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Acute Toxicity: dermal

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acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22 November 1988 to 23 December 1988
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study conducted to an appropriate test guideline with no or minor deviations.
Reason / purpose:
reference to same study

Data source

Reference Type:
study report
Report Date:

Materials and methods

Test guideline
according to
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
Test type:
standard acute method
Limit test:

Test material

Details on test material:
Batch an other numbers SNC No. 1986: 88009
Toxicology reference No. St88/253Source: Shell Nederland Raffindarerij BV Rotterdam
Date received: 18 Oct 1988
Appearance: clear colourless liquid
Analysis: 94.51-97.51% cis isomer with 1.5% trans isomer
Density: 1.224 g/mL @ 15.2 ºC
Date released 18 Nov 1988
Storage: dark at ambient temperature
Stability: stable for the duration of the study (no changes from 21 Nov 1988 to 19 Jan 1989

Test animals

Fischer 344
Details on test animals and environmental conditions:
Fischer 344 rats aged 8-9 weeks were obtained from Charles River U.K. Ltd. On arrival they were housed in single sex groups of up to 12 rats to a cage. The animals were quarantined for a minimum of five days in a non-barriered animal room with access restricted to essential personnel. At least five days before dosing the animals were rehoused (as single sex groups of up to four rats) in cages with stainless steel wire-mesh walls, floors and tops. Each cage measured 38 cm x 25 cm x 18 cm. Paper-lined trays for excreta were placed beneath each cage and changed three times weekly. A pelleted diet (PRD, Labsure Animal Foods) and water from the public supply were provided ad libitum. There were no excursions of animal room environmental
conditions beyond target values of 19° to 23°C and 30% to 70% R.H. that were considered to have influenced the outcome of the study. Lighting (fluorescent tubes) was automatically controlled to provide a 12 hour day and 12 hour night. Animals assigned to the study were identified by cage-labels displaying the animal numbers, experiment number, sex and dose-level and by ear-notches denoting the animal number.

Administration / exposure

Type of coverage:
unchanged (no vehicle)
Details on dermal exposure:
On the day before dosing dorsal fur removed with clippers and any rat with damage or irritation ot the skin was not used. On day 1 animals were weighed and a single dose of test material applied to skin. Test material was held in place with lint dressing (6x8 cm) and covered with waterproof adhesive tape. Animals individually housed. After 24 h dressing removed, skin was washed with warm dilute detergent, dried and animals returned to grouphousing.
Duration of exposure:
24 h
400, 560, 784, 1098, and 1537 mg/kg
No. of animals per sex per dose:
Control animals:
not required
Details on study design:
Groups of five male and five female rats were used. On the day before dosing the dorsal fur was removed from the animals using electric clippers. Any rat showing signs of damage or irritation of the dorsum was replaced. On Day 1 the animals were weighed and a single dose of the test material applied to the skin. The test material was held in place with a lint dressing (approx 6 x 8 cm) covered with waterproof adhesive tape. The rats were then individually housed. Following a 24 hour exposure the dressings were removed, the skin washed with warm dilute detergent solution, dried, and the animals returned to group housing.

A careful clinical examination was made up to three times daily for the first three days and once daily thereafter for the remainder of the 14 day observation period. The initial (Day 1), Day 7 and Day 14 bodyweights were recorded, and changes in bodyweight calculated.
All animals were subject to necropsy. Animals sacrificed for humane reasons during the study or surviving to the end of the study were killed by an intraperitoneal injection of sodium pentobarbitone. The cranial, thoracic and abdominal cavities and viscera were examined and any gross pathological changes recorded.
The 14-day LD50, 95% confidence interval and the dose-mortality slope were calculated using a method based on probit analysis (Finney 1977)

Results and discussion

Effect levelsopen allclose all
Dose descriptor:
Effect level:
1 068 mg/kg bw
95% CL:
722 - 3 669
Remarks on result:
other: slope = 2.5
Dose descriptor:
Effect level:
1 109 mg/kg bw
95% CL:
983 - 1 315
Remarks on result:
other: slope = 40.2
Dose descriptor:
Effect level:
1 090 mg/kg bw
95% CL:
901 - 1 403
Remarks on result:
other: slope = 4.0
Mortalities occurred on days 2 and 3.

Mortality folloeing acute dermal administration

dose (mg/kg) male female Total
400 1/5 0/5 1/10
560 0/5 0/5 0/10
784 2/5 0/5 2/10
1098 2/5 2/5 4/10
1537 4/5 5/5 9/10

Clinical signs:
Systemic toxicity was observed at 400 mg/kg other than the death of a single death on day 3. Voiding of soft feces and lethargy were common among rats given higher dose levels and a few cases of unkempt appearance. hypothermia, abasia, ataxia, hunched back or bloody discharge from the nose in groups dosed at 784 mg/kg and above. Rats that died showed no ante-mortem clinical changes, nor did those surving treatment. Recovery of rats surving treatment was generally advanced by day 3 but remained incomplete until day 6. Sites of application commonly developed a slight erythema or erythema that persisted upt o 4 days after removal of patch. Oedema was apparent among rats treated at 1537 mg/kg.
Body weight:
Despite loss of body weight during the first week of observation, all surviving rats gained wieght relative to their day 1 body weight on day 14.
Gross pathology:
Necropsy of decedents commonly revealed abnormal contents, inflammation, haemorrhage of the stomach, discolouration of the subcutaneous muscle, discolouration of the renal medulla, lung congestion, and petechiae on the thymus. No macroscopic abnormalities were found in surviving rats.

Applicant's summary and conclusion

Interpretation of results:
Migrated information Criteria used for interpretation of results: EU
The acute dermal LD50 of the undiluted test material in rats (males and females combined) was 1090 mg/kg (95% confidence interval 901 -1403 mg/kg).
LD50 males only = 1068 mg/kg
LD50 females only = 1109 mg/kg
Executive summary:

A GLP compliant study has been conducted in accordance with OECD Guideline 402.

The acute dermal LD50 of the undiluted test material in rats (males and females combined) was 1090 mg/kg (95% confidence interval 901 -1403 mg/kg).

LD50 males only = 1068 mg/kg

LD50 females only = 1109 mg/kg