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Description of key information

Oral LD50 values of reliable rat studies lie within the range of 1160-3135 mg/kg bw, and a fixed dose rat study reports mortality and other toxic effects at 2000 mg/kg bw.  In a reliable inhalation study no mortality was observed in rats exposed to saturated vapour (ca. 0.03 mg/L). No reliable data for the test substance are availbale for the dermal route. 

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1986-06-02 to 1986-06-12
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
This study was performed according to guideline OECD 401 with some minor variations.
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
, no constant volume at the different dose levels, partially shorter acclimatisation period than 5 days
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Bor:WISW (SPF TNO)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Weight at study initiation: 169,2 g (average)
- Fasting period before study: 16 h
- Housing: 1-5 animals per cage
- Diet: R10 Alleindiät für Ratten, Ssniff Spezialfutter, Soest, Germany, ad libitum
- Water: ad libitum)
- Acclimation period: 4-8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 1
- Humidity (%): 60 +/- 5
- Air changes (per hr): 15-fold
- Photoperiod (hrs dark / hrs light): 12 h/12 h
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Doses:
631, 794, 1000, 1250, 1580 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Animals were weighed at day 0, 1, 7 and 14
- Clinical symptoms were recorded up to 6 h following treatment and daily thereafter
- Dead animals were examined macroscopically
- Observation period: 14 days
Statistics:
LD50 values and 95% confidence intervals were calculated using a method of Litchfield and Wilcoxon (reference stated)
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 160 mg/kg bw
95% CL:
> 1 018 - < 1 322
Mortality:
631 mg/kg bw: 0/5 (males), 0/5 (females)
794 mg/kg bw: 0/5 (males), 0/5 (females)
1000 mg/kg bw: 1/5 (males), 2/5 (females)
1250 mg/kg bw: 1/5 (males), 5/5 (females)
1580 mg/kg bw: 5/5 (males), 5/5 (females)
Clinical signs:
15-30 min after dosage, the animals showed clinical signs of toxicity in form of ruffled fur, cowering, stagger, slight sedation and ataxia as well as prone position. Subsequently animals showed lacrimation, hypoactivity diarrhoea, laboured breathing, moderate to severe sedation and ataxia, gasping respiratory sounds, hypothermia, trembling and wide opened eyes. Surviving animals recovered completely after 48 h.

Animals with clinical signs of toxicity:
631 mg/kg bw: 5/5 (males), 5/5 (females)
794 mg/kg bw: 5/5 (males), 5/5 (females)
1000 mg/kg bw: 5/5 (males), 5/5 (females)
1250 mg/kg bw: 5/5 (males), 5/5 (females)
1580 mg/kg bw: 5/5 (males), 5/5 (females)
Body weight:
The body weight gain was not affected by the treatment.
Gross pathology:
Macroscopic examination of perished animals showed hyperemia of stomach and intestinal mucosa, scattered discolouration of liver and kidneys as well as extensively filled urinary bladders. Further observations were: hyperemia of the mucosa of the urinary bladder in 1 animal, hyperemia of the lung: 2 animals, hyperemia of the pancreas: 4 animals, hyperemia of the subcutis: 4 animals. Necroscopy of surviving animals at the end of the observation period revealed partially severe hyperemia of the small intestine mucosa.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Under the conditions of this study, all tested doses (single oral doses of 631 mg/kg bw and above) were toxic to rats and the LD50 was 1160 mg/kg bw.
Executive summary:

Single oral doses of > 631 mg/kg bw were toxic to fasted rats, producing clinical signs of toxicity and an increased mortality at doses of > 1000 mg/kg bw. The LD50 was 1160 (1018 -1322) mg/kg bw (Hüls AG, 1986).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 160 mg/kg bw
Quality of whole database:
sufficient for evaluation

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
Inhalation hazard test
Deviations:
no
GLP compliance:
no
Test type:
traditional method
Limit test:
yes
Species:
rat
Strain:
not specified
Sex:
male/female
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Rats exposed for 7 h, respectively, to a vapour saturated atmosphere. Vapour was generated by bubbling 200 l/h dry air (no CO2) through the liquid substance column (volume ca. 50 ml) of about 5 cm above a fritted glass disc in a glass cylinder. The glas cylinder was heated in a water bath. Temperature in the exposure chamber was 20°C. Concentration was stated in the raw data to be 0.436 mg/L. This was calculated based on the substance loss. Based on a vapour pressure of 0.0044 hPa (see 4.6) and a molecular weight of 158.24 a saturated vapour concentration of 0.03 mg/L can be calculated. Due to this discrepancy, this latter value is assumed to be more reliable with respect to human exposure.
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
7 h
Concentrations:
0.03 mg/l (nominal)
No. of animals per sex per dose:
3 males and 3 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
Statistics:
not necessary
Key result
Sex:
male/female
Dose descriptor:
LC0
Effect level:
0.03 mg/L air (nominal)
Exp. duration:
7 h
Remarks on result:
other: inhalation hazard test
Mortality:
No Mortality was observed
Clinical signs:
other: Slight irritation of mucous membranes, nasal discharge, accelerated breathing, ruffled fur
Body weight:
no data
Gross pathology:
no substance related findings

The acute inhalation risk test demonstrates that no hazard has to be expected from exposure to saturated vapour of 3,5,5 -trimethylhexanoic acid at room temperature.

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study, a saturated atmosphere did not produce mortality, but only slight signs of toxicity
Executive summary:

6 rats (3 males, 3 females) were exposed to a saturated atmosphere (calculated to 0.03 mg/L) of the test substance for 7 h. Within the observation period of 14 days, there was no mortality, but only slight signs of toxicity during exposure. No organ damage was detected at necropsy.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Study is reliable with restrictions

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The oral LD50 values reported in reliable rat studies vary by a factor of about 3 (Hüls, 1986: 1160 mg/kg bw (key study, RL1); Hoechst, 1970: 3135 mg/kg bw; RL2), which is not unusual in different studies. The findings of the key study are supported by a (reliable) limit test, which reports mortality of most of the animals and other overt signs of toxicity at 2000 mg/kg bw (Exxon, 1997, RL2), a reliable acute toxicity test with a rat LD50 of 1350 mg/kg bw (BASF AG, 1980) as well as by a (not reliable) secondary report of an oral LD50 value of 1598 mg/kg bw in rats (Exxon, undated).

Note: The application form may have influenced the result: Low acute toxicity (high LD50) was observed, when the test compound was administered as a 10 % solution in sesame oil (Hoechst 1970), while higher intoxication resulted from the oral treatment with the undiluted test material (Hüls 1986; Exxon 1997).

In a reliable study 6 rats (3 males, 3 females) were exposed to a saturated vapour atmosphere (calculated to 0.03 mg/L) of the test substance for 7 h. Within the observation period of 14 days, there was no mortality, but only slight signs of toxicity during exposure. No organ damage was detected at necropsy (BASF AG, 1980).

A value of > 3 mg/l (Exxon, undated) is reported only in secondary sources. The original study is not available.

A dermal LD50 of > 2000 mg/kg bw for the test substance is reported in a less reliable study (Exxon, undated, RL 4). This data are reported only in secondary sources. The original study is not available

Justification for classification or non-classification

Based on the findings of the key study reporting an oral LD50 of 1160 mg/kg in rats the substance should be classified for acute oral toxicicity Category 4 according to Regulation (EC) No 1272/2008.

Based on an inhalation LC0 in the key study of 30 mg/m3, the vapour saturation concentration at room temperature, no classification according to Regulation (EC) No 1272/2008 is required with respect to inhalation toxicity.

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