Tar, coal, high-temp.

Endpoint summary

Description of key information

 In a 6-months feeding study, mice received a by-product from coal gasification, a coal-tar material. Body weight was retarded at a dietary level of 0.25 % [>= 200 mg/(kg bw*d)], mainly due to reduced food intake. No gross or histopathological lesions were observed up to the highest concentration in the feed of 0.5 % [>= 350 mg/kg bw*d)]. Observed histopathological effects were sporadic and not considered treatment-related.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral, other

Remarks:

subchronic+chronic

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

no full examination protocol: hematology, urinalysis are lacking

GLP compliance:

not specified

Limit test:

no

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Wilmington/Mass
- Age at study initiation: 49 - 56 d
- Weight at study initiation: 23 - 24 g (m); 17 - 18 g (f) (estimated from Report, Fig. 1
- Fasting period before study: none- Housing:
- Diet: ad libitum- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- controlled conditions: no details
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

oral: feed

Vehicle:

other: water and gelling agent

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): 1x- Preparation of the diet (basal gel diet): 3020 mL of boiling water was blended with 100 g of a gelling agent (not specified) for 1 min, then 1948 g dry food added and blending continued for additional 2-3 min.
- Mixing appropriate amounts: Aliquots of MPG was added, followed by homogenisation (2-3 min). The food blends were cooled down in bar molds.
- Storage temperature of food: packaged into plastic bags and stored at -20 °C.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

94 d and 185 d

Frequency of treatment:

continuous

Remarks:

Doses / Concentrations:0.05, 0.25, and 0.50 %; basis:nominal in diet

Remarks:

Doses / Concentrations:0, 51, 251, or 462 mg/(kg bw*d) (males) / 0, 42, 196, or 344 mg/(kg bw*d) (females); basis: actual ingested

No. of animals per sex per dose:

12 (94 d)12 (185 d)

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: previous range finding and acceptance (palatability) testing

Positive control:

Benzo(a)pyrene (BaP): 0.005 % in diet

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes, no details
DETAILED CLINICAL OBSERVATIONS: Yes, no details
BODY WEIGHT: Yes
- Time schedule for examinations: throughout (see Report, Fig. 1)
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/mouse/day: Yes, per mouse
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No (bone marrow was examined, 94 d and 185 d)
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 94 d or 185 d- How many animals: 12 per group
- Parameters: glucose, creatine, BUN, protein, Asp-aminotransferase, ala-aminotransferase, alk. phosphatase
URINALYSIS: No data on standard parameters / Chemical analysis of PAH metabolites in male mice over time (1-OH-pyrene + 3-OH-BaP)

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, all organs after 94 d and 185 d
HISTOPATHOLOGY: Yes, in in 10 animals per sex of the 0.5% group, BaP and control group (after 94 d and 185 d)

Other examinations:

DNA adducts in various tissues, lung and forestomach

Clinical signs:

no effects observed

Mortality:

no mortality observed

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:

no effects observed

Urinalysis findings:

not specified

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Other effects:

effects observed, treatment-related

Description (incidence and severity):

1. Covalent binding to DNA - DNA-adducts: dose-related increase in lung
2. Urinary excretion of 1-OH-pyrene: dose-related increase in urine

Details on results:

CLINICAL SIGNS AND MORTALITY
no mortality

BODY WEIGHT AND WEIGHT GAIN (estimated from Report, Fig. 1)
Dose-related decrease, exception 0.05% (females).
0.25% (males): significant decrease in body weight of 10 - 12 % at 94 d and 185 d, respectively, as compared to the control /
0.50 % (males): significant decrease in body weight of ~22 and ~15 % at 94 d and 185 d, respectively, as compared to the control /
0.05% (female): significant increase in body weight of ~16 % at 94 d and 185 d, respectively, as compared to the control /
0.50 % (female): significant decrease in body weight of ~20 % at 94 d and 185 d, respectively, as compared to the control.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study) [Report, Tab. 1]
Dose-related decrease as compared to the untreated control / increase for the 0.05 % female group. Changes in body-weight development may be partly explained by the differences in food consumption.

HISTOPATHOLOGY: NON-NEOPLASTIC
After 94 d, lesions observed included minimally to moderate vacuolisation of hepatocytes, increased hematopoietic cell proliferationin spleens, modest hyperplasia of granulocytic cells in the bone marrow of the femur, and cytoplasmic alteration of the olfactory epithelial cells.
After 185 d, microscopic lesions observed included irregular cytoplasmic vacuoles in hepatocytes, infiltration of lymphoid cells in various tissues, and changes in the olfactory epithelial cells of the nose.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
After 185 d, a squamous cell carcinoma was present in the forestomach of one male (0.5 %), one squamous papilloma was found in the forestomach of a female. The effects were sporadic and not considered treatment-related.

Dose descriptor:

NOAEL

Remarks:

highest concentration tested

Effect level:

0.5 other: % in diet

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Clinical signs; mortality; clinical chemistry; gross pathology; histopathology

Dose descriptor:

NOAEL

Remarks:

highest dose tested

Effect level:

ca. 350 - ca. 460 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: Clinical signs; mortality; clinical chemistry; gross pathology; histopathology

Dose descriptor:

NOAEL

Effect level:

0.25 other: % in diet

Sex:

male/female

Basis for effect level:

other: body weight

Dose descriptor:

NOAEL

Effect level:

ca. 200 - ca. 250 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: Body weight

Key result

Critical effects observed:

not specified

System:

respiratory system: lower respiratory tract

Organ:

other: comparatively high increase in DNA-adducts in lung

Endpoint conclusion

Dose descriptor:

NOAEL

350 mg/kg bw/day