Registration Dossier

Administrative data

Description of key information

oral: LD50 (rat) = 8000 mg/kg bw
inhalation: LD50 (rat) > 3.55 mg/L (6h), read across
dermal: LD50 (rabbit) >= 15.2 g/kg, read across

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is comparable to OECD Guideline 401 with acceptable restrictions (partly limited documentation, e.g. no details about the test substance; post exposure observation period 7 days)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Mean body weight at initiation: 180-208g (males), 144-170g (females)
No further details.
Route of administration:
oral: gavage
Vehicle:
other: aqueous suspension with 0.5% carboxymethylcellulose
Details on oral exposure:
concentration in test solution 35%; application volume 28.5 or 13.3 ml/kg bw, respectively; no data about fasting prior to application.

Doses:
4640 or 10000 mg/kg bw
No. of animals per sex per dose:
5 males and 5 females per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations:daily
- weighing: day 0, 2, or 7
- Necropsy of survivors and rats found dead
Statistics:
no data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
8 000 mg/kg bw
Remarks on result:
other: for males and females combined
Mortality:
Data on mortality are presented in the Table below. At the high dose levels rats died within 4 h as well as one female at the low dose level. Females more susceptible than males.
Clinical signs:
Clinical signs in both dose groups: immediately after gavage prone and side position, apathy, atony, gasping, cyanosis; 2nd day red encrusted noses; symptoms still present after 2 days. No symptoms detected 5 days after application.
Body weight:
No effects on body weight gain.
Gross pathology:
Surviving rats: darkened liver and some cases of splenomegaly.
Rats found dead: dilatation of the heart; hyperemia
Other findings:
no data

Mortality in male and female rats after gavage; observation period 7 days

 Dose in mg/kg bw  Males  Females
 4640  0/5  1/5
 10000  3/5  4/5
Conclusions:
The oral LD50 is 8000 mg/kg bw in male and female rats combined.
Executive summary:

The study is comparable to OECD Guideline 401 with acceptable restrictions (partly limited documentation, e.g. no details about the test substance; post exposure observation period 7 days)

Groups of 5 male and 5 female rats were gavaged with 35% aqueous suspension at dose levels of 4640 and 10000 mg/kg bw. The post exposure observation period was 7 days. Clinical signs occurred immediately after gavage: prone and side position, apathy, atony, gasping, cyanosis, and 2nd day red encrusted noses; symptoms were still present after 2 days. No symptoms were detected 5 days after application.. Generally, females were more susceptible than males. The body weight gain was not reduced. Necropsy revealed dilatated heart and some cases of splenomegaly.

Conclusion: The oral LD50 is 8000 mg/kg bw in male and female rats combined.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
8 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Data for the structural analogon Texanol from a collection of data (OECD/SIDS 1994) with limited details.
Principles of method if other than guideline:
Animals were exposed for 6 h to an atmosphere generated by passing air (3.5 L/min) through the test material heated to 100 °C. Eastman Kodak Company Laboratory of Industrial Medicine Protocol.
GLP compliance:
no
Species:
rat
Strain:
not specified
Sex:
not specified
Route of administration:
inhalation
Type of inhalation exposure:
not specified
Duration of exposure:
6
Concentrations:
2.73 and 3.55 mg/L
No. of animals per sex per dose:
3rats/group
Control animals:
no
Dose descriptor:
LC0
Effect level:
> 3.55 mg/L air
Exp. duration:
6 h

Two groups of animals (3 rats/group) were exposed to nominal concentrations of either 2.73 or 3.55 mg/L. There were no abnormal clinical signs or mortality observed.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating conc.
3 550 mg/m³

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data for the structural analogon Texanol from a collection of data (OECD/SIDS 1994) with limited details.
Qualifier:
no guideline followed
Principles of method if other than guideline:
The test chemical was applied to the skin under an impervious plastic film for 24 h. Animals were observerd for 14 days following dosing. Melon Institute Protocol.
GLP compliance:
no
Remarks:
Test predates GLP.
Limit test:
no
Species:
rabbit
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
no further data
Type of coverage:
other: pervious
Duration of exposure:
24 h
Doses:
16 ml/kg (with density of 0.95 g/cm3: 15.2 g/kg bw)
No. of animals per sex per dose:
no details
Control animals:
not specified
Dose descriptor:
LD50
Effect level:
>= 15 200 mg/kg bw

Dermal LD50 to rabbits was reported as >= 16 mL/kg (15.2 g/kg). No further details.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
15 200 mg/kg bw

Additional information

ORAL:

The study (BASF AG, 1974) is comparable to OECD Guideline 401 with acceptable restrictions (partly limited documentation, e.g. no details about the test substance; post exposure observation period 7 days). Groups of 5 male and 5 female rats were gavaged with 35 % aqueous HPN (CAS 1115 -20 -4) at dose levels of 4640 and 10000 mg/kg bw with a post exposure observation period of 7 days. Clinical signs occurred immediately after gavage: prone and side position, apathy, atony, gasping, cyanosis, and 2nd day red encrusted noses; symptoms were still present after 2 days. No symptoms were detected 5 days after application. Generally, females were more susceptible than males. The body weight gain was not reduced. Necropsy revealed dilatated heart and some cases of splenomegaly. The oral LD50 is 8000 mg/kg bw in male and female rats combined.

 

INHALATION:

In the available acute inhalation toxicity test (BASF test, 1974) for HPN (CAS 1115 -20 -4) rats were exposed for 8h to HPN dust, generated at 20 °C (estimated concentration 0.05 mg/L). The mortality rate was 0/6 in males and 0/6 in females. No clinical signs were observed during and after exposure. Necropsy after 7 days revealed no treatment related effects. The test demonstrates that there is no relevant acute inhalation risk, when handling the substance without extensive dust formation. However the test system is unsuitable concerning information going beyond this statement.

Supportingly, the study with the structural analogon Texanol (CAS 25265 -77 -4) (Eastman Kodak Company Reports 1960, summarized in the OECD/SIDS 1994) revealed no abnormal clinical signs or mortality in rats after 6 h exposure with nominal concentrations of 2.73 or 3.55 mg/L.

A study with the metabolite NPG (CAS 126 -30 -7) (Eastman Kodak Company Reports 1963, published by NIOSH 1982) supported these data: Three rats exposed for 6 h to 39400 ppm (168 mg/L) showed symptoms of irritation of the respiratory tract, laboured respirations, accelerated respiration, loss of coordination and prostration during the exposure period. One out of 3 rats died within 24 h, the other survived the post exposure observation period of 14 days (increased body weight, no necropsy).

 

DERMAL:

There are no data for acute dermal toxicity of HPN available. But in a study with the structural analogon Texanol (CAS 25265 -77 -4), published by Carpenter et al. in 1974 (summarized in the OECDE/SIDS 1994), the dermal LD50 for New Zealand rabbits was >= 15.2 g/kg bw after 24 h semiocclusive exposure.


Justification for selection of acute toxicity – inhalation endpoint
Read across to Texanol.

Justification for selection of acute toxicity – dermal endpoint
Read across to Texanol.

Justification for classification or non-classification

Due to the results from the acute toxicity studies with HPN and its read across substances, classification and labelling according to Annex VI of Directive 67/548/EWG or Annex I of Directive 1272/2008 (EU-GHS) is not required for HPN (= 3-hydroxy-2,2-dimethyl-propyl- 3'-hydroxy-2',2'dimethylpropionate), because - if mortality was observed - it occured above threshold for classification and labeling.