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Description of key information

ORAL 
28-day study in rats (0, 1.5, 5, 15, 50 mg/kg bw/d by gavage), equivalent to OECD TG 407. (Nihon Bioresearch, Inc.,)
The LOAEL is 5 mg/kg bw for males and 15 mg/kg bw for females.
The NOEL is 1.5 mg/kg bw for males and 5 mg/kg bw for females.
DERMAL
No data are available.
INHALATION
26- week study in rats (ca. 0.15 or 0.3 mg/l) (Hine et al., 1954).
A NOAEL could not be established, based on adverse findings observed at both dose levels.

Key value for chemical safety assessment

Additional information

ORAL

In a subacute toxicity study (Nihon Bioresearch Inc., undated) p-tert-Butyltoluene (purity 95.93%) was administered to 12 Sprague-Dawley rats/sex/dose by gavage at dose levels of 0, 1.5, 5, 15, 50 mg/kg bw/day. Satellite groups were allowed a 14-day recovery. The study was conducted in accordance with Japanese testing guidelines for 28-day oral toxicity in rodents, equivalent to OECD TG 407.

No deaths occurred. No treatment-related clinical signs of toxicity were observed. Body weights and body weight gain were similar in all groups. Lower food consumption was noted in the 15 mg/kg males and in both sexes given 50 mg/kg. Higher water intake was noted in the males at 15 mg/kg and in both sexes at 50 mg/kg.

Hematology revealed shortened APTT (males; 5, 15, 50 mg/kg bw) and lower values for fibrinogen concentration (males; 5, 15, 50 mg/kg bw; females; 50 mg/kg bw) and prolonged PT (females; 50 mg/kg bw).

Blood chemical analysis, revealed decreased total protein (males; 5, 15, 50 mg/kg bw; females;15, 50 mg/kg bw), decreased albumin (males; 15, 50 mg/kg bw; females; 15, 50 mg/kg bw), decreased total cholesterol (males; 50 mg/kg bw; females; 15, 50 mg/kg bw), decreased triglycerides (males, 5, 15, 50 mg/kg bw; females 15, 50 mg/kg bw), increased AST (males; 5, 15, 50 mg/kg bw), increased A/G ratio (males; 15, 50 mg/kg bw), increased gamma-GTP (females; 15, 50 mg/kg bw), increased total bilirubin (males; 15, 50 mg/kg bw; females; 50 mg/kg bw), increased urea nitrogen (males; 5, 15, 50 mg/kg bw), increased creatinine (males; 50 mg/kg bw), increased inorganic phosphorus (males; 5, 15, 50 males; mg/kg bw), decreased sodium (males; 50 mg/kg bw), decreased potassium (females 50 mg/kg bw), and decreased calcium (females; 15, 50 mg/kg bw).

Urinalysis revealed a higher urinary volume (males; 15, 50 mg/kg bw; females, 50 mg/kg bw), a tendency for pH lowering (males, 50 mg/kg bw; females, 50 mg/kg bw), decreased urinary specific gravity (males, 50 mg/kg bw), and decreased protein (males, 50 mg/kg bw).

On organ weight measurement, the following changes were reported: increased absolute liver weights (males; 50 mg/kg bw; females, 15, 50 mg/kg bw), increased relative liver weights (males; 15, 50 mg/kg bw; females, 15, 50 mg/kg bw), increased relative kidney weights (female; 50 mg/kg bw), increased relative adrenals weights (female; 50 mg/kg bw), decreased absolute testis and epididymis weights (males; 50 mg/kg bw), decreased relative testis weights (males, 50 mg/kg bw), and decreased absolute ovary weights (females, 50 mg/kg bw).

No gross pathological findings were reported.

Histopathology revealed the following findings: hypertrophy of periportal hepatocytes (males and females; 50 mg/kg bw), atrophy of seminiferous tubules (males; 50 mg/kg bw), hyperplasia of Leydig cells (males; 50 mg/kg bw), decrease in sperm (males; 50 mg/kg bw). At the termination of recovery period, atrophy of seminiferous tubules in the testes and decrease in sperm in the epididymides were still evident in the males which had received 50 mg/kg bw.

The LOAEL is 5 mg/kg bw for males and 15 mg/kg bw for females.

The NOAEL is 1.5 mg/kg bw for males and 5 mg/kg bw for females.

This subacute toxicity study in the rat is acceptable and satisfies the guideline requirement for a subacute oral study (OECD 407) in rats.

DERMAL

No data are available.

INHALATION

In a subchronic inhalation toxicity study (Hine et al., 1954), p-tert-butyltoluene (purity not given) was administered to 10 female Long-Evans rats/sex/concentration by whole body exposure at concentrations of 25-30 ppm or 50-60 ppm (ca. 0.15 or 0.3 mg/l, respectively) 1, 2, 4, and 7 hours per day, 5 days/week for a total of 26 weeks; Half of the rats were sacrificed after 10 weeks of exposure.

The majority of exposed animals did not display any evidence of substance-related damage or abnormal behaviour. One of three high dose rats exposed for 7 h/d died after the 42nd exposure; the remaining two rats displayed injury at the front and hind limbs. During the study, clinical symptoms were limited to slight irritation of the eyes and slightly elevated respiratory rate. A time- and dose-related increase in relative liver and kidney weights was observed. Clinical laboratory investigations revealed a depression of erythropoiesis; however, this was not considered to be substance-related. No statistically significant changes in blood parameters were noted after 26 weeks of exposure, with exception of significantly decreased leukocyte counts observed in high dose rats treated for 2, 4, or 7 h/d.

At histopathological examination, chronic encephalomeningitis was observed in both low and high dose rats exposed for 4 and 7 h. Slight fatty degeneration of the liver was noted in individual high dose rats.

A NOAEL could not be established, based on adverse findings observed at both dose levels; the LOAEL was ca. 0.15 mg/l.

A classification of this subchronic toxicity study in the rat is not possible due to rather poor documentation. It cannot be stated if this study satisfies or does not satisfy the guideline requirement (OECD 412) for a subchronic inhalation study in the rat.

Justification for classification or non-classification

The effects observed at a dose level of 5 mg/kg bw/day after oral exposure and a concentration of 0.15 mg/l after inhalative exposure would lead to a classification for repeated dose oral toxicity (R48/20/22 or STOT repeated Cat. 1) according to the Directive 67/548/EC or GHS criteria.

However, due to the effects on the central nervous system observed after single inhalative administration of the substance at a dose level of 1,5 mg/l a classification with R39/23/24/25 or STOT single Cat 1 is warranted.

Due to this an additional classification regarding repeated dose toxicity is considered to be not appropriate.