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Diss Factsheets

Administrative data

Endpoint:
two-generation reproductive 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 416 (Two-Generation Reproduction Toxicity Study)
Version / remarks:
EPA/TSCA
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Alkylate 215
IUPAC Name:
Alkylate 215
Constituent 2
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
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Housing: wire mesh cages
- Diet: Ralson Purina commercial laboratory feed, ad libitum
- Water: tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 65 - 79
- Humidity (%): 17 - 76
- Photoperiod (hrs dark / hrs light): 12

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
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Daily
Frequency of treatment:
F0: Treatment was started 10 weeks before mating. For males, dosing continued for 2 weeks after mating (total of 105 days). For females, dosing continued through lactation for a total of 127 treatment days.

F1: The F1 generation was treated similarly to the F0 generation, but were exposed beginning 11 weeks pre-mating.
Doses / concentrationsopen allclose all
Dose / conc.:
5 mg/kg bw/day (actual dose received)
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
30
Control animals:
yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: males - weekly, females - weekly before mating, days 0, 7, 14, and 20 of gestation, and days 0, 4, 14, and 21 of lactation

FOOD CONSUMPTION: weekly

Litter observations:
STANDARDISATION OF LITTERS
- F1 pups were selected for mating at weaning, at least one pup per litter was selected for the adult F1 generation

PARAMETERS EXAMINED
The following parameters were examined in F1 and F2 offspring:
- number and sex of pups on days 0, 4, 7, 14, and 21 of lactation,
- postnatal mortality
- presence of gross anomalies daily, weights on days 0, 4, 7, 14, and 21 of lactation

GROSS EXAMINATION OF DEAD PUPS:
yes
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals 2 weeks after mating.
- Maternal animals: All surviving animals at weaning.

GROSS NECROPSY
- Gross necropsy consisted of examination for gross lesions

HISTOPATHOLOGY / ORGAN WEIGHTS
pituitary glands, testes and epididymides, prostate and seminal vesicles, vagina, uterus, ovaries, and gross lesions
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at weaning.
- These animals were subjected to postmortem examinations similar to parental animals above.
Reproductive indices:
Mating index, pregnancy rate, fertility index
Offspring viability indices:
Pup survival

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
No mortality attributed to treatment was observed.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean body weights of high-dose-group (500 mg/kg bw/d) males were significantly and consistently reduced (12 = 0.01) in the F0 (since premating week); mean body weights of high-dose females were significantly decreased in the F0 generation since the 9th week of premating until the first week of lactation (p = 0.05); body weight reduction was significant on day 20 of gestation in both generations (p = 0.01)
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
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
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No histopathological findings.
Histopathological findings: neoplastic:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
Mating, pregnancy and fertility rates were not influenced.

Effect levels (P0)

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
reproductive performance
Effect level:
>= 500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: no effect of reproductive performance was observed
Key result
Dose descriptor:
NOEL
Remarks:
systemic toxicity
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
other: Litter size
Dose descriptor:
LOAEL
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
other: Litter size

Target system / organ toxicity (P0)

Key result
Critical effects observed:
no

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
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:
no effects observed
Other effects:
effects observed, treatment-related
Description (incidence and severity):
OTHER FINDINGS (OFFSPRING)
In the high-dose-group, gestation length was significantly increased for the F2 litter interval (22.4 d compared to 22.0 in controls).

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined

Effect levels (P1)

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
reproductive performance
Effect level:
>= 500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: no effect of reproductive performance was observed
Key result
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: gestation length

Target system / organ toxicity (P1)

Key result
Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
Litter size F1: significant decrease at 500 mg/kg bw/d (p = 0.05 and 0.01 respectively).
Pup viability index at birth F1: significant decrease at 50 and 500 mg/kg bd/d (p = 0.05); survival of pups at day 4 was significantly decreased at 500 mg/kg bw/d in the F1 litters.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean pup weight F1 litters; significant reduction at 50 and 500 mg/kg bw/d at day 7 and only at 500 mg/kg bw/d at day 14 and 21 (p = 0.05), since the reduction in the 50 mg/kg bw/d group was only noted at day 7 and only in the F1 generation, this effect was not considered biologically significant
Food consumption and compound intake (if feeding study):
not examined
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:
no effects observed
Urinalysis findings:
not examined
Sexual maturation:
not examined
Anogenital distance (AGD):
not examined
Nipple retention in male pups:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Effect levels (F1)

open allclose all
Key result
Dose descriptor:
NOEL
Remarks:
developmental toxicity
Generation:
F1
Effect level:
5 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
body weight and weight gain
Dose descriptor:
LOAEL
Generation:
F1
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
body weight and weight gain

Target system / organ toxicity (F1)

Key result
Critical effects observed:
no

Results: F2 generation

General toxicity (F2)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
Litter size F2: significant decrease at 500 mg/kg bw/d (p = 0.05 and 0.01 respectively).
Pup viability index at birth F2: significant decrease at 500 mg/kg bw/d (p = 0.05), since effects at 50 mg/kg bw/d was only noted in a single generation, these effects were not considered biologically significant; survival of pups at day 4 was significantly decreased at 500 mg/kg bw/d in F2 litters; survival of pups at day 21 (related to day 4) was significantly decreased only in the F2 litter at 50 mg/kg bw/d (p = 0.05), since effects at 50 mg/kg bw/d was only noted in a single generation, these effects were not considered biologically significant
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean pup weight F2 litters: significant reduction at 500 mg/kg bw/d at day 14 and 21 (p = 0.05).
Food consumption and compound intake (if feeding study):
not examined
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
Sexual maturation:
not examined
Anogenital distance (AGD):
not examined
Nipple retention in male pups:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not specified

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not examined

Effect levels (F2)

Key result
Dose descriptor:
NOEL
Remarks:
developmental toxicity
Generation:
F2
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Sex:
not specified
Basis for effect level:
viability
body weight and weight gain

Target system / organ toxicity (F2)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Any other information on results incl. tables

Table 1: Litter Size and Pup Survival Indices

Dose (mg/kg/day)

Litter size (mean)

Pup viability index at birth (%)

Pup survival days 0 - 4 (%)

Pup survival days 0 - 4 (%)1

Pup survival days 4 - 21 (%)

F1 litters

0

12.7

99.1

93.8

95.7

5

12.8

98.0

93.4

91.0

50

13.1

95.4

92.3

84.2

500

10.0

95.4

85.0

94.7

F2 litters

0

11.3

98.6

80.2

93.5

98.1

5

11.6

98.2

87.3

94.4

97.1

50

13.1

97.3

89.5

92.3

89.1

500

7.0

89.0

84.1

85.9

97.3

1Excludes data for litters in which all pups died during the Day 0 - 3 interval.

Table 2: Mean Pup Weights (g)

Dose (mg/kg/day)

Day 0

Day

4 - Precull

Day

4 - Postcull

Day

7

Day 14

Day

21

F1 litters

0

6.0

8.4

8.4

13.2

27.0

42.7

5

5.9

8.1

8.1

12.9

27.3

42.1

50

5.8

7.5

7.6

11.4

25.1

39.6

500

5.8

8.1

8.1

11.4

23.5

37.7

F2 litters

0

5.8

8.1

8.3

13.9

27.0

40.5

5

5.8

8.5

8.5

14.4

26.9

42.0

50

6.0

8.1

8.1

13.4

25.3

39.5

500

5.8

8.1

8.1

12.1

22.3

34.6

Applicant's summary and conclusion

Conclusions:
The NOEL for the maternal and paternal generation was 50 mg/kg bw/day and for the offspring generations. No effects on fertility were observed.
Executive summary:

This study in accordance with OECD 416 and in compliance with GLP the effects of exposure to the test substance on reproduction were examined. Groups of 30 female and 30 male rats were exposed to concentrations of 0, 5, 50 and 500 mg/kg day of test substance by oral gavage beginning ten weeks before mating. Animals were then mated. The resulting generation was also exposed to the test substance and mated. Exposure continued through the mating period, and in females through the gestation and lactational periods. All animals were sacrificed and necropsied after exposure. Pups not used for mating were sacrificed at weaning. During the study, animals were observed for clinical signs, mortality, and body weight. Pups were examined for viability and body weight gain. Reproductive indices were also calculated. The NOAEL for parental toxicity was 50 mg/kg/day and the LOAEL was 500 mg/kg/day based on reduced weight gain and litter size in the high dose group. The NOAEL for offspring was 50 mg/kg/day based on reduced body weight gain and survival in the high and mid-dose groups. The LOAEL for offspring was 50 mg/kg/day. No effects on fertility were observed.