Registration Dossier

Administrative data

Description of key information

Acute oral rat, similar to OECD TG 401: LD50 > 3000 mg/kg bw  
Acute toxicity inhalation, route to route extrapolation, LD50: >21000 mg/m3
Acute toxicity dermal, similar to OECD TG 402: LD50 > 6500 mg/kg bw
- Standard acute method (limit test): LD50 > 6.5 g/kg bw (equivalent or similar to OECD402)

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:
From 7 JUNE 1977 to 12 AUGUST 1977
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study was conducted prior to GLP and OECD guidelines but was conducted according to acceptable procedures at the time.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
Shorter observation time than recommended in OECD guideline 401: 7 days vs. 14 days
GLP compliance:
not specified
Remarks:
This study was prior to GLP and OECD guidelines but was conducted according to acceptable procedures at the time.
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 104-141 grams
- Fasting period before study: YES, overnight
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Doses:
0.215, 0.464, 1.0, 2.15 and 4.64 g/kg bw Galaxolide 50, equivalent to doses of HHCB of 0.14, 0.30, 0.65, 1.4 and 3.0 g/kg when corrected for the 65% dilution).
No. of animals per sex per dose:
5 females per dose
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: Immediately after dosing at one, four and 24 hrs and once daily thereafter for a total of 7 days.
- Necropsy of survivors performed: yes
Statistics:
Mortality data was analyzed statistically, utilizing the tables of Horn, HJ. Biometrics 12, 311, 1956.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 4 640 mg/kg bw
Remarks on result:
other: The LD50 was >3 g/kg BW expressed in HHCB equivalents.
Mortality:
There was one death as a result of gavage error at 1.0 g/kg but no deaths at any other dose
Clinical signs:
One animal at 2.15 g/kg appeared distressed shortly after dosing but appeared normal after 2h. There were no effects at the high dose.

Table 1: mortaility in the study.

Time of death Time of death
Dose (g/kg) Concentration (%) Immediate Hours (1-24) Days (2-7)
0.215 100 0/5 0/5 0/5
0.464 100 0/5 0/5 0/5
1 100 0/5 1/5 1/5
2.15 100 0/5 0/5 0/5
4.64 100 0/5 0/5 0/5

LD50= >4.64 g/kg total product

Since 50% active LD50= >2.15 g/kg

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
The material does not need to be classified for acute oral toxicity.
Executive summary:

Galaxolide 50 (Non-GLP; 65% HHCB in diethyl phthalate (DEP)) was administered undiluted (hence, there was variation in volume of dosing) by oral intubation at doses of 0.215, 0.464, 1.0, 2.15 or 4.64 g/kg bw (equivalent to doses of HHCB of 0.14, 0.30, 0.65, 1.4, 3.0 g/kg when corrected for the 65% dilution) to groups of 5 female Charles River Sprague Dawley rats (initial bodyweight 104–141 grams) that were then observed for mortality and signs of effects for 7 days. There was one death as a result of gavage error at 1.0 g/kg but no deaths at any other dose. One animal at 2.15 g/kg appeared distressed shortly after dosing but appeared normal after 2 hr. There were no effects at the high dose. An LD50of >4.64 g/kg bw (equivalent to >3 g/kg bw HHCB) was calculated. This study was conducted prior to GLP and OECD guidelines but was conducted according to acceptable procedures at the time.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Quality of whole database:
The information is adequate for this Annex X dossier.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information is adequate for this Annex X dossier.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 7 JUNE 1977 to 12 AUG 1977
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study was carried out prior to GLP and OECD guidelines but was conducted according to acceptable procedure at that time.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
Animals used where lighter than described in OECD guideline 402. 108 - 187 grams vs 200 - 300 grams
GLP compliance:
not specified
Remarks:
This study was carried out prior to GLP and OECD guidelines but was conducted according to acceptable procedures at that time.
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
Initial bodyweight 108-187 g
Type of coverage:
not specified
Vehicle:
unchanged (no vehicle)
Duration of exposure:
7 days
Doses:
0.464, 1.0, 2.15, 4.64 and 10.0 g/kg bw Galaxolide 50, equivalent to doses of HHCB of 0.30, 0.65, 1.4, 3.0 and 6.5 g/kg when corrected for the 65% dilution
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: Immediately after dosing at one, four and 24 hrs and once daily thereafter for a total of 7 days.
- Necropsy of survivors performed: yes
Statistics:
Mortality data was analyzed statistically, utilizing the tables of Horn, HJ. Biometrics 12, 311, 1956.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 10 000 mg/kg bw
Remarks on result:
other: The LD50 was > 6500 mg/kg BW expressed in HHCB equivalents.
Mortality:
There were no deaths at any dose.
Clinical signs:
All animals in the high dose group exhibited urine staining on their fur.
Gross pathology:
There were no major effects noted in any of the animals in any dosage level.
Table 1: Mortalility in the study.
  Time of death Time of death Time of death
   Dose (g/kg)   Concentrations (%)   Immediate Hours (1 -24)   Days (2 -7)
 0.464 100  0/5  0/5  0/5 
100  0/5  0/5  0/5 
2.15 100 0/5  0/5  0/5 
4.64  100  0/5  0/5  0/5 
10  100 0/5  0/5  0/5 

LD50= > 10 g/kg total product

Since 50% active, LD50 = > 5 g/kg

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
The material does not need to be classified for acute dermal toxicity
Executive summary:

Galaxolide 50 (65% HHCB in DEP) was administered undiluted by inunction to the shaved skin (area not reported) of groups of five female Charles River Sprague Dawley rats (initial bodyweight 108–187 g) in doses of 0.464, 1.0, 2.15, 4.64 or 10.0 g/kg bw (equivalent to 0.30, 0.65, 1.4, 3.0, 6.5 g/kg HHCB) that were then observed for 7 days. There were no deaths at any dose but all animals in the high dose group exhibited urine staining on their fur. A dermal LD50 of >10.0 g/kg bw (equivalent to >6.5 g/kg bw HHCB) was reported (Minner and Foster, 1977). This study was conducted prior to GLP and OECD guidelines but was conducted according to acceptable procedures at the time.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information is adequate for this Annex X dossier.

Additional information

Acute oral toxicity: Key study: Galaxolide 50 (Non-GLP; 65% HHCB in diethyl phthalate (DEP)) was administered undiluted (hence, there was variation in volume of dosing) by oral intubation at doses of 0.215, 0.464, 1.0, 2.15 or 4.64 g/kg bw (equivalent to doses of HHCB of 0.14, 0.30, 0.65, 1.4, 3.0 g/kg when corrected for the 65% dilution) to groups of 5 female Charles River Sprague Dawley rats (initial bodyweight 104–141 grams) that were then observed for mortality and signs of effects for 7 days. There was one death as a result of gavage error at 1.0 g/kg but no deaths at any other dose. One animal at 2.15 g/kg appeared distressed shortly after dosing but appeared normal after 2 hr. There were no effects at the high dose. An LD50of > 4.64 g/kg bw (equivalent to >3 g/kg bw HHCB) was calculated (Minner and Forster, 1977). This study was conducted prior to GLP and OECD guidelines but was conducted according to acceptable procedures at the time.

Additional information: a supporting study was available which confirmed the findings in the key study (Moreno, 1975).

Acute inhalation toxicity: Based on the acute oral toxicity study, an acute study via the inhalation is waived and an acute toxicity value for this route has been derived using route to route extrapolation.

An acute inhalation toxicity study is not needed for substances with high viscosity (the substance has a viscosity of 12915 mP.s) and acute oral and dermal toxicity values are available. For inhalation, an LD50 of 3000 mg/kg bw can be roughly converted into 21000 mg/per person by multiplying it with a person’s weight: (70 kg). An inhalation volume for one person during 4 h (standard exposure time in the OECD TG for acute inhalation is 5m3(assuming 10m3/8h for workers). This means that an LC50 concentration in 1 m3and 4 hours exposure is 42000 mg/m3 (210000 mg/5m3). Taking into account that during that the absorption during the inhalation route is twice the oral route the LC50 and therefore the LC50 for inhalation could be 21000 mg/m3. When the maximum saturates vapour pressure for HHCB is taken into account, a maximum concentration of 7.72 mg/m3 can be calculated (0.0727 Pa (Vap Pr. HHCB) x 258.2 (MW) / 8.3 (R, gas constant) x 293 (oK) = 7.72 mg/m3). This means that HHCB cannot reach a concentration higher than 7.72 mg/m3. Therefore an LC50 for inhalation cannot be reached and no classification and labelling is needed for the acute inhalation route.

Acute dermal toxicity: Key study: Galaxolide 50 (65% HHCB in DEP) was administered undiluted by inunction to the shaved skin (area not reported) of groups of five female Charles River Sprague Dawley rats (initial bodyweight 108–187 g) in doses of 0.464, 1.0, 2.15, 4.64 or 10.0 g/kg bw (equivalent to 0.30, 0.65, 1.4, 3.0, 6.5 g/kg HHCB) that were then observed for 7 days. There were no deaths at any dose but all animals in the high dose group exhibited urine staining on their fur. A dermal LD50 of >10.0 g/kg bw (equivalent to >6.5 g/kg bw HHCB) was reported (Minner and Foster, 1977). This study was conducted prior to GLP and OECD guidelines but was conducted according to acceptable procedures at the time.

Additional information: a supporting study was available which confirmed the findings in the key study (Moreno, 1975)

(Summary in line with EU-RAR 2008)


Justification for selection of acute toxicity – oral endpoint
Two acute oral toxicity studies were available. The key study was a study performed prior to GLP and OECD guidelines but conducted according to acceptable procedures at that time and considered equivalent to OECD 401.

Justification for selection of acute toxicity – inhalation endpoint
In view of the absence of acute oral effects no acute inhalation effects are anticipated based on route to route extrapolation.

Justification for selection of acute toxicity – dermal endpoint
Two acute dermal toxicity studies were available. The key study was a study performed prior to GLP and OECD guidelines but conducted according to acceptable procedures at that time and considered equivalent to OECD 402.

Justification for classification or non-classification

Based on the oral and dermal LD50 values of > 3000 mg/kg bw and the derived inhalation value of > 21000 mg/m3, HHCB does not need to be classifief for for acute toxicity in accordance with the criteria outlined in Annex VI of 67/548/EEC (DSD) and Annex I of 1272/2008/EC (CLP).