Registration Dossier

Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restrictions because it was carried out in a method equivalent/similar to OECD TG 421.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Toxicity evaluation of petroleum blending streams: reproductive and developmental effects of hydrodesulfurized kerosine
Author:
Schreiner, C., Bui, Q., Breglia, R., Burnett, D., Koschier, F., Podhasky, P., Lapadula, L., White, R., Feuston, M., Krueger, A., Rodriguez, S.
Year:
1997
Bibliographic source:
Journal of Toxicology and Environmental Health 52:211-229
Reference Type:
study report
Title:
Unnamed
Year:
1995

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OTS 798.4900 (Prenatal Developmental Toxicity Study)
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
Kerosine (petroleum), hydrodesulfurized
EC Number:
265-184-9
EC Name:
Kerosine (petroleum), hydrodesulfurized
Cas Number:
64742-81-0
IUPAC Name:
Kerosine (petroleum), hydrodesulfurized
Constituent 2
Reference substance name:
hydrodesulphurised kerosine
IUPAC Name:
hydrodesulphurised kerosine
Test material form:
other: low viscosity liquid hydrocarbon
Details on test material:
- Name of test material (as cited in study report): Hydrodesulfurised kerosine, CAS No. 64742-81-0
Other: The chemical composition of the sample of hydrodesulfurised kerosine was determined by ASTM method D 1319-1 and the results are tabulated below.
Component Weight % Nonaromatics 80.27 Saturates 78.61 Olefins 1.66 Aromatics 19.72 <3-ring PAC >19.72 3-7 -ring PAC <0.01

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS- Source: Charles River Breeding Laboratories, Kingston, New York-
Age at study initiation: Females were approximately 8 weeks old
Weight at study initiation: Females: 183 to 187 grams
Use of restrainers for preventing ingestion (if dermal): yes
Diet (e.g. ad libitum): ad libitum
Water (e.g. ad libitum): ad libitum
Acclimation period: 12 days
ENVIRONMENTAL CONDITIONS
Temperature (°C): 20 to 22
Humidity (%): 40 to 60%
Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light

Administration / exposure

Route of administration:
dermal
Vehicle:
other: mineral oil (340 SUS)
Details on exposure:
TEST SITE
Area of exposure: Entire dorsal back
Type of wrap if used: None
Time intervals for shavings or clippings: Once a week

REMOVAL OF TEST SUBSTANCE
Washing (if done): Washing was only stated to have been done during mating and consisted of wiping the area clean with a piece of gauze.
Time after start of exposure: A minimum of 6 hours

TEST MATERIAL
Amount(s) applied (volume or weight with unit): 1 ml/kg body weight/day
Concentration (if solution): 0, 20%, 40%, or 60% - Constant volume or concentration used: yes

VEHICLE
Justification for use and choice of vehicle (if other than water): Vehicle was used to reduce skin irritation without compromising dermal absorption. Amount(s) applied (volume or weight with unit): 1 ml/kg body weight/day

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes, Elizabethan collars were used.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Details only specify that all test solutions were within +/- 5.42% of the original calculated concentration or of the nominal concentration.
Details on mating procedure:
M/F ratio per cage: 1 to 1- Length of cohabitation: Overnight- Proof of pregnancy: Vaginal plug or sperm in vaginal lavage sample referred to as day 0 of pregnancy
Duration of treatment / exposure:
Exposure period: 14 days premating to day 20 of gestation.
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
165 (20%), 330 (40%) & 494 (60%) mg/kg/day
Basis:
other: Different concentrations in solution and amount applied
No. of animals per sex per dose:
Ten
Control animals:
yes
Details on study design:
Dose selection rationale: Doses were selected based on a two-week range finding study.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: No
DETAILED CLINICAL OBSERVATIONS: Yes
Time schedule: Twice a day, but once a day on weekends and holidays
BODY WEIGHT: Yes
Time schedule for examinations: Females were weighed on the first day of dosing, weekly thereafter until mating was confirmed, then on gestational days 0, 3, 6, 10, 13, 16, and 20, on postpartum day 0 and 4, and at terminal sacrifice.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: skin irritation only

Details on maternal toxic effects:
The only signs of maternal toxicity were skin irritaaion in the highest dose level

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 494 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Remarks on result:
other: The only signs of maternal toxicity were skin irritaaion in the highest dose level

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 494 mg/kg bw/day
Basis for effect level:
other: developmental toxicity
Remarks on result:
other: no developmental effects

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

One pregnant mid-dose female died before delivery. No other animals died or were prematurely sacrificed and no clinical signs of toxicity were observed.
Skin irritation among males varied from slight to moderate with increasing dose and was most severe in the high dose group.
 Mild to moderate skin irritation was observed in females at the highest concentration.
At terminal sacrifice, no findings were reported except for those on the skin. Microscopic changes were found in the skin of males in the vehicle control and all kerosine-treated groups. In females changes were only observed in the high dose group animals. The skin findings (macroscopic and microscopic) are shown in the following table.

 

 

 Kerosine (mg/kg)

 

Parameter 

Control

Mineral oil

165

330

494

Males

 

 

 

 

 

No animals

10

10

  10

 10

 10

Max. skin irritation score, sum of means

 

 

 

 

 

Week of max severity

-

 2

 5

 5

Mean (SD)

 0

1.3(1.2)

2.4(0.7)

2.5(2.0)

3.3(2.1)

Min/max score

0

0/3

 1/3

 0/7

  1/7

Gross necropsy observations

 

 

 

 

 

Crust/scab

1

0

  0

 0

   1

Scaly/dry/flaky

0

  0

 1

   2

 3

Histopathological observations

 

 

 

 

 

Acanthosis/hyperkeratosis

 2

 5

 8

 7

 8

Hyperplasia, sebaceous glands

 3

 5

 5

 3

 5

Inflammation, dermal

 1

 6

 6

 7

Necrosis, epidermal, focal

 1

 0

 1

 1

 5

Females

 

 

 

 

 

No animals

10

6

  10

 10

 10

Max. skin irritation score, sum of means

 

 

 

 

 

Week of max severity

 6

 7

 3

 4

 4

Mean (SD)   

 0.2 (0.6)

0.7 (1.0) 

 0.4 (0.8)

 1.1 (0.9)

 2.3 (1.8)

Min/max score

0/2

0/2

 0/2

 0/2

  1/7

Gross necropsy observations

 

 

 

 

 

Crust/scab

0

1

  1

 0

   3

Scaly/dry/flaky

0

  0

 0

   0

 0

Histopathological observations

 

 

 

 

 

Acanthosis/hyperkeratosis

 3

 2

 5

 5

 6

Hyperplasia, sebaceous glands

 1

 0

 0

 0

 1

Inflammation, dermal

 0

 1

 1

 1

 4

Necrosis, epidermal, focal

 0

 0

 0

 0

 0


Body weights were unaffected by treatment. However over the course of the 8 weeks, high dose males gained less weight than the controls (201 g compared to 237g for the sham controls). Food consumption was unaffected by treatment. High dose males had a higher mean relative kidney weight than sham controls (0.76 vs 0.66).
 This was attributed to the lower mean final body weights of the high dose group. No other organ or organ/body weight changes were recorded.

Controls

Kerosine (mg/kg)

Parameter

Sham

Oil

165

330

494

No animals

10

10

10

10

10

Fertility index

100%

90%

90%

80%

100%

Litter with liveborn pups

 10

 9

 7a

 10

Corpora lutea 

 

 

 

 

 

Number

      169

151

158

122

172

Mean

16.9

16.8

17.6

17.4

17.2

(SD)

       (1.9)

(2.4)

(2.0)

(0.8)

(2.9)

Implantation sites

 

 

 

 

 

Number

      163

149

155

118

167

Mean

      16.3

16.6

17.2

16.9

16.7

(SD)

      (1.9)

(2.4)

(1.8)

(1.3)

(2.8)

Pups delivered

 

 

 

 

 

Total

      152

131

147

109

150

Mean

      15.2

14.6

16.3

15.6

15.0

(SD)

      (2.0)

(2.7)

(2.3)

(2.9)

(2.9)

Liveborn

152

130

143

108

148

Livebirth index

100%

99%

97%

99%

99%

Pups dying

 

 

 

 

 

day 0

      3

0

1

1

1

days 1-4

2

4

1

1

9bc

Pups surviving

 

 

 

 

 

4 days

       147

126

141

106

138

Viability index

97

97

99

98

93c

Pup weight/litter (g)

 

 

 

 

 

day 1 mean

6.9

6.8

7.0

7.0

6.7

day 4 mean

9.9

9.6

10.1

9.9

9.8 

a       one dam died on gestation day 21; the cause of death was unrelated to treatment
b
       significantly different from control (P<0.05)
c
       One dam had a malfunctioning water bottle; when 4 dead pups from this litter are excluded from the analysis, no
significant difference from control was found.

No test-material-related microscopic changes were observed in the testes or epididymides of adult male rats or in the ovaries of adult female rats.

Applicant's summary and conclusion

Conclusions:
Dermal application of hydrodesulphurised kerosine did not cause any developmental effects on progeny.
Executive summary:

In a reproductive/developmental toxicity screening study, ten male Sprague Dawley rats (aged approximately eight week old, weighing 275-285g) and 10 females (same age and weighing 183-187g) were treated dermally with hydrodesulfurised kerosine at concentrations of 0 (sham-treated and vehicle control groups), 20, 40 or 60% (v/v) in mineral oil in a dosing volume of 1 mL/kg. Dosage equivalents were 0, 165, 330 and 494 mg/kg/day. Test material was applied daily to the shorn skin of the animals 7 days/week beginning 14 days premating, during the 14 day mating period and through 20 days of gestation. Males were treated for an additional week. Collars were fitted to the animals during the dosing period to prevent ingestion of applied materials, but the test site was not covered. After the final dose, the collars were removed and residual test material was wiped from the skin. There were two control groups: the vehicle control was given mineral oil only and in the sham-treated group the animals had been fitted with collars and were stroked with the tip of a syringe, but no material was applied.

During the mating period the test material remained on the animal's backs for at least 6 hours. Prior to pairing, the test material was removed by wiping. Rats were mated overnight on a 1:1 ratio and were separated the following morning. Collars were then reapplied prior to the next dose being applied. Females were monitored for evidence that mating had taken place. Pregnancy was determined by the presence of a vaginal plug or sperm in a vaginal lavage sample. If observed, the female was considered to be at day 0 of gestation. Any female that did not show evidence of mating was placed with the same male the following evening. Any female that did not show evidence of mating at the end of a 2 week mating period was presumed pregnant (gestation day 0 = last day of cohabitation).

Skin irritation among males varied from slight to moderate with increasing dose and was most severe in the high-dose group. Mild to moderate skin irritation was observed in females at the highest concentration. At terminal sacrifice, no findings were reported except for those on the skin. Microscopic changes were found in the skin of males in the vehicle control and all kerosine-treated groups. In females changes were only observed in the high-dose group.

Body weights were unaffected by treatment. However over the course of the 8 weeks, high-dose males gained less weight than the controls. Food consumption was unaffected by treatment. High-dose males had a higher mean relative kidney weight than controls (0.76 vs 0.66). This was attributed to the lower mean final body weights of the high-dose group. No other organ or organ/body weight changes were recorded.

No test-material-related microscopic changes were observed in the testes or epididymides of adult male rats or in the ovaries of adult female rats.

There is no parental systemic LOAEL, based on the lack of any significant treatment-related findings except dermal irritation. The parental systemic NOAEL is greater than or equal to 494mg/kg/day.

 

There is no offspring LOAEL, based on the lack of any effects noted in the offspring. The offspring NOAEL is greater than or equal to 494 mg/kg/day.

 

This study received a Klimisch score of 1 and is classified as reliable without restrictions because it was carried out in a method equivalent/similar to OECD TG 421.

Categories Display