Tar, coal, high-temp.

Carcinogenicity

Description of key information

In a 2-years feeding study in female B6C3F1 mice, coal tar induced tumors in lung, small intestine, and liver, as well as sarcomas, hemagiosarcomas,and histiocytic sarcomas in several sites. No tumorigenic effect was observed at a dietary level of  0.03% [approx. 36 mg/kg bw*d)], while 0.1% [approx. 120 mg/(kg bw *d)] produced significant tumours.

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:

no guideline available

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 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 with only "Overall Summary Table" attached.

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 dietCTM 1

Remarks:

Doses / Concentrations:12, 36, 120, 360, 720, and 1200 mg/(kg bw*d)Basis:actual ingestedCTM1: 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 dietCTM 2

Remarks:

Doses / Concentrations:36, 120, and 360 mg/(kg bw*d)Basis:actual ingestedCTM 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:

NOAEL

Remarks:

(= 0.03 % in diet)

Effect level:

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

Based on:

test mat.

Sex:

female

Basis for effect level:

histopathology: neoplastic

Dose descriptor:

LOAEC

Remarks:

(= 0.1 % in diet)

Effect level:

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

Based on:

test mat.

Sex:

female

Basis for effect level:

histopathology: neoplastic

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

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

System:

respiratory system: lower respiratory tract

Organ:

lungs

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

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.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

120 mg/kg bw/day

Study duration:

chronic

Species:

mouse

System:

respiratory system: lower respiratory tract

Organ:

other: lung > jejunum and liver

Additional information

Carcinogenicity: via oral route (target organ): respiratory: lung; digestive: jejunum; digestive: liver (depending on dose, most sensitive was lung).