Pitch, coal tar, high-temp., < 1% 4- to 5-membered condensed ring aromatic hydrocarbons

Carcinogenicity

Description of key information

After oral ingestion (feed, mouse) of coal tar, the target organs of tumorigenicity in particular included lung and liver.

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.

Following inhalation, the lung and the respiratory tract are the target organs (not shown, as toxicity data relevant to humans has been derived from a meta-analysis of epidemiological studies in workers: see Toxicological information: discussion).

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:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

yes

Remarks:

only female animals used

Principles of method if other than guideline:

Part of a comprehensive test programme using coal tar mixtures and neat benzo[a]pyrene as test materials.The tumour profiles and DNA-adduct distribution were compared after tar and BaP administration.
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

Specific details on test material used for the study:

- Name of test material (as cited in study report): coal tar, coal tar mixture, CTM 1, CTM 2
- Physical state: viscous liquid at room temperature
- Samples: CTM 1 = composite sample of tars from seven sites: should be identical to MGP-M7 in Goldstein et al. 1998, Tab. 1
(Note: Though, there are distinct divergencies in either composition)
CTM 2 = composite of tars of two of the seven sites plus a third site having very high BaP content

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 using HPLC with fluorescence detection.

Duration of treatment / exposure:

2 years

Frequency of treatment:

continuous

Remarks:

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

Remarks:

CTM 1:
Doses / Concentrations (actual ingested): 12, 36, 120, 360, 720, and 1200 mg/(kg bw*d);
Basis: estimated from food consumption and bw development

Remarks:

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

Remarks:

CTM 2:
Doses / Concentrations (actual ingested): 36, 120, and 360 mg/(kg bw*d);
Basis: 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) (nominal);
estimated from food consumption and bw development: 0.6, 3, and 12 mg BaP/kg bw/day (actually ingested)

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.

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:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Neuropathological findings:

not examined

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/day and higher) and in mice exposed to BaP of >=25 mg/kg diet (3 mg/kg bw/day and higher.
None of the animals fed 1.0 % or 0.6 % CTM 1 survived the treatment period. The same applies to mice treated with 100 mg BaP/kg diet.

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

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

ORGAN WEIGHTS
Liver weights of mice fed 360 mg/kg bw/day CTM 1 or CTM 2 (0.3 % in diet) were significantly increased, approximately 40% vs control group. Corresponding BaP doses were 6.6 and 11.1 mg/kg bw/day. Treatment with 3 mg BaP/kg bw/day (25 mg BaP/kg diet) 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 and early death)

HISTOPATHOLOGY: NEOPLASTIC (see Attached background material, from Culp et al 1998, Tab. III)
CTM 1: at 0.01 up to 0.1 % [12 - 120 mg/kg bw/day], no significant increases in any tumor rate
>=0.3 % [360 mg/kg bw/day], 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 %,
>=0.6 % [720 mg/kg bw/day], increase in adenosarcomas in small intestine
CTM 2: at 0.03 % [36 mg/kg bw/day], no significant increase in any tumor rate
>=0.1 % [120 mg/kg bw/day], significant increase in lung tumor rate, but not in other tissues
>=0.3 % [360 mg/kg bw/day], significant and rapid increases in tumor rates (liver, forestomach, hemangiosarcomas
histiocytic sarcomas and sarcomas in various tissues), no 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 BaP/kg diet [0.6 mg/kg bw/day], no significant increase in any tumour rate
>= 25 mg BaP/kg diet [3 mg/kg bw/day], significant increase in the tumour rate of the forestomach (papillomas and/or carcinomas)
at 100 mg BaP/kg diet [12 mg/kg bw/day], additionally significant increase in the tumour rates of the tongue and esophagus, insignificant of the larynx; no increases in liver, lung, and other tissues.

Key result

Dose descriptor:

T25

Remarks on result:

other: not determined by the authors

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 120 mg/kg bw/day (actual dose received)

Based on:

test mat.

Remarks:

CTM 1

Sex:

female

Basis for effect level:

other: histopathology: liver and lung tumours

Remarks on result:

other: nominal dose is 0.1 % CTM 1 in diet; corresponds to 2.2 mg BaP/kg diet

Key result

Dose descriptor:

NOAEL

Effect level:

5 other: mg BaP/kg diet

Based on:

test mat.

Remarks:

benzo[a]pyrene, direct application

Sex:

female

Basis for effect level:

other: histopathology: forestomach papillomas/carcinomas

Remarks on result:

other: effect level corresponds to 0.6 mg BaP/kg bw/day

Key result

Dose descriptor:

LOAEC

Effect level:

ca. 120 mg/kg bw/day (actual dose received)

Based on:

test mat.

Remarks:

CTP 2

Sex:

female

Basis for effect level:

other: histopathology: lung tumours

Remarks on result:

other: nominal dose is 0.1 % CTP 2 in diet, corresponds to 3.7 mg BaP/kg diet

Key result

Dose descriptor:

LOAEL

Effect level:

25 other: mg BaP/kg diet

Based on:

test mat.

Remarks:

benzo[a]pyrene, direct application

Sex:

female

Basis for effect level:

other: histopathology: forestomach papillomas/carcinomas

Remarks on result:

other: effect level corresponds to 3 mg BaP/kg bw/day

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 male B6C3F1 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.

Reference 2

Endpoint:

carcinogenicity: oral

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Main components of the source test material, coal tar/manufactured gas plant residue, are besides other substances polycyclic aromatic hydrocarbons.
The target substance Pitch, coal tar, high-temp., < 1% 4- to 5-membered condensed ring aromatic hydrocarbons [EC no. 701-305-8] (CTPhtht)] also contains PAH. However, in the source compound, coal tar material, the spectrum of PAH is more comprehensive, and concentrations in general but in particular of the 2- to 4-membered PAHs are much higher than in coal-tar pitch and derivatives.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source material coal tar/manufactured gas plant residue is a (by-)product (condensation product) in the process of oxygen free, high-temperature (destructive) distillation of coal. The material is a UVCB substance forming a viscous liquid. It consists of a complex mixture with PAHs being a major part of it. Components are beside others two- up to six-ring polyaromatic hydrocarbons. Percentage of individual PAH is between ca. 4 % (two-ring PAH) and 0.1 % (six-ring PAH). In general, water solubility of the coal tar material is low. It is determined by the solubility properties of its constituents.
The target material Pitch, coal tar, high-temp., < 1% 4- to 5-membered condensed ring aromatic hydrocarbons [EC no. 701-305-8] (CTPhtht) is a UVCB substance as well. It is the product (residue) of the oxygen-free high-temperature re-distillation of coal tar pitch and consists of a complex mixture of polycyclic aromatic hydrocarbons, predominantly of highly condensed aromatic ring systems forming an inert matrix. In this matrix, individual PAH with a lower degree of condensation are greatly immobilised. This fraction comprises polycyclic aromatic hydrocarbons with predominantly 4- and 5- (up to 6-) ring aromatic hydrocarbons. The sum of identifiable PAHs is less than 1 % in the GC, consisting mainly of 4 - 6 ring structures. Based on results from Coal-tar pitch, high temp. [CAS no. 65996-93-2] , the water solubility of CTPhtht is << 0.24 mg dissolved C/L at a loading of 1000 mg substance/L. Obviously, individual PAH are dissolved only at concentrations below their maximum water solubility.

3. ANALOGUE APPROACH JUSTIFICATION
The source test material, coal tar/manufactured gas plant residue, was orally applied in food. Constituents of the tar material are assumed to be largely bioavailable and thus can be resorbed from the gastrointestinal tract. Principally, this may also hold for the target substance CTPhtht, but to a much lower extent. Hence, the source test material is considered a worst-case because systemic bioavailability of coal tar through the gut is expected to be much higher than of the largely inert target material, CTPhtht.

Reason / purpose for cross-reference:

read-across source

Principles of method if other than guideline:

Read-across to preceding entry:
Source test material: coal tar, mixture from manufactured gas plant waste sites (CTM);
Reference: Culp SJ et al. 1998; Goldstein LS et al. 1998

Key result

Dose descriptor:

T25

Remarks on result:

other: not determined by the authors

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Remarks:

CTM 1

Sex:

female

Basis for effect level:

other: histopathology: liver and lung tumours

Remarks on result:

other: nominal dose is 0.1 % CTM 1 in diet; corresponds to 2.2 mg BaP/kg diet

Remarks:

test result of the source substance is adopted for the target substance CTPht

Key result

Dose descriptor:

NOAEL

Effect level:

5 other: mg BaP/kg diet

Based on:

test mat.

Remarks:

benzo[a]pyrene, direct application

Sex:

female

Basis for effect level:

other: histopathology: forestomach papillomas/carcinomas

Remarks on result:

other: effect level corresponds to 0.6 mg BaP/kg bw/day

Remarks:

the test result of the source substance is adopted for the target substance CTPht

Key result

Dose descriptor:

LOAEL

Effect level:

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

Based on:

test mat.

Remarks:

CTP 2

Sex:

female

Basis for effect level:

other: histopathology: lung tumors

Remarks on result:

other: nominal dose is 0.1 % CTP 2 in diet, corresponds to 3.7 mg BaP/kg diet

Remarks:

the test result of the source substance is adopted for the target substance CTPht

Key result

Dose descriptor:

LOAEL

Effect level:

25 other: mg BaP/kg diet

Based on:

test mat.

Remarks:

benzo[a]pyrene, direct application

Sex:

female

Basis for effect level:

other: histopathology: forestomach papillomas/carcinomas

Remarks on result:

other: effect level corresponds to 3 mg BaP/kg bw/day

Remarks:

the test result of the source substance is adopted for the target substance CTPht

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

12 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

high; yet, of limited relevance for the evaluation of the inherent properties of the target compound, CTPhtht, since the analogue approach is worst-case .

Organ:

liver

lungs

Carcinogenicity: via dermal route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

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

Specific details on test material used for the study:

- Name of test material: coal tar creosote, WEI-Type B, standard with 10 ppm BaP, named CTP 1 in the report
- Note: in this study, a second oil was examined for comparison, assigned as CTP 2 containing 270 ppm BaP.

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:

CTM 1:
Doses / Concentrations: 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;
Basis: nominal conc.

Remarks:

CTP 2:
Doses / Concentrations: 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 Benzo[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

Dermal irritation (if dermal study):

effects observed, treatment-related

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

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Neuropathological findings:

not examined

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 CTP-1 groups (Report, p. 24).
In the solvent controls, apart from the occurrence of one haemangioma (1/124), no skin tumours were observed.
In the BaP 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:

not determined

Remarks on result:

other: no T25 was identified by the authors

Key result

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: histopathology: skin tumours

Remarks on result:

other: Dose-response relationship for BaP content, oil (CTP) 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.)

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-BaP				CTP 2 [mg] high BaP					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 µg/kg bw/day

Study duration:

chronic

Species:

mouse

Quality of whole database:

of scientific interest and for information, analogue approach disregarded for assessment of the carcinogenic potential of the target substance CTPhtht.

Organ:

skin

Mode of Action Analysis / Human Relevance Framework

Pitch, coal tar, high-temp., < 1% 4- to 5-membered condensed ring aromatic hydrocarbons [EC no. 701-305-8] (CTPhtht) is obtained as residue from the distillation of the precursor material pitch, coal tar, high-temp [CAS no. 65996-93-2]. Due to repeated processing at high temperatures, the substance matrix becomes increasingly condensed and inert. Volatile substances will be depleted, and the biological availability of individual toxic components will be reduced. Therefore, test substances of the carcinogenicity studies represent worst-case situations compared to CTPhtht, since the PAH concentration in those test substances is higher than the concentrations of PAH analysed in CTPhtht, and the bioavailability from CTPhtht is very low.

Hence, in principle, the analogue approaches applied do not properly reflect the real beneficial toxicological profile of CTPhtht, therefore, are of limited practical relevance for humans.

Justification for classification or non-classification

Pitch, coal tar, high-temp., < 1% 4- to 5-membered condensed ring aromatic hydrocarbons [EC no. 701-305-8] (CTPhtht) has been classified by the registrant as carcinogenic Cat. 1B. Reason is a benzo[a]pyrene concentration in CTPhtht of up to 0.1 %. According to Regulation (EC) No. 1272/2008, benzo[a]pyrene is classified as carcinogenic Cat. 1B and concentration in CTPhtht is above or equal to the generic concentration limit of ≥ 0.1 % that triggers classification of a mixture with this ingredient as carcinogenic itself.