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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:
21 Sep - 07 Oct 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report Date:
1999

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
adopted in 1987
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Version / remarks:
adopted in 1998
Qualifier:
according to
Guideline:
other: JMAFF, 59 NohSan No. 4200
Version / remarks:
adopted in 1985
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
adopted in 2017
Deviations:
yes
Remarks:
both sexes are used instead of recommended females, two concentrations in females instead of one starting dose, 6 animals per sex and dose instead of sequential manner with two animals, animals were individually housed instead of group-caging
GLP compliance:
yes
Test type:
other: acute dermal toxicity
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: pellets
Details on test material:
Batch No.: E0136

Test animals

Species:
rat
Strain:
other: Wistar Hannover (Crl:Wl(Glx/BRL/Han) IGS BR)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, lnc., Raleigh, NC, USA
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approximately 9 weeks (males), approximately 12 weeks (females)
- Weight at study initiation: 230 - 269 g (males), 202 - 227 g (females)
- Housing: individually in suspended stainless steel wire-mesh cages
- Diet: Purina Mills Rodent Lab Chow 5001-4, ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal and lateral areas of the trunk
- % coverage: a minimum of 10% of the total body surface area
- Type of wrap if used: The test material was held in contact with the skin using a plastic-backed, two-ply gauze patch with hypoallergenic tape. The animal was then wrapped with an elastic bandage, which was also secured with tape.

REMOVAL OF TEST SUBSTANCE
- Washing: Residual test material was removed by wiping using paper towels dampened with tap water.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied: 1 mL (males at 5000 mg/kg bw), 0.5 and 1 mL (females at 2000 and 5000 mg/kg bw/day)
- For solids, paste formed: yes
Duration of exposure:
24 h
Doses:
5000 mg/kg bw (males)
2000 and 5000 mg/kg bw (females)
No. of animals per sex per dose:
6
Control animals:
yes, concurrent no treatment
Remarks:
control animals received dermal application of deionised water
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Detailed observations were conducted at least twice daily (once daily on weekends and holidays). Body weights were measured at the time of treatment (Day 0), and for all surviving animals on Days 7 and 14 following treatment. Terminal body weights were measured for all animals found dead.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
Analysis of Variance test followed by the Dunnett's t-statistic where significant differences were detected

Results and discussion

Effect levelsopen allclose all
Sex:
male
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 - < 5 000 mg/kg bw
Based on:
test mat.
Mortality:
MALES
5000 mg/kg bw: no mortalities occured

FEMALES
5000 mg/kg bw: 3/6 animals died (at 1 day post-dose)
2000 mg/kg bw: 2/6 animals dies (at 3 days post-dose)
Clinical signs:
MALES
5000 mg/kg bw: ataxia, decreased activity, eye twitching, clear lacrimation and urine staining as signs of systemic toxicity as well as edema, erythema, exfoliation, induration and sloughing as signs of irritation and tissue damage

FEMALES
2000 and 5000 mg/kg bw: ataxia, decreased activity, eye twitching, clear lacrimation, urine staining, red lacrimation and myoclonus as signs of systemic toxicity as well as edema, erythema, exfoliation, induration and sloughing as signs of irritation and tissue damage
Body weight:
MALES
5000 mg/kg bw: significantly decreased body weight gain on Day 7 post-dose; thereafter body weight gains were in the normal range

FEMALES
Body weight gains of all dose groups were within the normal ranges in females during the whole study period.
Gross pathology:
MALES
5000 mg/kg bw:
- animals sacrified at termination: crusty zones and thickened skin at the application sites

FEMALES
2000 and 5000 mg/kg bw:
- animals found dead: lacrimation, urine stained ventrum, discolored urine and discolored treated skin
- animals sacrified at termination: crusty zones and thickened skin at the application sites

Any other information on results incl. tables

Table 1:Results of acute dermal toxicity testing

Dose [mg/kg bw]

Toxicological results*

Duration of clinical signs

Time of death

Mortality (%)

Females

0

0/5/6

day 0 - day 2

---

0

2000

2/6/6

day 0 - end

day 1, day 3

33.33

5000

3/6/6

day 0 - end

day 1

50

Males

0

0/6/6

day 0 - day 1

---

0

5000

0/6/6

day 0 - end

---

0

* number of dead animals/ number of animals with signs of toxicity/ number of animals used

Applicant's summary and conclusion

Interpretation of results:
other: CLP/GHS criteria not met; no classification required according to Regulation (EC) No. 1272/2008
Conclusions:
CLP: not classified
Executive summary:

A study for acute dermal toxicity in the rat was conducted with the test substance according to the OECD Guideline 402 (1987) and in compliance with GLP. Six male and six female Wistar Hanover rats per sex and dose group received a single dermal dose of 0 and 5000 mg/kg bw test substance. 6 additional females received also a dose of 2000 mg/kg bw. The test substance was prepared as a paste using 0.5 mL (for the 2000 mg dose group) and 1 mL (for the 5000 mg dose group) of de-ionised water and applied occlusively to the shaved skin of the animals (a minimum of 10% of body surface). The dressing was removed after 24 h and residual test substance was removed with paper towels moistened with tap water. The animals were inspected at least twice daily during the 14-day observation period (once on weekends and holidays) for mortality, moribundity and clinical signs of toxicity. The animals were weighed individually directly before administration (day 0) and for all surviving animals on day 7 and 14. Terminal body weights were recorded for all animals found dead. A complete gross necropsy was performed on all animals of the study. As a result of dermal application of the test substance, 2/6 females treated with 2000 mg/kg bw died and 3/6 females in the 5000 mg/kg bw group died. No mortalities occurred in male animals. Compound-related clinical signs were observed in all males and females of the treatment groups and included signs indicative of systemic toxicity (ataxia, decreased activity, eye twitching, clear lacrimation, red lacrimation (females), myoclonus (females) and urine staining) as well as tissue damage and irritation at the application sites. A significant decrease in body weight gain was observed for the males of the 5000 mg/kg bw group on day 7 and was considered to be compound-related. Thereafter, body weight gains were in the normal range. Compound-related gross pathological observations were found at necropsy in females found dead before study termination (lacrimation, urine stained ventrum, discolored urine and discolored treated skin) as well as in all surviving males and females at terminal sacrifice (crusty zones and thickened skin at application sites). Under the conditions of this study the LD50 values were considered to be > 5000 mg/kg bw for male rats and > 2000 - < 5000 mg/kg bw in female rats. According to Regulation (EC) No 1272/2008 the test material does not need to be classified for acute dermal toxicity.