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Description of key information

Two key studies for read-across source substances of Benzene, C15-16-alkyl derivs. have been conducted that provide information on repeated dose toxicity.  At very high daily dietary doses to the test substance, rats exhibited reduced food consumption and body weight gains beginning at the lowest dose of 2500 ppm .  No other effects or abnormalities were observed.  In rats exposed to daily oral gavage doses ranging from 5 to 500 mg/kg bw/day of LAB through two generations, no adverse effects were observed except for reductions in body weight gain at the highest dose.  Therefore it is clear that the primary effect of the test substance at high daily doses is reduced body weight gain, probably as a function of the poor palatability of the test substance.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP study published in peer-reviewed journal.
Qualifier:
according to guideline
Guideline:
other: OECD 416 2-generation reproductive study
GLP compliance:
yes
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 (e.g. ad libitum): Ralson Purina commercial laboratory feed, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 65-79
- Humidity (%): 17-76
- Photoperiod (hrs dark / hrs light): 12 hrs light/12 hrs dark
Route of administration:
oral: gavage
Vehicle:
corn oil
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.
Remarks:
Doses / Concentrations:
0, 5, 50 and 500 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
30 animals of each sex per dose
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
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
Sacrifice and pathology:
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
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
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No mortality attributed to treatment was observed.


BODY WEIGHT AND FOOD CONSUMPTION
Mean body weights of high-dose-group (500 mg/kg bw/d) males were significantly and consistently reduced {12 = 0.01) in the FO (since premating week); mean body weights of high-dose females were significantly decreased in the FO 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


GROSS PATHOLOGY (PARENTAL ANIMALS)
No gross postmortem findings.

HISTOPATHOLOGY (PARENTAL ANIMALS)
No histopathological findings.

Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw (total dose)
Sex:
male/female
Basis for effect level:
other: reduced weight gain in the high dose group
Dose descriptor:
LOAEL
Effect level:
500 mg/kg bw (total dose)
Sex:
male/female
Basis for effect level:
other: reduced weight gain
Critical effects observed:
not specified
Conclusions:
The NOAEL was 50 mg/kg bw/day in both male and female rats.
Executive summary:

In cases where no data were available on the target substance, Benzene, C15 -16 -alkyl derivs., data were read across from a structurally related material (the test substance).

This study examined the effects of repeated exposure to the test substance. 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. Males were exposed for a total of 105 days, and females 127 days. All animals were sacrificed and necropsied after exposure. During the study, animals were observed for clinical signs, mortality, and body weight. The NOAEL was 50 mg/kg/day and the LOAEL was 500 mg/kg/day based on reduced weight gain in the high dose group.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In cases where no data were available on the target substance, Benzene, C15-16-alkyl derivs., data were read across from a structurally related material (the test substance).

Two key studies for read-across source substances of Benzene, C15 -16 -alkyl derivs. have been conducted that provide information on the repeated dose toxicity of LAB. At very high daily dietary doses to LAB, rats exhibited reduced food consumption and body weight gains beginning at the lowest dose of 2500 ppm . No other effects or abnormalities were observed. In rats exposed to daily oral gavage doses ranging from 5 to 500 mg/kg bw/day of LAB through two generations, no adverse effects were observed except for reductions in body weight gain at the highest dose. Therefore it is clear that the primary effect of LAB at high daily doses is reduced body weight gain, probably as a function of the poor palatability of the test substance.

Two key studies are available to document the potential effects from repeated exposures to a read-across source substance for Benzene, C15 -16 -alkyl derivs. The first key study (Monsanto 1997) examined the effects of dietary exposure of rats to the test substance. Groups of rats were given daily diets containing 0, 2500, 5000, 7500, or 20000 ppm test substance (corresponding to 0, 125, 250, 375, 1000 mg/kg bw/day) for 28 days. Animals were observed for food consumption and body weight changes. At the end of the study, the animals were sacrificed and examined for gross pathology. Histopathology was not carried out. Reduced food consumption and body weight gain was noted at all dose levels. No abnormalities were seen in the gross pathology examinations. Since there were effects at the lowest dose tested (2500 ppm, which corresponds to 125 mg/kg bw), the LOAEL was 125 mg/kg/day (NOAEL <125 mg/kd/day).

In the second key study (Robinson and Schroeder 1992), groups of 30 female and 30 male rats were exposed to concentrations of 0, 5, 50 and 500 mg/kg bw/day of test substance by oral gavage beginning ten weeks before mating. Animals were then mated and 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. Males were exposed for a total of 105 days, and females 127 days. All animals were sacrificed and necropsied after exposure. During the study, animals were observed for clinical signs, mortality, and body weight. No effects were observed in mortality, clinical signs, food consumption, histopathology, or other parameters, with the exception of body weight gain. Mean body weights of males in the high dose group (500 mg/kg bw/d) were significant and consistently reduced in F0 group (since premating week). Mean body weights of high dose females were significantly decreased in the F0 generation beginning in the 9th week of premating until the first week of lactation. Body weight reduction was significant on day 20 of gestation in both generations. Therefore, the NOAEL was 50 mg/kg/day and the LOAEL was 500 mg/kg/day based on reduced weight gain in the high dose group.

Justification for classification or non-classification