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Administrative data

Description of key information

Two studies from the same authors (Lenz et al., 1990 and 1991), conducted with accepted scientific principles, were used for the evaluation of the oral acute toxicity. Lenz et al., 1990, the selected key study, evaluated the nephrotoxicity of DPA in male Syrian hamsters, male Sprague-Dawley rats, and male Mongolian gerbils, by administering doses of 400, 600 and 800 mg/Kg bw intraperitonally or orally. Lenz et al. 1991, the supporting study, assessed the renal papillotoxicity of diphenylamine dissolved in DMSO, investigated in male Surian hamsters, male Sprague-Dawley rats and female Mongolian gerbils.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication which meets basic scientific principles
Qualifier:
no guideline followed
Principles of method if other than guideline:
The renal papillotoxicity of diphenylamine dissolved in DMSO was investigated in male Surian hamsters, male Sprague-Dawley rats and female Mongolian gerbils
GLP compliance:
not specified
Limit test:
no
Species:
other: hamsters, rats, gerbils
Strain:
other: Syrian, Sprague-Dawley, Mongolian
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS (Male Hamsters)
- Source: Harlan Sprague-Dawley, Indianapolis, USA
- Weight at study initiation: 50-65 g
- Housing: 5 animals/plastic box
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 d

TEST ANIMALS (Male Rats)
- Source: Harlan Sprague-Dawley, Indianapolis, USA
- Weight at study initiation: 50-75 g
- Housing: 5 animals/plastic box
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 d

TEST ANIMALS (Female Gerbils)
- Source: Tumblebrook Frams, West Brookfield, USA
- Weight at study initiation: 40-55 g
- Housing: 5 animals/plastic box
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 d

ENVIRONMENTAL CONDITIONS (all)
- Temperature (°C): 22
- Humidity (%): 50-60
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: DMSO (experiments 1,2) and peanut oil (experiment 3)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 0.5 ml/100 g bw/day
Doses:
Experiment 1 (all species): 400, 600 and 800 mg/kg bw/day (single oral dose for 9 consecutive d)
Experiment 2 (Hamsters + Rats): 400, 600 and 800 mg/kg bw/day ( single ip injection for 3 consecutive d)
Experiment 2 (Gerbils): 0, 50, 100, 200, 400, 600 and 800 mg/kg bw/day (single ip injection for 3 consecutive d)
Experiment 3 (Hamsters): 400, 600 and 800 mg/kg (single oral dose for 3 consecutive d) 1 h after or not an oral dose of 0.5 ml/100 g bw DMSO
No. of animals per sex per dose:
Experiment 1 (all species): 30 animals/dose + 15 animals in a control group
Experiment 2 (Hamsters + Rats): 10 animals/dose + 5 animals in a control group
Experiment 2 (Gerbils): 5 animals/dose
Experiment 3 (Hamsters): 10 animals/dose
Control animals:
yes
Statistics:
chi-square test, P<0.05
Mortality:
Experiment 1: Few of animals dosed orally died as a result of chemical-related toxicity
Experiment 2: Most of the hamsters (50 %), rats (83 %) and gerbils (97 %) died within 12-20 hr of the first or second ip dose
Experiment 3: No animals died in the groups given DMSO before diphenylamine
Clinical signs:
other: other:

When diphenylamine in DMSO was administered orally to hamsters, the incidence of renal papillary necrosis was almost zero.

Hamsters pretreated with DMSO had significantly reduced incidences of papillary necrosis.

Renal papillary necrosis was not observed in any of the Mongolian gerbils

Conclusions:
The concurrent oral administration of DMSO could reduce the renal papillotoxicity of diphenylamine in male Syrian hamsters, whereas Mongolian gerbils seem to be refractory to diphenylamine-induced renal papillary necrosis, irrespective of the vehicle.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication which meets basic scientific principles
Qualifier:
no guideline followed
Principles of method if other than guideline:
The nephrotoxicity of diphenylamine, the parent compound of the mefenamate family of nonsteroidal anti-inflammatory drugs, was evaluated in male Syrian hamsters, male Sprague-Dawley rats, and male Mongolian gerbils
GLP compliance:
not specified
Limit test:
no
Species:
other: Hamster, Rat, Gerbil
Strain:
other: Syrian, Sprague-Dawley, Mongolian
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS (Hamsters)
- Source: Harlan Sprague-Dawley, Indianapolis, IN
- Weight at study initiation: 80-120 g
- Housing: 5 animals/box with wood shavings for bedding
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 d

TEST ANIMALS (Rats)
- Source: Harlan Sprague-Dawley, Indianapolis, IN
- Weight at study initiation: 150-175 g
- Housing: 5 animals/box with wood shavings for bedding
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 d

TEST ANIMALS (Gerbils)
- Source: Tumblebrook Farms, West Brookfield, MA),
- Weight at study initiation: 45-55 g
- Housing: 5 animals/box with wood shavings for bedding
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 d

ENVIRONMENTAL CONDITIONS (all)
- Temperature (°C): 22
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
other: oral gavage and intraperitoneal injection
Vehicle:
peanut oil
Doses:
Experiment 1: 400, 600 and 800 mg/kg bw/day (single daily gavage)
Experiment 2: 400, 600 and 800 mg/kg bw/day (single daily ip injection)
No. of animals per sex per dose:
Experiment 1: 10 animals/dose + 10 animals in a control group
Experiment 2: 10 animals/dose + 5 animals in a control group
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 3 consecutive days of administration + 24 hr observation
- Necropsy of survivors performed: yes
Sex:
male
Dose descriptor:
LD50
Effect level:
ca. 600 mg/kg bw
Based on:
not specified
Remarks on result:
other: Syrian hamsters
Sex:
male
Dose descriptor:
LD50
Effect level:
> 800 mg/kg bw
Based on:
not specified
Remarks on result:
other: Sprague-Dawley rats
Sex:
male
Dose descriptor:
LD50
Effect level:
> 800 mg/kg bw
Based on:
not specified
Remarks on result:
other: Mongolian gerbils
Mortality:
Experiment 1
- Syrian hamsters: 4/10 (400 mg/kg/d) and 10/10 (600 and 800 mg/kg/d)
-Sprague-Dawley rats and Mongolian gerbils: no mortality

Experiment 2:
- Syrian hamsters: 0/10 (400 mg/kg/d), 5/10 (600 mg/kg/d) and 4/10 (800 mg/kg/d)
Clinical signs:
other: other:
Gross pathology:
Syrian hamsters: brown kidneys and yellow-brown papilla at the highest doses
Sprague-Dawley rats: no significant lesions
Mongolian gerbils: no gross lesions
Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: not specified
Conclusions:
Syrian hamster is more susceptible to the papillotoxic effects of diphenylamine than the Sprague-Dawley rat and the Mongolian gerbil.
The male Syrian hamster may prove useful as an alternative experimental rodent model of non-steroidal, anti-inflammatory, drug-induced papillary necrosis
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
800 mg/kg bw
Quality of whole database:
K2

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

According the results of the key study, the LD50 from the male Sprague-Dawley rats was > 800 mg/Kg bw based on oral route.

Justification for classification or non-classification

Regarding the selected oral acute toxicity LD50, DPA should be classified "Acute Toxicity Category 4" according to the CLP Regulation.