Registration Dossier

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
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 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 car bon, 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 reactivity or availability, and which has chemistry more similar to a branched, perfluorinated alkane than any other structure.  Because these substances exhibit similar phy sicochemical properties they can be considered to constitute a chemical category. The data gap for repeated dose 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:
Version / remarks:
REACH Guidance on QSARs and grouping of chemicals.
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:
-Perfluoro-N-C1,3-alkyl morpholines, CAS# 1093615-61-2

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
No toxicologically relevant clinical signs were observed.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No test article-related mortality occurred during the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
In treated females prior to mating, there was a slight reduction in group mean body weight gains and food consumption over the first two weeks of treatment, compared with Control; these reductions achieved statistical significance in animals treated at 500 and 1000 mg/kg/day. However, absolute body weights and food consumption of the females was also slightly lower than Control prior to the treatment period, and therefore this slight reduction that persisted from commencement of treatment could not be positively attributed to treatment. Group mean body weight gains and food consumption in the males throughout the study, and for females during gestation and lactation were similar to Control.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
In treated females prior to mating, there was a slight reduction in group mean body weight gains and food consumption over the first two weeks of treatment, compared with Control; these reductions achieved statistical significance in animals treated at 500 and 1000 mg/kg/day. However, absolute body weights and food consumption of the females was also slightly lower than Control prior to the treatment period, and therefore this slight reduction that persisted from commencement of treatment could not be positively attributed to treatment. Group mean body weight gains and food consumption in the males throughout the study, and for females during gestation and lactation were similar to Control.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No toxicologically-relevant histopathological findings were observed.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No toxicologically-relevant histopathological findings were observed.

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
All animals mated within one estrous cycle.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
At 1000 mg/kg/day, one animal (Animal 31) had a small right testis and eipdidymis with histological findings of oligospermia, aplasia and marked seminiferous epithelial degeneration. These findings were considered to be typical of the background pathology in young rats of this strain and not related to treatment.
Reproductive performance:
no effects observed
Description (incidence and severity):
Mating performance, fertility, duration of gestation, litter size and survival, and litter and pup weights did not indicate any obvious effect of treatment at any of the dose levels tested.

Effect levels (P0)

Key result
Dose descriptor:
NOEL
Effect level:
ca. 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
histopathology: neoplastic
reproductive function (oestrous cycle)
reproductive function (sperm measures)
reproductive performance
other: No toxicologically-relevant findings were observed at the highest dose administered (1000 mg/kg/day).

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Description (incidence and severity):
No toxicologically relevant clinical signs were observed.
Dermal irritation (if dermal study):
not examined
Description (incidence and severity):
Survival rates of pups were similar to controls.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No toxicologically-relevant body weight effects were observed in the test article-treated pups.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No abnormal externally visible abnormalities were observed at higher rates in any test article-treated pups compared to controls.
Histopathological findings:
not examined

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Effect levels (F1)

Key result
Dose descriptor:
NOEL
Generation:
F1
Effect level:
ca. 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
clinical signs
mortality
body weight and weight gain
gross pathology
other: No toxicologically-relevant findings were observed at the highest dose administered (1000 mg/kg/day).

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
Based on the results of the study, the chemical category of Perfluorinated Organic Chemicals, C5-C18 has a parental and reproductive and developmental No Observed Effect Level (NOEL) of 1000 mg/kg/day.
Executive summary:

Reproductive-Developmental screen results for category member FC-770 (PIPM, CAS# 1093615-61-2) are reported for read-across to the category Perfluorinated Organic Chemicals, C5-C18.  This study evaluated the potential reproduction and/or development effects following treatment with the test article in Sprague Dawley rats. This study was performed in compliance with OECD GLP. The test method was based on OECD 421. The test article was diluted in a vehicle composed of 0.5% Natrosol 250HX and 0.1% Tween 80 in Water for Irrigation. Rats (10/sex/group) received vehicle, 100, 500, or 1000 mg/kg-day of the test article via oral gavage. Males were dosed once daily for 4 weeks overall, commencing 2 weeks prior to mating. Females were dosed once daily from 2 weeks prior to mating and then continued until at least Day 4 of lactation. Females were euthanized with their litters between Days 5 and 6 of lactation. Parameters evaluated: Clinical observations (daily); body weights (weekly and Days 0, 7, 14, 16, 20 of gestation and Days 1 and 4 of lactation for females); food consumption (weekly and Days 0-4 of lactation for females); litter live/dead evaluation (Day 0 of lactation); necropsy; ovary and testis weights; histopathology of ovary, epididymis, and testis of control and 1000 mg/kg-day animals. Reproductive indices were calculated. Pups were examined for external abnormalities. Externally normal pups were discarded at necropsy. Externally abnormal pups were fixed in formalin for possible future analysis. In treated females prior to mating, there was a slight reduction in group mean body weight gains and food consumption over the first two weeks of treatment, compared with control; these reductions achieved statistical significance in animals treated at 500 and 1000 mg/kg-day. However, absolute body weights and food consumption of the females was also slightly lower than control prior to the treatment period, and therefore this slight reduction that persisted from commencement of treatment was not likely attributed to treatment. Group mean body weight gains and food consumption in the males throughout the study, and for females during gestation and lactation were similar to control. Mating performance, fertility, duration of gestation, litter size and survival, and litter and pup weights did not indicate any obvious effect of treatment at any of the dose levels tested. Based on the results of this study, the no observed effect level (NOEL) for adults and for reproductive parameters was considered to be 1000 mg/kg-day.  By read-across, the target substance is also considered to have a NOEL of 1000 mg/kg-day.

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.