Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

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 application of tar oils (creosote, a distillation product of coal tars) for 78 weeks resulted in the development of skin tumours in a dose related manner. Tumour frequency clearly increased in the dose range of 90 to 800 ng BaP per treatment.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
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 to 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.
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:
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 were 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:
histopathology: neoplastic
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:
ca. 36 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks:
CTM 2
Sex:
female
Basis for effect level:
histopathology: neoplastic
Remarks on result:
other: nominal dose is 0.03 % CTM 2 in diet; corresponds to 1.1 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:
LOAEL
Effect level:
ca. 360 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks:
CTM 1
Sex:
female
Basis for effect level:
histopathology: neoplastic
Remarks on result:
other: nominal dose is 0.3 % CTM 1 in diet; corresponds to 6.6 mg BaP/kg diet (analytical)
Key result
Dose descriptor:
LOAEL
Effect level:
ca. 120 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks:
CTM 2
Sex:
female
Basis for effect level:
histopathology: neoplastic
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.

Conclusions:
Female B6C3F1 mice were fed three different diets for two years. Two diets contained graduate doses of two different coal tar mixtures (CTM 1 and CTM 2), while the third diet comprised graduate doses of benzo[a]pyrene (BaP). All three materials induced the development of tumours, but the tumour spectrum resulting from the coal tar mixtures (liver and lung tumours) was different from the spectrum of tumours caused by BaP (forestomach papillomas/carcinomas). Effect levels based on the BaP concentration in diet were lower for the two tar mixtures (NOAEL ≤ 2.2 mg BaP/kg diet) compared to the effect level resulting from BaP treatment (NOAEL 5 mg BaP/kg diet). Overall, all three materials proved to be potent carcinogens after oral ingestion in the animals tested.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
12 mg/kg bw/day
Study duration:
chronic
Species:
rat
Organ:
liver
lungs

Carcinogenicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: inhalation
Type of information:
experimental study
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
Specific details on test material used for the study:
FORM AS APPLIED IN THE TEST
- aerosol was generated by heating the source material coal tar pitch to a temperature of 750 °C under nitrogen atmosphere and deluting the resulting high temperature tar/pitch vapour with 12 °C clean air.
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
Mass median aerodynamic diameter (MMAD):
0.5 µm
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
Dose / conc.:
0 mg/m³ air
Remarks:
control
Dose / conc.:
1.1 mg/m³ air (analytical)
Remarks:
corresponds to ca. 20 µg BaP/m³
Dose / conc.:
2.6 mg/m³ air (analytical)
Remarks:
corresponds to ca. 46 µg BaP/m³
No. of animals per sex per dose:
72
Control animals:
yes, concurrent no treatment
Mortality:
mortality observed, treatment-related
Description (incidence):
increased mortality rate when compared to controls in the high exposure group (2.6 mg aerosol/m³ ) for both exposure durations, 43 and 86 weeks.
Especially the animals exposed for 86 weeks had to be sacrificed because of the development of large, multiple lung tumours.
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Tumour rates: 4.2 % and 33.3 %, exposure with low dose (1.1 mg/m³) for 43 and 86 weeks (cumulative doses 71 and 142 mg BaP/m³ x h, respectively)
Tumour rates: 38.9 % and 97.2 %, exposure with high dose (2.6 mg/m³) for 43 and 86 weeks (cumulative doses 158 and 321 mg BaP/m³ x h, respectively)
Most of the lung tumours were benign and malignant keratinising squamous-cell tumours, while some broncho-alveolar adenomas and adenocarinomas were found.
No exposure-related tumours were observed in organs other than the lung.
Details on results:
Cumulative doses were calculated based on BaP exposure concentration multiplied by total exposure time.
The cumulative BaP doses of the 4 exposure groups (two different doses with two different exposure durations) were 71, 142, 158, and 321 mg BaP/m³ × h.
The corresponding lung tumour rates were 4.2, 33.3, 38.9 and 97.2%.
Using the US Environmental Protection Agency (EPA) linearized multistage model, the lifetime lung tumour risk for rats exposed to 1 mg/m³ BaP as a constituent of a complex PAH mixture was estimated to be 2 % or correspondingly 2 per 100,000 with a BaP concentration of 1 mg/m³.
Key result
Dose descriptor:
LOAEC
Remarks:
lowest dose tested
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:
other: tumour incidence 33 %, exposure period 86 weeks
Dose descriptor:
T25
Remarks:
not identified by authors
Sex:
female
Basis for effect level:
other: histopathology: lung tumours
Remarks on result:
not measured/tested
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
1.1 other: mg CTP aerosol/m³ air (lowest dose tested)
System:
respiratory system: lower respiratory tract
Organ:
lungs
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
1.1 mg/m³
Study duration:
chronic
Species:
rat
Organ:
lungs

Carcinogenicity: via dermal route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
the 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
Dose / conc.:
0.3 other: mg oil (CTP1) in 25 µL toluene per treatment (nominal conc.)
Remarks:
equivalent to 0.003 µg benzo[a]pyrene
Dose / conc.:
1 other: mg oil (CTP1) in 25 µL toluene per treatment (nominal conc.)
Remarks:
equivalent to 0.01 µg benzo[a]pyrene
Dose / conc.:
3 other: mg oil (CTP1) in 25 µL toluene per treatment (nominal conc.)
Remarks:
equivalent to 0.03 µg benzo[a]pyrene
Dose / conc.:
9 other: mg oil (CTP1) in 25 µL toluene per treatment (nominal conc.)
Remarks:
equivalent to 0.09 µg benzo[a]pyrene
Dose / conc.:
0.1 other: mg oil (CTP 2) in 25 µL toluene per treatment (nominal conc.)
Remarks:
equivalent to 0.027 µg benzo[a]pyrene
Dose / conc.:
0.3 other: mg oil (CTP 2) in 25 µL toluene per treatment (nominal conc.)
Remarks:
equivalent to 0.08 µg benzo[a]pyrene
Dose / conc.:
1 other: mg oil (CTP 2) in 25 µL toluene per treatment (nominal conc.)
Remarks:
equivalent to 0.27 µg benzo[a]pyrene
Dose / conc.:
3 other: mg oil (CTP 2) in 25 µL toluene per treatment (nominal conc.)
Remarks:
equivalent to 0.81 µg benzo[a]pyrene
Dose / conc.:
9 other: mg oil (CTP 2) in 25 µL toluene per treatment (nominal conc.)
Remarks:
equivalent to 2.43 µg benzo[a]pyrene
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 (unscheduled 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 of 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.
Key result
Dose descriptor:
NOAEL
Effect level:
30 other: ng BaP per treatment (twice a week)
Based on:
act. ingr.
Remarks:
benzo[a]pyrene (BaP)
Sex:
male
Basis for effect level:
other: histopathology: skin tumours
Remarks on result:
other: no significantly increased tumour incidence at this dose level
Key result
Dose descriptor:
T25
Remarks:
estimated from dose-response relationship
Effect level:
ca. 53 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: T25, obtained from dose-response relationship by linear regression (528 ng BaP per treatment), was recalculated to a skin area (4 cm²) specific value applied for 5 d/w (528 ng BaP x 2 (weekly treatments) / 4 cm² / 5 days = 53 ng BaP/cm²).
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
80 other: ng BaP per treatment
System:
respiratory system: lower respiratory tract
Organ:
lungs
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified

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

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
Study duration:
chronic
Species:
mouse
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) tumours 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.
Organ:
skin

Justification for classification or non-classification

Pitch, coal tar, high temp. is classified as carcinogenic Cat. 1B according to Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures. With Regulation (EU) No 944/2013, harmonised classification is amended to carcinogenic Cat. 1A. This is based on a comprehensive meta-analysis of epidemiological studies on workers in respective industrial settings (see EU Risk Assessment Report for Coal tar pitch, high temperature: EU RAR 323, 2008, Sect. 4.1.2.8.2 and Sect. 4.1.3.2.6). Relevant information is also summarised in the discussion part of the endpoint summary of IUCLID Sect. 7 - Toxicological information (derivation of DN(M)EL) or of CSR Sect. 5.11. - Derivation of DNEL(s) and other hazard conclusions.

Additional information

Carcinogenicity data are derived from experiments with coal tar and pitch (fumes).

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 to characterise potential effects of pitch, coal tar, high temp.


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 oncogenicity study in mice conducted with two coal-tar oils for 78 weeks: worst case, representative of constituents in pitch material.

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