Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well conducted published NTP study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2005

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Study conducted according to NTP protocol.Information concerning the used methods can be found at NTP homepage.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
Trimethylolpropane triacrylate (lot 01031AW) was obtained from Aldrich Chemical Company (Milwaukee, WI).
Acetone was used as the vehicle. Analyses of the bulk chemicals are performed. The chemical, a colorless to yellow viscous liquid, was identified as trimethylolpropane triacrylate by the analytical chemistry laboratory using infrared spectrometry and proton and carbon-13 nuclear magnetic resonance (NMR) spectroscopy and by the study laboratory using infrared spectrometry. All spectra were consistent with the
structure of trimethylolpropane triacrylate; the infrared spectrum was also consistent with a literature spectrum.

Test animals

Species:
other: rats and mice
Strain:
other: F344/N rats and B6C3F1 mice
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:Taconic Laboratory Animals and Services (Germantown, NY)
- Age at study initiation: average age 6 weeks
- Housing: single housing in polycarbonate cages (Lab Products, Inc., Maywood, NJ), changed at least once per week, rotated every 2 weeks with SaniChip® hardwood chips (P.J. Murphy Forest Products Corp., Montville, NJ), changed at least once per week and Spun-bonded cage filters DuPont 2024 polyester (Snow Filtration Co., Cincinnati, OH), changed every 2 weeks
- Diet (e.g. ad libitum):NTP-2000 pelleted diet (Zeigler Brothers, Inc., Gardners, PA), available ad libitum, changed weekly
- Water (e.g. ad libitum):Tap water (Columbus municipal supply) via, automatic watering system (Edstrom Industries, Waterford, WI), available
ad libitum
- Acclimation period: Rats: 11 days, Mice: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C (72° ± 3° F)
- Humidity (%): 50% ± 15%
- Air changes (per hr):10/hour
- Photoperiod (hrs dark / hrs light):12 hours/day

IN-LIFE DATES:
- Date of First Dose: Rats: May 6, 1996, Mice: May 7, 1996
- Date of Last Dose: Rats: May 21, 1996, Mice: May 22, 1996
- Necropsy Dates:Rats: Rats: May 22, 1996 Mice: May 23, 1996

Administration / exposure

Type of coverage:
not specified
Vehicle:
acetone
Details on exposure:

REMOVAL OF TEST SUBSTANCE
- Washing (if done):
- Time after start of exposure:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): (dosing volume 0.5 mL/kg for rats and 2 mL/kg for mice
- Dosage: 0, 12.5, 25, 50, 100, or 200 mg/kg in acetone
- Constant volume or concentration used: yes

VEHICLE
- Justification for use and choice of vehicle (if other than water):common high volatile vehicle for dermal application
- Amount(s) applied (volume or weight with unit): see above
- Acetone was obtained in two lots from Honeywell Burdick and Jackson (Muskegon, MI) (lots BK792 and BL631) and in five lots from Spectrum Chemical Manufacturing Corporation (Gardena, CA) (lots JE342, KP206, LS0051, MI0172, and NE0173). Lots BK792, BL631, and JE342 were used in the 2-week studies

USE OF RESTRAINERS FOR PREVENTING INGESTION: no data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Stability studies of the 6.25 and 100 mg/mL dose formulations for the 2-week studies as well as 50 and 400 μg/mL
dose formulations were performed by the study laboratory with GC. GC with flame ionization detection was used ( RTX-5, 30 m x 0.25 mm,0.25 µm film thickness (Restek, Bellefonte, PA, Helium at approximately 3 mL/minute, Oven Programm 70° C for 2.5 minutes, then 9° C/minute to 210° C, held 10 minutes) Stability was confirmed for at least 35 days for dose formulations stored in amber glass bottles with Teflon®-lined lids or septa,
with minimal headspace, at temperatures up to 25° C and for 3 hours under animal room conditions, periodically or
continually exposed to air and light.
The dose formulations were prepared twice (2-week studies) by mixing trimethylolpropane triacrylate and acetone to give the required concentration
Duration of treatment / exposure:
0, 12.5, 25, 50, 100, or 200 mg trimethylolpropane triacrylate/kg body
weight in acetone 5 days per week for 16 days
Frequency of treatment:
5 days per week for 16 days
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
12.5 mg/kg bw
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
25 mg/kg bw
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
50 mg/kg bw
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
100 mg/kg bw
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
200 mg/kg bw
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
common starting concentration based on irritation information
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: initially twice daily
- Cage side observations checked in table were included: No

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:Clinical findings were recorded daily

DERMAL IRRITATION (if dermal study): yes
- detailed skin parameters were measured (see NTP results)

BODY WEIGHT: Yes
- Time schedule for examinations initially, on day 8, and at the end of the studies

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
Histopathologic examinations were performed on the skin (site of application) of all animals and the thymus of all mice
Other examinations:
Necropsies were performed on all animals. Organs weighed were the heart, right kidney, liver, lung, right testis, and thymus
Statistics:
Common statistical approaches were used

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
Dosed rats/mice had irritation at the site of application
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
At necropsy, all dosed rats except 12.5 mg/kg females had crusts at the site of application. For mice crusts were observed grossly at the site of application in 50 mg/kg and greater males and in 100 and 200 mg/kg females.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
effects on skin at application site: Epidermal hyperplasia, hyperkeratosis, and sebaceous gland hyperplasia, chronic active inflammation of the dermis.
Histopathological findings: neoplastic:
not specified
Details on results:
All rats survived to the end of the study. Final mean body weights and body weight gains of all dosed
groups were similar to those of the vehicle control groups. Dosed rats had irritation at the site of application;
this clinical finding was most commonly seen in rats administered 50 mg/kg or greater.


All mice survived to the end of the study. The final mean body weight gain of 200 mg/kg males was significantly less than that of the vehicle controls; final mean body weights of 100 and 200 mg/kg females were significantly increased. Irritation at the site of application
occurred in all dosed males, all 100 and 200 mg/kg males, and one 50 mg/kg female. Thymus weights of male mice administered 50 mg/kg
or greater were significantly decreased.Hyperplasia of the epidermis, hyperkeratosis, dermal chronic active inflammation,
and sebaceous gland hyperplasia occurred in most dosed mice.

For detailed information and raw data please refer to NTP study protocol

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
rats (systemic)
Effect level:
>= 200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No dose related systemic effect observed up to the highest tested concentration
Dose descriptor:
NOAEL
Remarks:
rats (local)
Effect level:
25 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: skin irritation
Dose descriptor:
NOAEL
Remarks:
mice (systemic)
Effect level:
>= 200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOAEL
Remarks:
mice (local)
Effect level:
25 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: irritation

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL (mice/rat, local, dermal): 25mg/kg bw; NOAEL (rat/mice, systemic, dermal):≥ 200mg/kg bw
Executive summary:

Groups of five male and five female F344/N rats were administered 0, 12.5, 25, 50, 100, or 200 mg trimethylolpropane

triacrylate/kg body weight in acetone 5 days per week for 16 days. All rats survived to the end of the study, and mean body weights of dosed groups were similar to those of the vehicle controls. Dosed rats had irritation at the site of application; this clinical finding was most commonly seen in rats administered 50 mg/kg or greater. Male and female rats had epidermal hyperplasia, hyperkeratosis, sebaceous gland hyperplasia, inflammation of the epidermis and dermis, ulceration, epidermal degeneration, and parakeratosis at the site of application.

Groups of five male and five female B6C3F1 mice were administered 0, 12.5, 25, 50, 100, or 200 mg trimethylolpropane

triacrylate/kg body weight in acetone 5 days per week for 16 days. All mice survived to the end of the study. The final mean body weight gain of 200 mg/kg males was less than that of the vehicle controls; 100 and 200 mg/kg females had significantly increased final mean body weights. Irritation at the site of application occurred in all dosed males, all 100 and 200 mg/kg females, and one 50 mg/kg female. Thymus weights of males administered 50 mg/kg or greater were significantly decreased. Dosed male and female mice had epidermal hyperplasia, hyperkeratosis, chronic active inflammation of the dermis, sebaceous gland hyperplasia, ulcer, epidermal degeneration, parakeratosis, and/or suppurative inflammation of the epidermis at the site of application. Atrophy of the thymus occurred in 100 and 200 mg/kg male mice.

According to the applicant opinion the slight reduced thymus weights and reduced body weight and body weight gain observed for mice starting at concentration of 50mg/kg are rated as not adverse.

In summary, based on the available information no test substance related adverse effect can be derived from the reduced bodyweight gain and thymus weights observed for male mice. In consequence to the applicant opinion a NOAEL (rat/mice, systemic, dermal):≥ 200mg/kg bw and NOAEL (mice/rat, local, dermal): 25mg/kg bw can be deduced from this study.