Benzene, mono-C10-14-alkyl derivs., fractionation bottoms, intermediate cut, sulfonated, sodium salts

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was not conducted to recognised guidelines, nor to GLP. The study report was unclear in places.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1981

Report date:

1981

Materials and methods

Test guideline

Qualifier:

no guideline followed

Deviations:

yes

Remarks:

only two treatment doeses were included (guidleine reccomends 3) Elizerabethan collars were used to prevent ingestion. The test site was not covered with a gauze patch

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

71786-47-5

Cas Number:

71786-47-5

IUPAC Name:

71786-47-5

Constituent 2

Reference substance name:

alkaryl magnesium salt derivatives

IUPAC Name:

alkaryl magnesium salt derivatives

Details on test material:

The test item belongs to the same chemical group as the submission substance (aryl/alkyl sulfonates).

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: HARE Rabbits for Research
- Weight at study initiation: males, 1.6-2.8kg; females, 1.6-2.5kg
- Housing: Individually in stainless steel cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 10-24°C
- Humidity (%): 17-65%
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle

Administration / exposure

Type of coverage:

open

Vehicle:

other: mineral oil

Details on exposure:

TEST SITE
- Area of exposure: 6.5 x 5 cm
- Surface area: 25%
- Time intervals for shavings or clipplings: Monday and Thursday of each week


REMOVAL OF TEST SUBSTANCE
- Washing (if done): Wiping with paper towels
- Time after start of exposure: 6 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2 ml/kg

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

6 hours

Frequency of treatment:

5 times per week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 25, 100 %
Basis:
other: w/v in primol 205

No. of animals per sex per dose:

15

Control animals:

yes, concurrent vehicle

Positive control:

none

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly


DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: Daily


BODY WEIGHT: Yes
- Time schedule for examinations: Weekly


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


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


WATER CONSUMPTION: No
- Time schedule for examinations:


OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:


HAEMATOLOGY: Yes
- Time schedule for collection of blood: Termination
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: Termination 10/sex/group


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
- Animals fasted: Yes
- How many animals:Termination: 10/sex/group


URINALYSIS: No
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.


NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Statistics:

ANOVA with Dunnett's test
Regression analysis
Kruskal-Walis and Dunn's summed rank test
Joncheere's test for monotonic trend

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Dermal irritation:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

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:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
There were a number of mortalities in the study, One control and four high dose animals died or were sacrificed early in the study. One control female was sacrificed during the recovery phase. Two high dose males were sacrificed moribund during the treatment period. one high dose male was found dead during recovery. One high dose female was sacrificed during recovery. Cause of death was not established.

Alopecia was observed throughout the study in treated animals. In addition there were numerous incidences of erythema, oedema, atonia, desquamation, fissuring and exfoliation in treated animals but without dose response. These findings decreased in recovery phase.

BODY WEIGHT AND WEIGHT GAIN
Mean body weights were slightly reduced in treated groups but evaluation is confounded by the small number of animals.

FOOD CONSUMPTION
Not recorded

FOOD EFFICIENCY
Not recorded

WATER CONSUMPTION
Not recorded

OPHTHALMOSCOPIC EXAMINATION
Not recorded

HAEMATOLOGY
The mean total leukocyte count of low and high dose females was lower at termination of treatment. Mean haemaglobin and haemocrit values and mean erythrocyte counts were also reduced.

CLINICAL CHEMISTRY
Decreases in total protein and globulin levels occurred.

URINALYSIS
Not recorded

NEUROBEHAVIOUR
Not recorded

ORGAN WEIGHTS
Absolute and relative weights of testes and epididymis were decreased in low and high dose males, together with increases in mean and absolute liver weights.

GROSS PATHOLOGY
Discolouration of the liver was observed in males and females. Testes were small.

HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopic examination revealed treatment related morphological changes in the skin, testes, epididymis and possibly liver.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Not recorded

HISTORICAL CONTROL DATA (if applicable)
Not recorded

Effect levels

1

Dose descriptor:

NOAEL

Basis for effect level:

other: Effects were observed at the lowest dose tested, therefore a NOAEL cannot be identified from this study.

Remarks on result:

not determinable

Remarks:

no NOAEL identified

2

Dose descriptor:

LOAEL

Effect level:

< 250 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: Effects observed at the lowest dose, therefore an arbitary LOAEL has been identified.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 1: Incidence of selected pathologies

 

Parameter	n=10/sex	Dose level
		Control	25	100	Recovery control	Recovery 25	Recovery 100
Small testis	M	0/10	3/10	6/13	0/5	0/5	1/3

 

Table 2: Absolute and relative organ weights

 

		Males				Females
DAILY DOSE (units e.g. mg/kg bw/day)		0	25	100	0		25	100
NUMBER OF ANIMALS		10	10	10	10		10	10
BODY WEIGHT (g)^a		-	-	-	-		-	-
LIVER
Absolute Weight^a	g	70.850	74.006	92.314	73.677		82.772	90.501
Per Body Weight^a	%	2.93	3.11	3.83	2.72		3.05	3.95
TESTES					n.a.^b		n.a.^b	n.a.^b
Absolute Weight^a	g	3.047	2.421	1.997	n.a.^b		n.a.^b	n.a.^b
Per Body Weight^a	%	12.49	10.16	7.76	n.a.^b		n.a.^b	n.a.^b

 

^aGroup means at the end of terminal necropsy are shown.

^bn.a. = not applicable

* p<0.05, ** p<0.01

Applicant's summary and conclusion

Conclusions:

Toxicity occurred at all doses tested, therefore a NOAEL has not been identified. an arbitary LOAEL of 250 mg/kg bw has been identified, based on effects at the lowest dose.

Executive summary:

In a  repeat-dose dermal toxicity study,  an alkaryl magnesium salt derivative was applied to the shaved skin of 15white rabbits/sex/dose at dose levels of 0, 25 and 100%, 6 hours/day for 5 days/week during a 28-day period.

 

A NOAEL cannot be identified from this study, as effects were observed at the lowest dose.

 

This dermal toxicity study in the rabbit is acceptable.