Registration Dossier

Diss Factsheets

Administrative data

Description of key information

No experimental repeated-dose data is available on petro pitch itself. A structure-related coal-tar material produced no particular, treatment-related toxicity in male and female mice receiving the test material in the feed for up to 6 months. The NOAEL, 0.5 % in the diet, is estimated to correspond to approximately 400 mg/kg bw/d. Early not verifiable reports indicate that young pigs may have a significant lower tolerance to ingested (coal-tar) pitch than the adult animals.    

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
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: Comparable to guideline study, acceptable for assessment
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 additionakl 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 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
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 proliferation
in 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 lympjoid 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.

Teh effects were sporadic and not considered treatment-related.
Dose descriptor:
NOAEL
Remarks:
(highest tested dose)
Effect level:
0.5 other: % in diet
Sex:
male/female
Basis for effect level:
other: Clinical signs; mortality; clinical chemistry; gross pathology; histopathology
Dose descriptor:
NOAEL
Remarks:
(highest tested dose)
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
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
400 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

Apart from one oral study of limited significance in pigs, no repeated-dose toxicity studies with petro pitch addressing effects other than carcinogenicity have been located. The subchronic feeding study in mice with coal-tar material (compared to petro pitch a worst case) indicates that more marked toxicity following long-term exposure to pitch is unlikely to occur.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
No adverse effects observed that were assessed treatment related at the highest dose tested (400 mg/kg bw/day)

Justification for classification or non-classification

Petro pitch is not classifiable, as there was no evidence for specific target-organ effects at doses lower than 100 mg/kg bw/d (test material: coal tar).