/124), no skin tumours observed.
In the B(a)P positive control group, a high number of animals carrying both squamous papillomas and carcinomas was observed (32/62 with malignant squamous cell carcinoma and 27/62 with benign squamous cell papillomas).
Only in this group, additional skin tumour types were detected (basal cell carcinoma, benign basal cell tumour, sebaceous carcinoma, sebaceous adenoma, malignant fibrous histiocytoma and malignant Schwannoma)

Relevance of carcinogenic effects / potential:

Using the combined results of both creosote oils (CTP 1 and CTP 2), the study demonstrates clear correlation between tumour incidences and BaP or PAH doses.
Yet, over a creosote dose range of one magnitude corresponding to a BaP dose from 3 to 30 ng per animal and treatment (first 3 CTP 1 and first CTP 2 group), there was no statistically significant increase in tumour yield with 2 malignant skin tumours in a high total of some 250 animals and no tumours in the two lowest dose groups (CTP 1, together 124 animals). Neither was there evidence of an increase in epidermal atypic hyperplasia which is considered as an early indicator for oncogenic transformation.
The tumour frequency clearly increases in the dose range of 90 - 800 ng BaP per treatment.

Dose descriptor:

T25

Remarks:

by the authors

Remarks on result:

not determinable

Remarks:

no T25 identified. Effect type:carcinogenicity (migrated information)

Dose descriptor:

T25

Remarks:

estimated

Effect level:

ca. 60 other: ng BaP/cm2 dosed skin

Based on:

act. ingr.

Remarks:

benzo[a]pyrene (BaP)

Sex:

male

Basis for effect level:

other: Dose-response relationship, oil dose recalculated to daily BaP dose, (240/4) ng/(cm2*d) (related to 5 d/wk). (Note: A treated skin-area of 4 cm2 is assumed.)

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

NEOPLASTIC LESIONS:
===================

Table. Number of tumour bearing animals (papilloma and squamous-cell
                        carcinoma) following skin treatment with two tar oils for 78 weeks
                        (Report, p. 28, Tab. 10/11, p. 69-71)

		Toluene (solvent control)		CTP 1 [mg] low-B(a)P				CTP 2 [mg] high B(a)P					BaP (pos. control)
	Oil dose per treatment [mg]	1	2	0.3	1	3	9	0.1	0.3	1	3	9§	7.5 µg
1	total number of animals	62	62	62	62	62	62	62	62	62	62	61	62
2	with skin tumours	(1)*	0	0	0	1	2	1	3	9	23	n.e.	47
	%	0	0	0	0	2	3	2	5	15	37	n.e.	76
3	with malignant tumours	0	0	0	0	1	0	1	1	3	16	n.e.	32
	%	0	0	0	0	2	0	2	2	5	26	n.e.	52
4	exclusively with benign tumours	(1)*	0	0	0	0	2	0	2	6	7	n.e.	15
	%	0	0	0	0	0	3	0	3	10	11	n.e.	24

* Skin tumour type atypical of PAH (cavernous hemangioma), to be considered incidental

§ terminated after 274 days, therefore: n.e. = not evaluable

 

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

T25

0.06

Study duration:

chronic

Species:

other: mouse) (related to BaP (creosote application)

Quality of whole database:

The derived and adjusted T25 is estimated to be 0.06 µg/(cm2*d) (related to 5 d/wk) (area-specific dose) [note: In the FhI study, the development of skin (local) tumors were investigated. Therefore, exposure data are provided as skin-area specific doses. However, the electronic system does not enable to do so. On the other hand, to specify a body-mass related dose for a local effect makes no sense.

Justification for classification or non-classification

The substance distillates (coal tar), heavy oils (anthracene oil high (> 50 ppm) BaP, AOH) is classified as carcinogenic Cat. 1B according to Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.

Additional information

Distillates (coal tar), heavy oils (anthracene oil high (> 50 ppm) BaP, AOH) [CAS no. 90640-86-1] is a UVCB and consists of a complex combination of polycyclic aromatic hydrocarbons (PAH). It comprises mainly 3- and 4-ring aromatic compounds and to a much lesser extent PAHs with 5 rings (see Chapter 1.). Main components are phenanthrene, anthracene (3-ring PAH), fluoranthene, pyrene, benz[a]anthracene, and chrysene (4-ring PAH) each accounting for ca. 3 to 10 %. The majority of other components of AOH fall within the molecular size range of these five substances.

Benzo[a]pyrene (5-ring PAH) is present in AOH up to a concentration of 1.5 %. Other PAH identified as carcinogenic (e.g. benz[a]anthracene, benzofluoranthenes) are also present at concentrations of 0.5 to 3 %. Dominant health effect for the assessment of AOH is the carcinogenicity related to its benzo[a]pyrene content.

AOH is a tar oil with properties somewhat different from the tar/pitch used in the oral and inhalation carcinogenicity studies. For the dermal study, creosote was used that corresponds to AOH in its composition especially with respect to 3-ring and larger size PAH. The data presented are used to roughly characterise the carcinogenic potential of AOH.

Health assessment of AOH will be based on benzo[a]pyrene as marker as this substance fundamentally triggers the classification of AOH as carcinogenic. DMELs will be derived based on Unit Relative Risks (URR) that were calculated for the development of cancer in workers exposed to complex volatile PAH mixtures for a working life (see Chapter 5.11).

Carcinogenicity data obtained from experiments with coal tar and pitch (fumes) are presented below.

Tars and pitches constitute a family of products that result from different distillation steps of coal (condensation products and distillation residues). Depending on distillation step and distillation temperature, constituents of the products and their portions are variable. But major components of all the distillation products and residues are condensed ring aromatic hydrocarbons in varying composition (i.e. polynuclear aromatic hydrocarbons). Major toxicological effects of these products will primarily be caused by the PAH fraction in the respective substances. Especially for toxicological endpoints that fall into the toxicological action profile of PAH, it is justified to use related tars and pitches as supporting substances.

Justification for selection of carcinogenicity via oral route endpoint:
Feeding study conducted with coal tar, representative for constituents of coal-tar pitch. Result refers to coal tar.

Justification for selection of carcinogenicity via inhalation route endpoint:
Result refers to aerosol of coal-tar pitch (MMAD = 0.5 µm).

Justification for selection of carcinogenicity via dermal route endpoint:
Dermal carcinogenicity study in mice conducted with two coal-tar oils (creosote containing different concentrations of BaP) for 78 weeks: worst case, representative of constituents in AOH.

Carcinogenicity: via oral route (target organ): digestive: liver; respiratory: lung

Carcinogenicity: via inhalation route (target organ): respiratory: lung

Carcinogenicity: via dermal route (target organ): other: skin