Paraffins (petroleum), normal C>10

Neurotoxicity

Administrative data

Endpoint:

neurotoxicity

Remarks:

subacute

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

1993/04/20-1993/04/27

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well-documented study report which meets basic scientific principles.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1993

Report date:

1993

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 424 (Neurotoxicity Study in Rodents)

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Hydrocarbons, C11-C14, n-alkanes, < 2% aromatics

IUPAC Name:

Hydrocarbons, C11-C14, n-alkanes, < 2% aromatics

Details on test material:

- Name of Test Material (in study): MRD-92-405
- Analytical purity: Assumed 100% pure
- Description: Colorless liquid
- Storage: Room Temperature

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hazelton Research Products
- Age at study initiation: Males: 13 weeks; Females: 11-12 weeks
- Weight at study initiation: Males: 1.96-2.19 g; Females: 1.90-2.26g
- Housing: Single Housed
- Diet (e.g. ad libitum): Agway Certified Diet RCA Rabbit, restricted feeding
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 65 to 70
- Humidity (%): 40 to 60
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

other: occlusive

Vehicle:

unchanged (no vehicle)

Details on exposure:

TEST SITE
- Area of exposure: dorsal surface
- % coverage: 10
- Type of wrap if used: appled under the gauze patch and secured with a piece of Saran wrap
- Time intervals for shavings or clipplings: twice per week


REMOVAL OF TEST SUBSTANCE
- Washing (if done): washed the dosed site with 1.0% mixture of baby shampoo
- Time after start of exposure: after 6 hours of exposure, the test material was washed off

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

6 hours a day; applied once a day for the duration of the experiment

Frequency of treatment:

once a day

Doses / concentrations

Remarks:

Doses / Concentrations:
doses: 500, 1000, 2000 mg/kg positive control (n-hexane): 2000 mg/kg
Basis:
nominal conc.

No. of animals per sex per dose:

2 males and 2 females per treatment group

Control animals:

yes, concurrent no treatment

Details on study design:

The study was conducted to assess the dermal irritation potential and systemic toxicity of repeated topical application of MRD-92-405 at dose levels of 500, 1000, and 2000 mg/kg in the rabbit when administered daily for 7 days. Four groups consisting of 2 rabbits/sex/group were used. To serve as a comparison control, one group of animals was treated with n-hexane.

Clinical observations were made daily as to the nature, onset, severity, and duration of toxicological signs. Dermal irritation was assessed prior to dosing on days 0, 4, and 7 and immediately after dosing on Day 0. Body weights were recorded the week prior to dosing, on day 0 and day 7. Food consumption was measured once during the test period. The study was terminated after 7 days of dosing and all rabbits in the 2000 mg/kg group and n-hexane group were subjected to whole body perfusion fixation. A modified gross necropsy, which did not include examination of the cranial cavity, was conducted on each of these animals. A gross necropsy was performed on the 500, 1000 mg/kg dosed animals and tissues with gross abnormalities were taken and preserved. Positive control (n-hexane): 2000 mg/kg

Examinations

Observations and clinical examinations performed and frequency:

Clinical observations were made daily as to the nature, onset, severity, and duration of toxicological signs. Dermal irritation was assessed prior to dosing on days 0, 4, and 7 and immediately after dosing on Day 0. Body weights were recorded the week prior to dosing, on day 0 and day 7. Food consumption was measured once during the test period.

Sacrifice and (histo)pathology:

The study was terminated after 7 days of dosing and all rabbits in the 2000 mg/kg group and n-hexane group were subjected to whole body perfusion fixation. A modified gross necropsy, which did not include examination of the cranial cavity, was conducted on each of these animals. A gross necropsy was performed on the 500, 1000 mg/kg dosed animals and tissues with gross abnormalities were taken and preserved.

Statistics:

Means and standard deviations of body weight, body weight change, and food consumption.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Clinical biochemistry findings:

not examined

Behaviour (functional findings):

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
All animals survived to the end of the study. All animals in the 1000 and 2000 mg/kg dose groups were observed with erythema, ranging from very slight to severe, throughout the study. The severity of erythema for these two groups increased as the study progressed. Two of the four 500 mg/kg dose group animals were observed with very slight to well-defined erythema on days 4 and 7. All animals in the n-hexane group were observed with erythema on days 4 and 7, ranging from very slight to severe. One n-hexane group animal was observed with very slight erythema on day 0. Edema, ranging from very slight to slight, was observed in all dose groups on days 4 and 7. Supplemental dermal observations consisting of desquamation and/or exfoliation, atonia, and cracking were observed in all dose groups on day 7. Fissuring was observed in the 1000 mg/kg and 2000 mg/kg groups and in the n-hexane group. One n-hexane dose group animal was observed with eschar on day 7. No additional observable abnormal clinical signs were noted in treated animals except for one female animal that was observed with mucoidal stool on day 2.

BODY WEIGHT AND WEIGHT GAIN
There were small decreases in body weight from the day 0 weights observed in individual animals from all groups.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
There were no apparent differences in food consumption between the groups.

GROSS PATHOLOGY
Dermal irritation was the most significant postmortem finding and was consistent with the supplemental dermal observations noted. No other finding was considered the result of test material administration.

NEUROTOXICITY
Topical application of MRD-92-405 for seven days did not cause any gross signs of neurotoxicity.

Effect levels

Dose descriptor:

NOAEC

Remarks:

LD50

Effect level:

>= 2 000 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: no sub-acute neurotoxicity noted

Remarks on result:

other:

Applicant's summary and conclusion

Conclusions:

Dermal application of 2000mg/kg MRD-92-405 for seven days did not cause any gross signs of neurotoxicity or any clinical signs except for skin irritation. All animals survived to study termination; NOAEC >2000 mg/kg.

Executive summary:

The study was conducted to assess the dermal irritation potential and systemic toxicity of repeated topical application of MRD-92-405 at dose levels of 500, 1000, and 2000 mg/kg in the rabbit when administered daily for 7 days. Four groups consisting of 2 rabbits/sex/group were used. To serve as a comparison control, one group of animals was treated with n-hexane. Dermal application of 2000mg/kg MRD-92-405 for seven days did not cause any gross signs of neurotoxicity or any clinical signs except for skin irritation, with erythema ranging from very slight to severe. All animals survived to study termination; NOAEC >2000 mg/kg.