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Description of key information

Repeated dose oral:
A 28-day oral toxicity study (Smith, 1989) was available which is key study. This study showed that No Observed Adverse Effect Level (NOAEL) for the test substance is 100 mg/kg/day.
A 90-day oral (capsule) toxicity study with dog (Liao, 1991) which run on analog substance N-(n-octyl)-2-pyrrolidinone (2687-94-7) is available which is key study. The NOAEL was 30 mg/kg bw/day.
Repeated dose inhalation:
Endpoint waived as the substance is corrosive to the skin.
Repeated dose dermal:
A repeated dose dermal study (Busch, 1987) used 2% w/v suspension in distilled water was available which is supporting study. This study showed that a mean comedogenic grade of ≥ 2.0 in rabbits.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
38 mg/kg bw/day
Study duration:
subacute
Species:
dog
Quality of whole database:
The No Observed Adverse Effect Level (NOAEL) for the analogue was 30 mg/kg bw/day, corrected for the molecular weight of N-(n-dodecyl)pyrrolidinone the NOAEL is 38 mg/kg bw/day.

Additional information

Repeated dose oral:

A 28 -day oral toxicity study had no guideline using rat (Smith, 1989). Key study.

This study showed that No Observed Adverse Effect Level (NOAEL) for the test substance is 100 mg/kg/day.

A 90-day oral (capsule) toxicity studies with dog (Liao, 1991) which run on analog substance N-(n-octyl)-2-pyrrolidinone (2687-94-7) was conducted according to EPA OPP 82-1 (90-Day Oral Toxicity). Key study. This study showed that No Observed Adverse Effect Level (NOAEL) for the test substance is 30 mg/kg bw/day for N-(n-octyl)-2-pyrrolidinone corresponding to 38 mg/kg bw/day for N-(n-dodecyl)-2-pyrrolidinone. The Lowest Observed Adverse Effect Level (LOAEL) in dogs is 90 mg/kg bw/day for N-(n-octyl)-2-pyrrolidinone corresponding to 115 mg/kg bw/day for N-(n-dodecyl)-2-pyrrolidinone.

The table below summarizes the repeated dose oral toxicity studies performed with either of the two molecules. Taking note of the direct comparison of the 28-day toxicity studies in rat (100 mg/kg bw/d for N-(n-dodecyl)pyrrolidinone and 55 mg/kg bw/d for N-(n-octyl)-2-pyrrolidinone) and furthermore making allowance for the difference in duration between 28-day and 90-day studies, the NOAELs are considered to be broadly comparable. In fact, the toxic potency of N-(n-octyl)-2-pyrrolidinone appears to be higher than that of N-(n-dodecyl)pyrrolidinone. This supports the assumption that read across from the first to the second molecule is overprotective. The final No Observed Adverse Effect Level (NOAEL) for N-(n-octyl)-2-pyrrolidinone of 30 mg/kg bw/day was based on the 90-day study in dogs. Corrected for the molecular weight of N-(n-dodecyl)pyrrolidinone the extrapolated NOAEL is 38 mg/kg bw/day.

Existing repeat dose toxicity studies are available on both substances:

Substance

N-(n-dodecyl)pyrrolidinone

N-(n-octyl)-2-pyrrolidinone

Duration

28 day

90 day

28 day

90 day

Route

Oral gavage

Oral capsule

Oral gavage

Dietary

Species

Rat

Dog

Rat

Rat

NOAEL (mg/kg bw/d)

100

30

55

33 – 69

Reference

Smith, 1989a

Liao, 1991b

Smith, 1989b

Liao, 1991a

 

Reapeated dose inhalation:

According to REACH Annex VIII column 2 this endpoint is waived as: the substance is classified as corrosive to the skin and the vapour pressure of the test substance has been determined as: 0.00204 Pa at 25℃.

Repeated dose dermal:

This endpoint waived due to positive skin corrosion classification.

A repeated dose dermal study was conducted according to 21 CFR Part 58 (Busch, 1987). Supporting study.

This study is primarily a Comedogenic study and so is conducted at low doses and investigations focussed on dermal reactions. While well run is not considered suitable to address this endpoint in isolation. It showed that a mean comedogenic grade of ≥ 2.0 in rabbits.

Justification for classification or non-classification

Repeated dose toxicity: Oral. The NOEL for the 28-day study with N-(n-dodecyl)-2-pyrrolidinone in rats was 100 mg/kg/day, while the LOEL was 1000 mg/kg/day. In addition, the 90 -day NOEL for rats was > 10 mg/kg/day and the LOEL calculated for dogs was > 100 mg/kg/day, both based on the studies with the analog N-(n-octyl)-2-pyrrolidinone. Application of the CLP Criteria (version 4.0, 2013) "STOT-RE clasification is assigned on the basis of findings of ‘significant’ or ‘severe’ toxicity. In this context ‘significant’ means changes which clearly indicate functional disturbance or morphological changes which are toxicologically relevant." Hence, these data were not considered as sufficient evidence for a STOT-RE classification in Category 2.