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Administrative data

Description of key information

In an acute oral toxicity test, the oral LD50 of 1,4-H6XDI was found to be > 300 mg/kg bw and < 2000 mg/kg bw. In an acute inhalation toxicity, conducted equivalent to OECD 403, the LD50 of 1,3-H6XDI was found to be > 0.147 mg/L and < 0.239 mg/L. An acute dermal toxicity study was performed with 1,3-H6XDI. Since no mortality occurred at 5000 mg/kg bw, the LD50 of 1,3-H6XDI is expected to exceed 5000 mg/kg bw. The results on acute inhalation and acute dermal toxicity are read across to 1,4-H6XDI.

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:
18 February 2009 - 13 May 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
(December 17, 2001)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Atsugi Breeding Center, Charles River laboratories Japan, Inc.
- Age at study initiation: 8 or 9 weeks
- Weight at study initiation: 198 - 208g
- Fasting period before study: yes, o/n (appr. 16 hours)
- Housing: one or two (individually after grouping) in bracket-type metallic wire-mesh cages
- Diet: ad libitum, pelleted diet CRF-1 (Oriental Yeast, Co., ltd.), except for appr. 16 hours before and 4 hours after test substance application
- Water: tap water, ad libitum
- Acclimation period: at least one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 51-59
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 18 February 2009 To: 13 May 2009
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30 mg/mL and 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/ kg bw
- Lot no.: V8N8411 (Nacalai Tesque, Inc.)

MAXIMUM DOSE VOLUME APPLIED: 10 mL/ kg bw
Doses:
300 and 2000 mg/kg bw (applied in a step-wise manner).
No. of animals per sex per dose:
3 (2000 mg/kg bw); 6 (300 mg/ kg bw)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Clinical signs were observed frequently for 6 hours after administration (immediately after to 5 minutes, 15 minutes and 30 minutes, and 1, 2, 4 and 6 hours after administration) and once every day for 14 days;
All animals were weighed on the day of administration, and on days 1,3, 7 and 14 (or at the time when found dead (if applicable)).
- Necropsy of survivors performed: yes (gross macroscopy)
Statistics:
Approximate LD50 value was estimated based on the deaths occurrence during the 14-day period after administration. For body weight, mean with standard deviation was calculated for each measurement day of each dose step. Body weight gain during the observation period was calculated from the body weight on day 0 and day 14 after administration, and mean with standard deviation calculated in the same manner.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Two animals died on the second day after dosing at 2000 mg/ kg bw. No other mortality occurred.
Clinical signs:
At 2000 mg/ kg bw, decrease in spontaneous movement was noted on day 1. For the surviving animals, this resolved after 3 days.
At 300 mg/ kg bw, no clinical signs were noted.
Body weight:
At 2000 mg/kg bw, weight decrease was noted in all animals. The surviving animal showed body weight decrease until day 3 after administration, but showed largely regular body weight gain thereafter. The body weight gain in animals dosed at 300 mg/kg bw was slightly low on the day following administration, but the rats showed largely regular body weight development thereafter.
Gross pathology:
No abnormalities in external appearance or in organs/ tissues in the cephalic, thoracic or abdominal regions were noted.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
In an acute oral toxicity test, the oral LD50 of 1,4-H6XDI was found to be > 300 mg/kg bw and < 2000 mg/kg bw.
Executive summary:

An acute oral toxicity test was performed according to OECD guideline 423 and GLP principles. Three female rats were exposed to 2000 mg 1,4 -H6XDI/ kg bw, which resulted in mortality of two rats on day 2. Decrease in spontaneous movement on day 1 was the only clinical sign observed in this group. The surviving animals showed decreased body weight, but regained body weight from day 4. Two groups of 3 females were exposed to 300 mg/kg bw in a step-wise manner. No mortality occurred, no clinical signs were noted. Slight depression in body weight gain was noted on the first day after administration, but this was resolved the next day. No abnormalities in external appearance or in organs/ tissues in the cephalic, thoracic or abdominal regions were noted. Based on these results, the oral LD50 of 1,4-H6XDI was found to be > 300 mg/kg bw and therefore 1,4 -H6XDI is classified cat. 4 for acute oral toxicity according to Regulation EC 1272/2008.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
300 mg/kg bw
Quality of whole database:
Study performed according to OECD guideline and GLP principles (Klimisch 1).

Acute toxicity: via inhalation route

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Reference
Endpoint:
acute toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
The rationale to read across the data is attached in section 13.
Reason / purpose:
read-across source
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 147.1 - < 239.1 mg/m³ air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: calculated LD 50 = 189.9 mg/m3 (standard error = 34.9 mg/m3)
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 0.147 - < 0.239 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
No mortality was seen in the control group. At 72.7 mg/m3 one male died 48 hours after exposure, and one female died 8 days after exposure. At 114.7 mg/m3, one male died at 5 hours after exposure. All rats survived exposure to 147.1 mg/m3. At 239.1 mg/m3, 9/10 rats died (2 rats during exposure, 2 rats died within 1 hour after exposure, the other 3 between 36 and 48 hours after exposure, one male rat surrvived) and at the highest concentration all rats died (during or immediately after exposure).
Clinical signs:
other: No clinical signs were seen in the control group during or after exposure. During exposure, rats exposed to 72.7 mg/m3 showed salivation and hunched posture. At higher concentrations salivation, lacrimation, hunched or prone posture, peripheral vasodilat
Body weight:
At 72.7 and 114.7 mg/m3 marked decrease in group mean bodyweight was noted in the first 3 days after exposure, subsequent body weight gain was comparable to that of the control rats. Surviving rats at 147.1 mg/m3 also showed decrease in body weight gain during first three days after exposure, after this body weight gain was lower than that of the control rats for a further 3 days. The surviving male at 239.1 mg/m3 showed decreased body weight gain during first 5 days after exposure.
Gross pathology:
Gross pathology of rats that dies as a result of exposure revealed haemorrhage, oedema and areas of hepatisation in the lung and distended gas filled stomachs at 72.7 and 114.7 mg/m3. At 147.1 mg/m3, scattered dark red foci or small area's of consolidation in the lungs of 4 rats were seen. Areas of hepatisation were also seen in the lungs of 2 rats exposed at 72.7 mg/m3 killed at the end of the observation period. A 7 mm diameter hemispherical lesion was observed on the liver of one male. At 239.1 mg/m3, oedema. Hepatisation affecting large areas of the lung and distended gas filled stomachs were seen in rats that died as a result of exposure. Findings for the rat that survived were small areas of hepatisation and a few scattered dark red foci in the lung. the adrenals of this rat were pale and enlarged. At the highest dose, oedema and hepatisation affecting large areas of the lung were seen in all rats.
Other findings:
Food and water consumption:
At 72.7, 114.7 and 147.1 mg/m3 food and water consumption was reduced to 25-30% of normal for 3 days following exposure. Normal food and water consumption resumed over the next 2-3 days.
The surviving male at 239.1 mg/m3 consumed little or no food during 5 days after exposure. Water consumption was 10-15% of normal consumption.

Lung weight to body weight ratio:
Within normal limits for surviving rats; high values for early decedents.
Interpretation of results:
Category 2 based on GHS criteria
Conclusions:
In an acute inhalation toxicity, conducted equivalent to OECD 403, the LD50 of 1,3-H6XDI was found to be > 0.147 mg/L and < 0.239 mg/L. This result is read across to 1,4-H6XDI.
Executive summary:

An acute inhalation toxicity was performed equivalent to OECD 403 with 1,3H6XDI. Five male and female rats were exposed to aerosols for 4 hours (whole body exposure) and followed for 14 days. Mortality was 0, 2, 1, 0, 9 and 10 rats at 0, 72.7, 114.7, 147.1, 239.1 and 531.6 mg/m3. The time of death correlated with exposure consentration. During exposure, rats showed salivation, lacrimation, hunched or prone posture, peripheral vasodilation and laboured breathing (gasping at two highest doses). The rapidity of onset of these reactions was related to the exposure level. During observation period, laboured breathing and rales were observed in all exposed animals. Brown staining (or dark red discharge) around snouts and peripheral vasodilation was observed in all rats 3 days post exposure. Persistence of the observations was dependent on exposure concentration. Dose-dependent decrease in body weight gain was noted during first 3 to 5 days after exposure. Subsequent body weight gain was comparable to that of the control rats for rats dosed at 72.7 and 114.7 mg/m3, but for rats dosed higher body weight gain remained lower, or further decreased (at 239.1 mg/m3). Gross macroscopy revealed substance related effects in the lungs (oedema and hepatisation, dose-dependent severity). This result is read across to 1,4-H6XDI. As the LD50 of 1,4-H6XDI was thus considerd to be > 147.1 mg/m3 and < 239 mg/m3, which correlates to > 0.147 mg/L and < 0.239 mg/L, 1,4H6XDI is classified as category 2 for inhalation toxicity according to Regulation EC 1272/2008.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
147.1 mg/m³
Quality of whole database:
The endpoint is filled with reliable data from substance analogue 1,3-H6XDI (Klimisch 2 study).

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
The rationale to read across the data is attached in Section 13.
Reason / purpose:
read-across source
Preliminary study:
No mortality occurred in the preliminary study.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred in the main study.
Clinical signs:
Hunched posture and abnormal gait (waddling) were noted for treated animals (resolved by day 5).
Body weight:
Depressed body weight gains compared to controls were seen for treated males in the first week, and for treated females in second week of observation.
Gross pathology:
Terminal autopsy revealed congestion of the subcutaneous blood vessels under the site of application in one treated male and three treated females.
Other findings:
Slight or well-defined oedema, accompanied by dryness and sloughing of the epidermis was observed in all test substance treated animals on second day after removal. A gradual increase in severity of the reactions was observed and "in depth" skin damage was observed in four rats by day 10 and in three further rats by day 12. Well-defined to moderate erythema accompanied by well-defined oedema was seen in the remaining animals.
At termination, "in depth" damage persisted in two animals. Drynes and sloughing of the epidermis, with or without scab formation, was observed in nine treated animals on day 15.
Interpretation of results:
GHS criteria not met
Conclusions:
An acute dermal toxicity study was performed with 1,3-H6XDI. Since no mortality occurred at 5000 mg/kg bw, the LD50 of 1,3-H6XDI is expected to exceed 5000 mg/kg bw. This result is read across to 1,4-H6XDI.
Executive summary:

An acute dermal toxicity study was performed comparable to OECD guideline 402 with male and female rats. The test was performed with 1,3-H6XDI. No mortality occurred at 5000 mg/kg bw. Hunched posture and abnormal gait (waddling) were noted for treated animals (resolved by day 5). Depressed body weight gains compared to controls were seen for treated males in the first week, and for treated females in the second week of observation. Slight or well-defined oedema, accompanied by dryness and sloughing of the epidermis was observed in all test substance treated animals on the second day after removal. A gradual increase in severity of the reactions was observed and "in depth" skin damage was observed in four rats by day 10 and in three further rats by day 12. Well-defined to moderate erythema accompanied by well-defined oedema was seen in the remaining animals. Skin effects were also seen at autopsy: one treated male and three treated females were found to have congestion of the subcutaneous blood vessels under the site of application. Based on these data, the LD50 of 1,3-H6XDI is expected to exceed 5000 mg/kg bw. This result is read across to 1,4-H6XDI.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The endpoint is filled with reliable data from substance analogue 1,3-H6XDI (Klimisch 2 study).

Additional information

An acute oral toxicity test was performed with 1,4-H6XDI according to OECD guideline 423 and GLP principles. Three female rats were exposed to 2000 mg 1,4-H6XDI/ kg bw, which resulted in mortality of two rats on day 2. Decrease in spontaneous movement on day 1 was the only clinical sign observed in this group. The surviving animals showed decreased body weight, but regained body weight from day 4. Two groups of 3 females were exposed to 300 mg/kg bw in a step-wise manner. No mortality occurred, no clinical signs were noted. Slight depression in body weight gain was noted on the first day after administration, but this was resolved the next day. No abnormalities in external appearance or in organs/ tissues in the cephalic, thoracic or abdominal regions were noted. Based on these results, the oral LD50 of 1,4-H6XDI was found to be > 300 mg/kg bw.

An acute inhalation toxicity was performed equivalent to OECD 403 with 1,3H6XDI. Five male and female rats were exposed to aerosols for 4 hours (whole body exposure) and followed for 14 days.Mortality was 0, 2, 1, 0, 9 and 10 rats at 0, 72.7, 114.7, 147.1, 239.1 and 531.6 mg/m3. The time of death correlated with exposure consentration. During exposure, rats showed salivation, lacrimation, hunched or prone posture, peripheral vasodilation and laboured breathing (gasping at two highest doses). The rapidity of onset of these reactions was related to the exposure level. During observation period, laboured breathing and rales were observed in all exposed animals. Brown staining (or dark red discharge) around snouts and peripheral vasodilation was observed in all rats 3 days post exposure. Persistence of the observations was dependent on exposure concentration. Dose-dependent decrease in body weight gain was noted during first 3 to 5 days after exposure. Subsequent body weight gain was comparable to that of the control rats for rats dosed at 72.7 and 114.7 mg/m3, but for rats dosed higher body weight gain remained lower, or further decreased (at 239.1 mg/m3). Gross macroscopy revealed substance related effects in the lungs (oedema and hepatisation, dose-dependent severity). This result is read across to 1,4-H6XDI.

An acute dermal toxicity study was performed comparable to with male and female rats. The test was performed with analogue 1,3-H6XDI. No mortality occurred at 5000 mg/kg bw. Hunched posture and abnormal gait (waddling) were noted for treated animals (resolved by day 5). Depressed body weight gains compared to controls were seen for treated males in the first week, and for treated females in the second week of observation. Slight or well-defined oedema, accompanied by dryness and sloughing of the epidermis was observed in all test substance treated animals on the second day after removal. A gradual increase in severity of the reactions was observed and "in depth" skin damage was observed in four rats by day 10 and in three further rats by day 12. Well-defined to moderate erythema accompanied by well-defined oedema was seen in the remaining animals. Skin effects were also seen at autopsy: one treated male and three treated females were found to have congestion of the subcutaneous blood vessels under the site of application. Based on these data, the LD50 of 1,3-H6XDI is expected to exceed 5000 mg/kg bw. This result is read across to 1,4-H6XDI.

Justification for classification or non-classification

The oral LD50 of 1,4-H6XDI was found to be > 300 mg/kg bw and therefore 1,4 -H6XDI is classified category 4 for acute oral toxicity according to Regulation EC 1272/2008.

As the LC50 of 1,4-H6XDI was considerd to be > 147.1 mg/m3 and < 239 mg/m3, which correlates to > 0.147 mg/L and < 0.239 mg/L, 1,4H6XDI is classified as category 2 for inhalation toxicity according to Regulation EC 1272/2008.

1,4 -H6XDI is not classified for acute dermal toxicity.