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Description of key information

A 28-day repeated dose study by oral route in rats has been carried out in order to evaluate the toxicity of DPX-C after repeated exposure.

Based on the findings of this study, it is concluded that the DPX-C (Di-Cloro-Di-p-Xililene) did not produce any toxicity or adverse effect at dose level 50 mg/kg b. wt./day when administered orally through gavage for 28 consecutive days, but it produces toxic effects at higher doses. Therefore, the No Observed Adverse Effect Level (NOAEL) of DPX-C (Di-Cloro-Di-p-Xililene) is 50 mg/kg b. wt./day. At higher doses effects on body weight and organ weights (kidney, liver, heart, brain, prostate, seminal vesicles, thyroid and parathyroid) were observed. Moreover, biochemical effects and effects on the produced urine were observed. There were histopathological lesions in kidneys and enlargement of liver associated with hypertrophy of hepatocyte (centriolobular and/or diffuse). In addition, follicular hypertrophy (thyroid) and hyaline droplets accumulation in cortical tubules in kidneys was observed. All dose groups showed minimal to mild severity of basophilic/ regenerating tubules in the cortex.

However, some of the effects observed at the end of treatment were continued with reduced severity after recovery period. Other effects were almost completely recovered after ceasing the treatment.

No studies by dermal and inhalation routes of exposure were performed, because exposure of humans via dermal / inhalation routes in production and or use is not likely as based on the provided thorough and rigorous exposure assessment . Therefore information by oral route was considered enough to sufficiently characterize the hazard of the substance.

According to a read-across approach (see justification of the read-across approach between endpoints of DPX-C and Dibenzetano), data obtained for DPX-C applies also to Dibenzetano.

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:
sub-acute oral repeated dose toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
See read-across justification report, attached to "Toxicological information" section.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No sign of toxicity was observed in animals treated from low group, while, salivation was observed in mid dose from day 21 to 28 [male (2/5) and female (3/5)] and high dose from day 18 to 28 [male (5/5) and female (5/5)]. Salivation could be considered due to test item treatment.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Statistically, significant decrease in terminal body weight was observed in male rats of mid and high dose groups when compared with vehicle control group. Similarly, inspite of statistical significant decrease in terminal body weight was biologically significant in female rats of high dose group when compared with vehicle control group.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Mean feed consumption male and female rats of treated groups was comparable with vehicle control group.
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Statistically, significant increase in RBC and monocyte were observed male rats of high dose group when compared with vehicle control group. Variation in RBC and monocyte could be considered as treatment related effect.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Statistically, significant increase in cholesterol, triglyceride, ALT and calcium were observed in either sex of high dose group when compared with vehicle control group except in female rats increase in triglyceride was statistically non significant (353% of control). Statistically, significant increase in creatinine level was observed in male rats of high dose group when compared with vehicle control group while in female, inspite of statistical significant, creatinine was biologically increase i.e. 10% of vehicle control. Statistically, significant increase in ALP was observed in female rats of high dose group when compared with vehicle control group. Statistically, significant decrease in chloride and albumin: globulin ratio was observed in female rats of high dose group when compared with vehicle control group. These variations were co-related with findings of dose range finding study, hence, they could be considered as treatment related effects.

During recovery period, the alterations observed in ALT, triglyceride, creatinine, ALP, chloride and albumin: globulin ratio were recovered. Also the effects of increase in cholesterol and calcium were diminished in males while continued in females.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Significant increase was observed in volume of urine in high dose (G4) males and females though statistical significance was registerd for males only. High dose females revealed statistically significant decrease in specific gravity and increase in pH. These effects could be related to test item treatment.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Statistically, significant increase relative weight of liver were observed in mid and high dose group of both sexes and low dose of females when compared with vehicle control group. Statistically, significant increase relative weight of thyroid and parathyroid in high dose group of both sexes when compared with vehicle control group. This effect was also observed in mid dose and low dose groups (without statistical support) in dose dependent manner.
In absolute weights of kidneys significant increase was registered in high dose males. It was supported by treatment related histopathological lesions in kidneys of only male animals. Increase in absolute weights was also noticed in mid dose males though it was devoid of statistical significance.
There was significant decrease in absolute weight of heart in high dose females. It was also observed in high dose males though it lacked statistical significance. Significant decrease in absolute weight was also observed in brain of G4 males. Decrease in absolute weight (without statistical support) was also observed in weight of prostate plus seminal vesicles in high dose. These effects were considered as related to test item treatment.
Some of the effects observed at the end of treatment (increase in relative weight of thyroid in females and kidneys in males; and decrease in weight of prostate and terminal body weight in males) were continued with reduced severity after recovery period. Other effects were almost completely recovered after ceasing the treatment.
Gross pathological findings:
no effects observed
Description (incidence and severity):
External examination of terminally and recovery sacrificed animals of either sex across various groups (G1 to G6) did not reveal any abnormality.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Internal examination of animals revealed enlargement of liver in all animal of high dose group of both sexes while in 2 animals (Animal No 21 and 26) from mid dose group
Test item treatment was associated with hypertrophy of hepatocyte (centriolobular and/or diffuse) in mid dose and high dose group. Severity and incidence was more in mid dose males than mid dose females. The lesion was also observed in low dose males.
Test item treatment was also associated with follicular hypertrophy (thyroid) in all 3 treated groups. Treatments also lead to hyaline droplets accumulation in cortical tubules in kidneys of male rats of all 3 treated groups. This effect was not observed in female animals. In treated males, all dose groups showed minimal to mild severity of basophilic/ regenerating tubules in the cortex.
In treated females, hepatocellular hypertrophy was recovered completely while in males thought it was continued, reduction in incidence and severity was observed after recovery period. Though follicular hypertrophy was observed in one treated female, marked recovery was observed at the end of recovery period.
For the lesion of hyaline droplets in kidneys, complete recovery was observed while basophilic/regenerative tubules were continued in treated male animal.
Histopathological findings: neoplastic:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Basis for effect level:
body weight and weight gain
clinical biochemistry
gross pathology
haematology
histopathology: non-neoplastic
organ weights and organ / body weight ratios
urinalysis
Key result
Critical effects observed:
no
Lowest effective dose / conc.:
50 mg/kg bw/day (nominal)
Critical effects observed:
yes
Lowest effective dose / conc.:
150 mg/kg bw/day (nominal)
System:
gastrointestinal tract
Organ:
oral cavity
Treatment related:
yes
Critical effects observed:
yes
Lowest effective dose / conc.:
150 mg/kg bw/day (nominal)
System:
musculoskeletal system
Organ:
other: body weight
Treatment related:
yes
Critical effects observed:
yes
Lowest effective dose / conc.:
450 mg/kg bw/day (nominal)
System:
cardiovascular
Organ:
blood
heart
Treatment related:
yes
Critical effects observed:
yes
Lowest effective dose / conc.:
450 mg/kg bw/day (nominal)
System:
urinary
Organ:
other: urine
Treatment related:
yes
Critical effects observed:
yes
Lowest effective dose / conc.:
150 mg/kg bw/day (nominal)
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Critical effects observed:
yes
Lowest effective dose / conc.:
150 mg/kg bw/day (nominal)
System:
endocrine system
Organ:
parathyroid gland
thyroid gland
Treatment related:
yes
Critical effects observed:
yes
Lowest effective dose / conc.:
450 mg/kg bw/day (nominal)
System:
urinary
Organ:
kidney
Treatment related:
yes
Critical effects observed:
yes
Lowest effective dose / conc.:
450 mg/kg bw/day (nominal)
System:
nervous system
Organ:
brain
Treatment related:
yes
Critical effects observed:
yes
Lowest effective dose / conc.:
450 mg/kg bw/day (nominal)
System:
male reproductive system
Organ:
seminal vesicle
other: prostate
Treatment related:
yes
Conclusions:
Dibenzetano is classified as STOT RE 2, H373 according to Regulation (EC) n. 1272/2008 (CLP), from the result of the source study.
Executive summary:

Dibenzetano is classified STOT RE 2, H373 according to Regulation (EC) n. 1272/2008 (CLP), based on the results of the source study (see read-across justification document).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The quality of the whole database is considered appropriate in order to properly assess the hazard of Dibenzetano.
System:
other: Effects on body weight and organ weights. Biochemical effects. Effects on urine. Effects in kidneys, liver and thyroid.
Organ:
blood
brain
heart
kidney
liver
parathyroid gland
seminal vesicle
thyroid gland
other: prostate

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
exposure considerations
Justification for data waiving:
a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
exposure considerations
Justification for data waiving:
a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
exposure considerations
Justification for data waiving:
a short-term toxicity study does not need to be conducted because exposure of humans via the dermal route in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
exposure considerations
Justification for data waiving:
a short-term toxicity study does not need to be conducted because exposure of humans via the dermal route in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

According to the results of the 28-day repeated dose toxicity study by oral route in rats (in read-across with DPX-C), Dibenzetano (target substance) is classified STOT RE 2, H373 according to Regulation (EC) n. 1272/2008 (CLP).

(See also read-across justification document)

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