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Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Aug. 22, 1979 to Sep. 21, 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was not conducted according to any particular guideline. However, it is well documented and meets generally accepted scientific principles.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report date:
1979

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
This study, was designed to assess the toxicity of the test substance when applied to the shaved intact skin of Sprague-Dawley CD rats (5/sex/group) for a period of 30 d at dose levels of 0.5, 1.0, 2.0 g/kg bw/day.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Trioctylphosphine oxide
EC Number:
201-121-3
EC Name:
Trioctylphosphine oxide
Cas Number:
78-50-2
Molecular formula:
C24H51OP
IUPAC Name:
trioctylphosphine oxide
Test material form:
solid: crystalline
Details on test material:
- Name of test substance (as cited in study report): Tri-N-Octylphosphine Oxide (TOPO)
- Physical state: solid
- Composition of test substance- percentage of components: 100% Active Ingredient
- Lot/batch No.: 731-16
- Storage condition of test substance: stored at ambient temperature, in a sealed container.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories Wilmington, Massachussetts
- Age at study initiation: 28 d
- Housing: individually in elevated stainless steel cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 13 d (9 August to 22 August 1979)

ENVIRONMENTAL CONDITIONS
- Photoperiod (h dark / h light): 12 h light/dark cycle

Administration / exposure

Vehicle:
other: Mineral oil
Details on exposure:
TEST SITE
- Area of exposure: approximately 10% of the total body surface
- Time intervals for shavings or clipplings: 2 d prior to the first application

VEHICLE
- Lot/batch no.: 9D 827
Duration of treatment / exposure:
30 d
Frequency of treatment:
Daily (7 d/week)
Doses / concentrations
Remarks:
Doses / Concentrations:
0.5, 1.0, 2.0 g/kg
Basis:

No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
Animals were observed for:
Mortality and gross signs of toxicologic or phanmacologic effects (twice daily), detailed physical examination for signs of local or systemic toxicity, pharmacologic effects and palpation for tissue masses (weekly), dermal responses (weekly), body weight (once pretest, weekly during treatment and terminally), food consumption (weekly, beginning one week prior to treatment). Food consumption for baseline was conducted over a 7 d period. Week 1 was measured over a 5 d period. All proceeding weeks (2, 3 and 4) were measured over a 3 d period.
Sacrifice and pathology:
Animals were sacrificed by exsanguination under ether anesthesia. Organs weighed and organ/body weight ratios calculated. Tissues were preserved in 10% neutral buffered formalin and observed for gross lesions (including a section of normal-appearing tissue). Necropsy was performed on all surviving animals. Complete gross postmortem examination on animals dying spontaneously or killed in a moribund condition.
Statistics:
Body weight, food consumption, organ weights and organ/body weight ratios were analyzed. Mean values of all dose groups were compared to control at each time interval. Statistically significant differences from control are indicated in appendices. Statistical analysis not performed on means when N (number of animals) was less than three.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
Mortality:
One mid-dose male, two mid-dose females and three high-dose females died spontaneously or were sacrificed in a moribund condition during the first week of test substance administration. In addition, one high-dose female was sacrificed in a moribund condition during the second week of test substance administration. All other animals survived the duration of the study.

Physical Observations:
There were no physical observations in the Group I males or females which were attributed to the administration of the vehicle. Slight to moderate degrees of erythema, edema, atonia, desquamation and fissuring as well as moderate to severe alopecia were observed in the low dose females. Similar observations were made in the low-dose males, with the exception of one or two animals in which the erythema and fissuring observed during the second week of the study were severe. The mid- and high-dose males and females displayed dermal reactions which were similar in nature, but which were, in general, of greater severity than those observed in the low-dose group. In addition to the observed dermal responses, the mid- and high-dose males and the low-, mid- and high-dose females exhibited varying degrees of reduced physical activity. In addition, three of the low- and mid-dose males and all of the low-dose females displayed varying degrees of poor physical condition and emaciation. The mid- and high-dose females and the high-dose males displayed similar observations with a greater degree of severity.

Body Weight:
Mean body weights in the male and female treated animals were reduced, relative to the vehicle controls, in a dose-related pattern during all weeks of test substance administration. Compared to the vehicle control at week four, mean body weights were reduced approximately 37, 42 and 53% in the low-, mid- and high-dose males and 25, 28 and 45% in the low- mid- and high-dose females, respectively.

Food Consumption:
Mean food consumption values in the male and female treated animals were reduced at Week 1, compared to the vehicle control (18 to 25%). During Weeks 2, 3 and 4, mean food consumption values in the treated animals were variable due to excessive food spillage or contamination by the animals and due to animal mortality. However, mean food consumption in the low- mid- and high-dose males and females appears, for the most part, to have been slightly increased during Weeks 2, 3 and 4.

Organ Weights and Organ/Body Weight Ratios:
Mean absolute kidney weights were slightly depressed in the low-, mid and high-dose females (4, 5 and 10%) and significantly depressed in the low-, mid- and high-dose males (40, 45 and 53%, respectively). The mean relative (organ to body weight ratio) kidney weights were statistically significantly increased in a dose-related pattern in the low- mid- and high-dose males and females. Mean absolute liver weights were depressed in the low-, mid- and highdose females (approximately 3, 15 and 27% respectively) and statistically significantly depressed in the low, mid- and high-dose males {38, 39 and 38%). The mean relative organ to body weight ratio, liver weights were increased in all treated groups compared to the vehicle control. These increases were approximately 3, 11 and 34% in the low-, mid- and high-dose males and 32, 22 and 36% in the low-, mid- and high-dose females.

Pathology:
The gross postmortem observations included emaciation as well as lesions of the dermis and underlying muscle. These findings were considered treatment related. There were no other gross postmortem findings which were considered treatment-related.

Effect levels

open allclose all
Dose descriptor:
LOAEL
Effect level:
500 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Systemic: Reduced mean body weights in the male and female treated animals, reduced mean absolute kidney and liver weights, increased mean relative kidney and liver weights.
Dose descriptor:
LOAEL
Effect level:
2.8 mg/cm² per day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Dermal: Erythema, edema, atonia, desquamation, fissuring and alopecia in all treated groups, emaciation as well as lesions of the dermis and underlying muscle in the post mortem observation.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The LOAEL of the test substance for systemic as well as local effects was 500 mg/kg bw/day. This dose level is equivalent to 2.8 mg/cm2 for dermal effects (Daly IW, 1979).
Executive summary:

A study was conducted to evaluate the toxic effects following repeated dermal exposure to the test substance in Sprague-Dawley rats. Groups of 5 male and 5 female rats were dermally exposed to 500; 1,000 and 2,000 mg test substance/kg bw/day in mineral oil for 7 d/wk for a period of 30 d. The vehicle control (group i) animals were treated with a volume of mineral oil comparable to that used in the treated groups. Animals were observed for mortality and gross signs of toxicological or pharmacological effects (twice daily), detailed physical examination for signs of local or systemic toxicity, pharmacological effects and palpation for tissue masses (weekly), dermal responses (weekly), body weight (once pre-test, weekly during treatment and terminally), food consumption (weekly, beginning one week prior to treatment). Animals were sacrificed by exsanguination under ether anesthesia. Organs weighed and organ/body weight ratios were calculated. Tissues were preserved in 10% neutral buffered formalin and observed for gross lesions (including a section of normal-appearing tissue). Reduced mean body weights in the male and female treated animals, reduced mean absolute kidney and liver weights, increased mean relative kidney and liver weights were observed at all the doses in a treatment related manner. Erythema, edema, atonia, desquamation, fissuring, alopecia, emaciation as well as lesions of the dermis and underlying muscle in the post mortem observation were also observed in all the treatment groups. Under the study conditions, the LOAEL for systemic as well as local effects was 500 mg/kg bw/day.This dose level is equivalent to 2.8 mg/cm2 for dermal effects(Daly IW, 1979).