Registration Dossier

Administrative data

Endpoint:
repeated dose toxicity: dermal
Adequacy of study:
other information
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Test material insufficient characterised.

Data source

Reference
Reference Type:
publication
Title:
Zur perkutanen Intoxikation mit Diphenyl-Kresyl-Phosphat beim Meerschweinchen
Author:
Geffke I. et al.
Year:
1970
Bibliographic source:
Z. ges. Hyg. Grenzgeb. 16, 167-170 (1970)

Materials and methods

Principles of method if other than guideline:
Diphenyl cresyl phosphate (purity not known) in olive oil was applied to the shaved skin (3 cm2 exposed area, position not stated) of groups of four guinea pigs (strain and sex not given) daily for 73 days. Administered doses were equivalent to approximately 120, 240, 480, 720 or 960 mg/kg bw/day.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
According to the authors, the determination of the structures of the of the test substance was not possible, However the authors assumed, the test substance was a mixture of diphenyl cresy isomers.

Test animals

Species:
guinea pig
Strain:
not specified
Sex:
not specified

Administration / exposure

Type of coverage:
other: Animals were immobilised until the test material has dried.
Vehicle:
olive oil
Details on exposure:
Route of Administration: dermal
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
73 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0.1 to 0.8 ml/kg bw/d = ca. 120 to 960 mg/kg bw
Basis:

Control animals:
other: yes (olive oil)
Details on study design:
Post-exposure period: no

Examinations

Observations and examinations performed and frequency:
Mortality, clinical signs, body weight, liver weight.
Sacrifice and pathology:
Histopathological examination.

Results and discussion

Results of examinations

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
At 480 mg/kg bw/day, hind limb paralysis was observed in two animals. At doses greater than 480 mg/kg bw/day, paralysis of the hind limbs and lower portions of the back muscles were observed in all animals (the time of onset of signs of paralysis were not given).
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
There was a dose-dependent increase in alopecia from 240 mg/kg bw/day, and body weight gains were reduced in the two highest doses.
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight gains were reduced in the two highest doses.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
At 480 mg/kg bw/day, hind limb paralysis was observed in two animals. At doses greater than 480 mg/kg bw/day, paralysis of the hind limbs and lower portions of the back muscles were observed in all animals (the time of onset of signs of paralysis were not given).
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Liver weights were increased.
Neuropathological findings:
effects observed, treatment-related
Description (incidence and severity):
Histologic changes in the spinal cord were observed.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Effects on the liver were apparent from 480 mg/kg bw/day. At 720 mg/kg bw/day, the severity of hepatic effects increased. The highest dose caused all of these effects plus necrosis of hepatocytes and complete glycogen depletion. At doses of 480 mg/kg bw/day or above, hyperplasia, formation of fatty cysts, lipid vacuoles in the cortex and hyperaemia in the cortex and medulla of the adrenal glands were noted.
Histopathological findings: neoplastic:
not examined

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
120 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: Diphyl cresyl phosphate applied dermally caused injuries of the liver, the nervous system and of the adrenals in guinea pigs.

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
120 mg/kg bw/day (nominal)
System:
other: Diphyl cresyl phosphate applied dermally caused injuries of the liver, the nervous system and of the adrenals in guinea pigs.
Treatment related:
yes
Dose response relationship:
yes

Any other information on results incl. tables

Alopezia, reduced body weight with 0.2 ml and higher doses dose dependant), increased liver weight, paralysis in the 0.4, 0.6 and 0.8 ml-groups, microscopical up to 0.2 ml no effects in the liver, with 0.4 and 0.6 ml hyperemia and fatty liver changes, with 0.8 ml liver cell necrosis; edema of the spinal cord in the high dose groups, hyperplasia and necrosis of the adrenal glands (purity not known).

Applicant's summary and conclusion

Conclusions:
Diphyl cresyl phosphate applied dermally caused injuries of the liver, the nervous system and of the adrenals in guinea pigs.
Executive summary:

Diphenyl cresyl phosphate (purity not known) in olive oil was applied to the shaved skin (3 cm2 exposed area, position not stated) of groups of four guinea pigs (strain and sex not given) daily for 73 days. Administered doses were equivalent to approximately 120, 240, 480, 720 or 960 mg/kg bw/day.

All guinea pigs, including those in the control group, showed slight erythema with scale formation; this was attributed to the presence of the vehicle, olive oil. There was a dose-dependent increase in alopecia from 240 mg/kg bw/day, and body weight gains were reduced in the two highest doses. At 480 mg/kg bw/day, hind limb paralysis was observed in two animals. At doses greater than 480 mg/kg bw/day, paralysis of the hind limbs and lower portions of the back muscles were observed in all animals (the time of onset of signs of paralysis were not given). Effects on the liver were apparent from 480 mg/kg bw/day. At 720 mg/kg bw/day, the severity of hepatic effects increased. The highest dose caused all of these effects plus necrosis of hepatocytes and complete glycogen depletion. At doses of 480 mg/kg bw/day or above, hyperplasia, formation of fatty cysts, lipid vacuoles in the cortex and hyperaemia in the cortex and medulla of the adrenal glands were noted. The NOAEL for this study was considered to be the lowest dose tested; 120 mg/kg bw/day (Geffke et al. 1970, cited in BG Chemie 2000).