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Toxicological information

Acute Toxicity: dermal

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Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
14 June 2006 - 18 June 2006
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Study performed according to GLP principles and similar to OECD 402. Minor deviations include lack of gross pathology, animals were only observed for 7 days instead of recommended 14 days.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2006
Report date:
2006

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
no gross pathology, observation time only 7 days (instead of 14 days), acclimatization period 3 days only (instead of recommended 5); test substance covered occlusively (semi-occlusive is recommended).
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Tetrabutylphosphonium bromide
EC Number:
221-487-8
EC Name:
Tetrabutylphosphonium bromide
Cas Number:
3115-68-2
Molecular formula:
C16H36P.Br
IUPAC Name:
tetrabutylphosphonium bromide
Test material form:
other: waxy solid
Details on test material:
- Name of test material (as cited in study report): CYPHOS 442 (CT-851-06)
- Substance type: organic
- Physical state: White waxy solid (odorless)
- Storage condition of test material: Room temperature and humidity
- pH: <2 in 25% water solution

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Millbrook Breeding labs, Amherst, MA, USA
- Age at study initiation: 2-3 months old
- Weight at study initiation: 2.1-2.8 kg
- Fasting period before study: No
- Housing: individually in suspended wire cages
- Diet: PMI Rabbit Chow, provided daily
- Water: ad libitum
- Acclimation period: at least three days

ENVIRONMENTAL CONDITIONS
- No further data, but animals kept in climate controlled room
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 14 June 2006 To: 18 July 2006

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- % coverage: appr. 10%
- Type of wrap if used: four layered surgical gauze patch, wrapped with plastic sheeting secured with non-irritating tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no (test substance was wiped of the skin)
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount applied: 2.4-2.7 g/ animal, 0.63-0.70 g/ animal, or 1.05-1.3 g/ animal
- For solids, paste formed: no, but patches were moistened with 6-13 ml of distilled water
Duration of exposure:
24 hours
Doses:
1000, 250 or 500 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: the animals were observed at 1, 4 and 24 hours postdose for mortality, toxicity and pharmacological effects, and once daily thereafter for mortality. Body weights were recorded pretest and at death.
- Necropsy of survivors performed: no
- Other examinations performed: test sites were scored for dermal irritation at 24 hours post-dose and on day 7.
Statistics:
None.

Results and discussion

Effect levels
Sex:
male
Dose descriptor:
LD50
Effect level:
> 500 - < 1 000 mg/kg bw
Based on:
test mat.
Mortality:
No animals survived the 1000 mg/ kg bw dose (4/5 animals died between 1 and 4 hours postdose, one animal died between 4 and 24 hours postdose). Four rabbits survived at 500 mg/ kg bw, one rabbit died between 4 and 6 hours post-dose. No mortality occurred at 250 mg/ kg bw.
Clinical signs:
At 250 mg/ kg bw no clinical signs were noted, except for instances of soiling of the anogenital area, ataxia and hunched posture 24 post dose. At 500 mg/ kg bw, tachypnea was observed in one animal one hour after start of exposure. One animal was noted to be lethargic, to have an abnormal posture an decreased responses in its hind legs at unwrapping. At the highest dose hunched posture was seen in the animal that died betwen 4 and 24 hours after exposure.
Body weight:
One animal dosed at 500 mg/kg bw/ day lost weight between day 1 and day 7 (appr. -7.7%), one animal remained at the same body weight. The body weight gain in the other surviving animals increased as expected.
Gross pathology:
Not performed.
Other findings:
At 24 hours, no erythema (in 1/4 animals), very slight (in 2/4 animals) to well defined (in 1/4 animals) was seen at 500 mg/kg bw. No edema was seen in 1/4 animals, two had very slight edema and one had slight edema (edges of area well defined by definitive raising). At day 7, 3/4 had flaking skin with very slight (1/4), well defined (1/4) or severe erythema (beet redness). Edema was absent (2/4), very slight or slight (1/4 each).
Exposure to 250 mg/kg bw resulted at 24 hours in very slight (in 3/5 animals) to well defined (in 2/5 animals) erythema. Edema was absent in 1 animal, very slight (2/5) or slight (2/5). On day 7, only 1/5 rabbits had very slight edema, 4/5 had no erythema (one of these animals had flaking skin) and one animal was found to have severe erythema.

Any other information on results incl. tables

After occlusive binding was removed, approximately 10% of the test substance (both concentrations) remained on the skin (estimated by visual inspection).

Applicant's summary and conclusion

Interpretation of results:
other: classified cat. 3
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Based on an acute dermal toxicity test performed with male rabbits, the LD50 of the test substance was found to be > 500 mg/kg bw and < 1000 mg/kg bw.
Executive summary:

An acute dermal toxicity test with male rabbits was performed under GLP principles. Male rabbits were exposed occlusively for 24 hours to 250, 500 or 1000 mg/kg bw and observed for 7 days after removal of the test substance. At the highest dose, all rabbits died within 24 hours. At 500 mg/ kg bw, 1/5 rabbits died. No other mortality occurred. Clinical signs were limited, incidental findings of ataxia and soiling of the anogenital area were seen (at 250 mg/ kg bw) and tachypnea (in the rabbit that died at 500 mg/kg bw) and lethargy, abnormal posture and responsiveness in the hind legs (1 animal) were seen at 500 mg/kg bw. Body weight reduction and arrest were seen in 2 animals at 500 mg/kg bw, all other surviving animals gained weight as expected. Dermal effects were seen in most animals, for one animal from each dose group the erythema was severe at day 7. For all other animals, skin effects were absent or very slight after 7 days.

Based on these results, the LD50 of the test substance was found to be > 500 mg/kg bw and < 1000 mg/ kg bw and therefore the test substance is classified for acute dermal toxicity category 3.

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