Registration Dossier

Toxicological information

Repeated dose toxicity: inhalation

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
2018
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read-across from data from a guideline study.
Justification for type of information:
MTDID 22327 is a member of the Perfluorinated Organic Chemicals, C5-C18, category. Unlike most members of the category, MTDID 22327 is a UVCB consisting mostly of perfluoro-N-methylmorpholine, a mixture of C5-C7 perfluoroamines, and perfluorohexane isomers. However, all of these chemicals stem from the same manufacturing process, have similar physicochemical properties including high vapor pressure and low water solubility relative to the hydrocarbon analogs (e.g., hexanes v. perfluorohexanes), and also lack any chemically reactive groups, which forms the technical basis for the category. Members of this category are fully fluorinated, meaning that fluorine, rather than hydrogen, is bonded to all carbon atoms in the molecule. Fluorine is the most electronegative of the elements (fluorine has an electronegativity of 3.98 on the Pauling scale, as compared to 2.55 for carbon, 3.04 for nitrogen or 2.20 for hydrogen). This electronegativity is expected to dominate over all other aspects of substance chemistry and is the underlying basis for similarity of substances in this category. For example, strong electron withdrawing in perfluorinated tertiary amines results in a molecule with essentially no lone pair influence, and which has chemistry more similar to a branched, perfluorinated alkane than any other structure. Because these substances exhibit similar physicochemical properties they can be considered to constitute a chemical category. The data gap for repeated dose inhalation toxicity can therefore be addressed by read-across between category members.

Because these substances exhibit similarity in their physicochemical properties and toxicological properties in mammals, and because available data indicates that parent molecules are not reactive toward biological molecules and cannot undergo bioactivation by normal enzymatic processes, they can be considered to constitute a chemical category. Data gaps for partitioning properties, mammalian and ecological toxicity can therefore be addressed by read-across and/or trend analysis between category members. The readacross is considered reliable with restrictions and the result is suitable for use in Risk Assessment, Classification & Labelling, and PBT Analysis. See section 13 for a fuller discussion of the category approach.

Data source

Reference
Reference Type:
other: Read-Across from other internal studies
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: REACH Guidance on QSARs and grouping of chemicals
Version / remarks:
May/July 2008
Deviations:
no
GLP compliance:
no
Remarks:
Source study was conducted under GLP conditions.

Test material

Constituent 1
Reference substance name:
Reaction mass of perfluoro(dimethyl - N - Butylamine ) and perfluoro (methyl - di - N - propylamine) and perfluoro (dimethyl - N - propylamine and 2,2,3,3,5,5,6,6, octafluoro-4-(trifluoromethyl)morpholine and perfluoro-N-pentane
EC Number:
908-205-5
Cas Number:
2187449-42-7
IUPAC Name:
Reaction mass of perfluoro(dimethyl - N - Butylamine ) and perfluoro (methyl - di - N - propylamine) and perfluoro (dimethyl - N - propylamine and 2,2,3,3,5,5,6,6, octafluoro-4-(trifluoromethyl)morpholine and perfluoro-N-pentane
Specific details on test material used for the study:
Read-across from category member:
-Perfluorohexanes, CAS# 1064697-81-9

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
Clinical Signs: During exposure and at other times there were no treatment-releated effects.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Mortality: One rat (female number 84) was found dead in the exposure cage. At necrospy a ruptured spleen with the blood in the abdominal cavity were noted. This death of this rat was considered not related to treatment with the test substance and was probaly traumatic in orgin.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No treatment-related differences between control and exposed groups were observed.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Statistically significant differences from control group consumption were seen between weeks 5 and 13 in male rats from Groups 3 (intermediate dose) and 4 (high dose). The differences were small and were not seen in female rats. In the absense of any significant differences in bodyweight gain it is considered that the differences in food consumption are not of toxicological significance.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
Pre-dose findings were consistent with the age of strain of animals examined. At week 13, no abnormalities were detected.
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
mean corpuscular volume: greater in females from group 3 (intermediate dose) and 4 (high dose).
white cells: lower total numbers in males from groups 3 (intermediate dose) and 4 (high dose) and greater total numbers in females from group 4 (high dose). Lower lymphocyte numbers in males from group 4 (high dose) and greater lymphocyte numbers in females from group 4. These differences were small, inconsistent between the sexes and all values were within normal limits. They are considered not to be of toxicological significance.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Alkaline phosphatase: lower activity in males from group 4 (high dose).
Electrolytes: higher inorganic phosphorus concentration in females from groups 3 (intermediate dose) and 4 (high dose). Lower chloride concentration in males from group 3 (intermediate dose) and males and females from Group 4 (high dose).
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no treatment-related differences seen at week 14.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No changes attributable to treatment with the test substance was seen at the terminal or withdrawal kill.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No histological changes were seen that were considered to be related to exposure to the test substance. The incidental changes that were seen were within the normally expected spontaneous profile for rats of this strain and age and were considered not to be of toxicological significance.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No histological changes were seen that were considered to be related to exposure to the test substance. The incidental changes that were seen were within the normally expected spontaneous profile for rats of this strain and age and were considered not to be of toxicological significance.

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
ca. 50 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
clinical signs
food consumption and compound intake
gross pathology
haematology
histopathology: neoplastic
histopathology: non-neoplastic
mortality
organ weights and organ / body weight ratios
other: No toxicologically-relevant adverse effects were noted in test article-treated rats compared to controls.

Target system / organ toxicity

Key result
Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
Based on the results of the study, the category Perfluorinated Organic Chemicals, C5 -C18 has a 90-day repeated dose inhalation No Observed Adverse Effect Level (NOAEL) of 50,000 ppm.
Executive summary:

The results of a 90 day repeated dose inhalation toxicity study on category member PFHx (CAS# 1064697-81-9) are reported for read across to the category Perfluorinated Organic Chemicals, C5 -C18.  A 90- day inhalation study on the test article was conducted using Albino CD (SD) BR Sprague-Dawley rats. The animals were whole-body exposed to the test substance for six hours a day, five days a week for 13 weeks.The animals were separated into 4 groups:1-control, 2-low dose, 3-intermediate dose, 4-high dose (administered zero, 5000, 15000 and 50000 ppm of the vaporized test substance). There were no toxicologically significant treatment-related signs of mortality, clinical signs of toxicity, bodyweight, food consumption, ophthalmoscopy, biochemistry, macroscopic pathology, organ weights and microscopic pathology. No adverse effects were observed due to test article-treatment up to 50,000 ppm. Based on the results of the study, the category Perfluorinated Organic Chemicals, C5 -C18 has a 90-day repeated dose inhalation No Observed Adverse Effect Level (NOAEL) of 50,000 ppm.

Study conducted under GLP conditions.   Because these substances exhibit similarity in their physicochemical properties and toxicological properties in mammals, and because available data indicates that parent molecules are not reactive toward biological molecules and cannot undergo bioactivation by normal enzymatic processes, they can be considered to constitute a chemical category. Data gaps for partitioning properties, mammalian and ecological toxicity can therefore be addressed by read across and/or trend analysis between category members.  The readacross is considered reliable with restrictions and the result is suitable for use in Risk Assessment, Classification & Labelling, and PBT Analysis.