Benzene, C10-13-alkyl derivs.

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1992

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Principles of method if other than guideline:

Groups of 24 mated female rats were exposed to concentrations of 0, 125, 500, and 2000 mg/kg bw/day of test substance by oral gavage during days 6 - 15 of gestation. On day 20 of gestation, the animals were sacrificed and the uterine contents examined. Pups were removed by caesarean section and soft tissue and skeletal examinations performed.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Benzene, C10-16-alkyl derivs.

EC Number:

272-008-4

EC Name:

Benzene, C10-16-alkyl derivs.

Cas Number:

68648-87-3

IUPAC Name:

tridecylbenzene

Details on test material:

- Composition of test material, percentage of components: <1% C9, 16% C10, 43% C11, 40% C12, 1% C13, <1% C14; avg C11.26
- Analytical purity: 98.5

Test animals

Species:

rat

Strain:

Sprague-Dawley

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: 7 nights, if female was still not pregnant, she was moved to another male for an additional 7 nights, and then to a third male if needed
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged individually

Duration of treatment / exposure:

Days 6 - 15 of gestation

Frequency of treatment:

Daily

Duration of test:

Section on 20th of gestation

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

125 mg/kg bw/day (actual dose received)

Remarks:

Group 2, low dose

Doses / concentrations 2

Dose / conc.:

500 mg/kg bw/day (actual dose received)

Remarks:

Group 3, mid dose

Doses / concentrations 3

Dose / conc.:

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

Remarks:

Group 4, high dose

No. of animals per sex per dose:

24 mated females rats/dose and control groups

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 6, 10, 12, 15, and 20 of gestation

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: complete post-mortem examination

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: number of live and dead fetuses, sex of fetuses

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter

Statistics:

Nair, RS, Auletta, CS, Schroeder, RE, and Johannsen, FR (1990). Chronic toxicity, oncogenic potential, and reproductive toxicity of p-nitroaniline in rats. Fundam. Appl. Toxicol. 15, 607 - 621.

Indices:

Incidence of fetuses and litters with malformations and resorption sites

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

not specified

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weight gains were significantly decreased since the 10th day of gestation in the 2000 mg/kg bw/d group (p <= 0.01) and from the 12th to 15th day of gestation in the 500 mg/kg bw/d group; compensatory increases of weight gains occurred in the posttreatment period in these groups;

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food consumption was significantly reduced during treatment (p ≤ 0.01) and significantly increased after treatment in the 500 mg/kg bw/d (p ≤ 0.005) and 2000 mg/kg bw/d groups (p 0= 0.01).

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Maternal developmental toxicity

Number of abortions:

not examined

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

not examined

Changes in number of pregnant:

no effects observed

Effect levels (maternal animals)

1

Key result

Dose descriptor:

NOAEL

Remarks:

maternal toxicity

Effect level:

125 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

body weight and weight gain

2

Dose descriptor:

LOAEL

Effect level:

500 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

body weight and weight gain

Maternal abnormalities

Key result

Abnormalities:

no effects observed

Results (fetuses)

Fetal body weight changes:

not examined

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

not examined

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

The incidence of fetuses with at least one ossification variation was significantly increased in the 2000 mg/kg/ bw/d group (p 0.05). Main variations were incomplete ossification of several cranial bones and vertebral elements and in addition in the 500 mg/kg bw/d group the incidence of rudimentary rib structures; a significant decrease of those variations in the 125 mg/kg bw/d group was not considered treatment related (p ≤0.05).

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

No treatment related increases in soft tissue malformations and variations were found.

Effect levels (fetuses)

Key result

Dose descriptor:

NOAEL

Effect level:

125 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Incomplete ossification of several cranial bones and vertebral elements and in addition in the 500 mg/kg bw/d group the incidence of rudimentary rib structures;

Fetal abnormalities

Key result

Abnormalities:

effects observed, treatment-related

Localisation:

other: see description

Description (incidence and severity):

The incidence of fetuses with at least one ossification variation was significantly increased in the 2000 mg/kg/ bw/d group (p 0.05): main variations were incomplete ossification of several cranial bones and vertebral elements and in addition in the 500 mg/kg bw/d group the incidence of rudimentary rib structures; a significant decrease of those variations in the 125 mg/kg bw/d group was not considered treatment related (p ≤0.05). the incidence of fetuses with at least one ossification variation was significantly increased in the 2000 mg/kg/ bw/d group (p 0.05): main variations were incomplete ossification of several cranial bones and vertebral elements and in addition in the 500 mg/kg bw/d group the incidence of rudimentary rib structures; a significant decrease of those variations in the 125 mg/kg bw/d group was not considered treatment related (p ≤0.05).

Overall developmental toxicity

Key result

Developmental effects observed:

yes

Lowest effective dose / conc.:

500 mg/kg bw/day (actual dose received)

Treatment related:

yes

Relation to maternal toxicity:

developmental effects as a secondary non-specific consequence of maternal toxicity effects

Dose response relationship:

yes

Relevant for humans:

yes

Any other information on results incl. tables

Table 1: Incidence of Fetal Skeletal Alterations

Dose (mg/kg/day)	0	125	500	2000
Rudimentary ribs	20 (14)	15 (10)	48 (18)	52 (20)
Total fetuses (litters) with variations	82 (21)	54 (22)	82 (23)	106 (22)
% fetuses (litters) with variations	57.3 (91.3)	41.9 (95.7)	57.2 (100)	79.7 (100)

Applicant's summary and conclusion

Conclusions:

Since no embryotoxicity was seen at doses that were not toxic to the maternal animals, the test substance is not classified as teratogenic.

Executive summary:

This OECD 414 study in compleance with GLP examined the potential developmental toxicity of the test substance. Groups of 24 mated female rats were exposed to concentrations of 0, 125, 500, and 2000 mg/kg bw/day of test substance by oral gavage during days 6 - 15 of gestation. On day 20 of gestation, the animals were sacrificed and the uterine contents examined. Pups were removed by caesarean section and soft tissue and skeletal examinations performed. The LOAEL for maternal toxicity was 500 mg/kg bw/day based on reduced body weight gain. The NOAEL for maternal toxicity was 125 mg/kg bw/day. The LOAEL for embryotoxicity was also 500 mg/kg bw/day based on increased incidence of incomplete ossification. The NOAEL for embryotoxicity was also 125 mg/kg bw/day. Since embryotoxicity was seen at doses that were toxic to the maternal animals, the test substance is not classified as teratogenic.