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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No data identified.

Additional information

Data on reproductive endpoints were derived from subchronic toxicity studies on four bright stock extracts (BSEs, a synonym for RAEs). The undiluted test materials were applied to the skin of rats, 5 days per week for 13 weeks. A summary of the studies are provided in Table 1.  The study director assigned NOAELs based on altered organ weights. The NOAEL was judged to be 500 mg/kg/day for Mobilsol 40. NOAELs could not be established for the other BSEs since only one dose level was tested (Mobil, 1990).

Some indication of the likely effect of a test substance on reproductive organs can be gained from the results of these studies. As shown in Table 1, no histopathological changes were noted in the reproductive organs of male or female rats. Further, neither epididymal spermatozoa morphology and count nor testicular spermatid counts were affected by treatment with RAEs (Mobil, 1990).

Table 1. Summaries of data on reproductive organs from subchronic studies with RAEs (CAS RN. 64742-10-5), derived from Mobil, 1990.

Test Material

Route, Species, Doses, Exposure Regimen

Endpoints

Results

Mobilsol 40

 

Dermal. Male and female rats.

0, 500, 2000 mg/kg on 5 d/wk for 13 wk.

Full necropsy. Weights of testes, prostate, epididymides, ovaries, and uterus. Histopathology of testes and ovaries. Weight of testicular parenchyma and cauda epididymis. Number of testicular sperm and number/g testis. Number and morphology of epididymal sperm, number/g cauda.

No treatment-related effect noted on reproductive organs.

BSE - Australia

Dermal. Male and female rats.

0, 2000 mg/kg on 5 d/wk for 13 wk.

Full necropsy. Weights of testes, prostate, epididymides, ovaries, and uterus. Histopathology of testes and ovaries. Weight of testicular parenchyma and cauda epididymis. Number of testicular sperm and number/g testis. Number and morphology of epididymal sperm, number/g cauda.

No treatment-related effect noted on reproductive organs.

BSE – Ninian

Dermal. Male rats.

2000 mg/kg on 5 d/wk for 13 wk.

Full necropsy. Weights of testes, prostate, and epididymides. Histopathology of testes.

No treatment-related effect noted on reproductive organs.

BSE-Statfjord

Dermal. Female rats.

2000 mg/kg on 5 d/wk for 13 wk.

Full necropsy. Weights of ovaries and uterus. Histopathology of ovaries.

No treatment-related effect noted on reproductive organs.

In addition to the reproductive endpoints, other endpoints of toxicity that were evaluated included skin irritation, body weight, haematology, serum chemistry, urine analysis, gross pathology, microscopic histopathology of ~22 organs.

Short description of key information:

Effects on reproductive performance are not expected. Nevertheless, a testing proposal is included for an extended one-generation reproductive toxicity study with a representative Residual Aromatic Extract.

Effects on developmental toxicity

Description of key information

Four key PNDT (OECD 414) studies were conducted by oral dietary administration in the rat and the rabbit. NOAELs were reported by the testing laboratory and reviewed by an independent expert.

In studies on CAS 91995 -70 -9, the maternal and developmental NOAELs were determined to be as follows:

Rat

Reported NOAEL

Review NOEL

Maternal toxicity

1164 mg/kg/day

382 mg/kg/day

Developmental toxicity

1164 mg/kg/day

1164 mg/kg/day

 

 

 

Rabbit

Reported NOAEL

Review NOAEL

Maternal toxicity

27 mg/kg/day

27 mg/kg/day

Developmental toxicity

27 mg/kg/day

65 mg/kg/day

 

In studies on CAS 64742 -10 -5), the maternal and developmental NOAELs were determined to be as follows:

Rat

Reported NOAEL

Review NOAEL/NOEL

Maternal toxicity

355 mg/kg/day

113 mg/kg/day

Developmental toxicity

1102 mg/kg/day

355 mg/kg/day

 

 

 

Rabbit

Reported NOAEL

Review NOAEL

Maternal toxicity

36 mg/kg/day

36 mg/kg/day

Developmental toxicity

No NOAEL

105 mg/kg/day

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
65 mg/kg bw/day
Species:
rabbit
Effect on developmental toxicity: via dermal route
Dose descriptor:
NOAEL
2 000 mg/kg bw/day
Additional information

Two key PNDT (OECD 414) studies were conducted by oral dietary administration in the rat.

In one study (on CAS 91995 -70 -9):

Maternal NOAEL: 4100 ppm (corresponding to an actual test item intake of 382 mg/kg/day).

Developmental NOAEL: 13000 ppm (corresponding with an actual mean test item intake of 1164 mg/kg/day).

Maternal findings:

No mortality occurred during the treatment period.

At 1000 mg/kg/day, a decrease in mean food consumption and accordingly in body weight gain was noted after start of treatment, with lower mean body weights as a result. Mean body weight gain corrected for gravid uterus weight was lower than control. However, as the reduction in body weight gain was not entirely correlated with reduced food consumption, and comparison of body weight gain with controls between gestation days 6 and 21 shows that the treated group had not reached parity with control), the NOAEL for maternal toxicity is conservatively set at the mid-dose group (382 mg/kg/day).

Developmental findings

No test item-related changes were noted in any of the developmental parameters investigated in this study (i.e. litter size, sex ratio, fetal body weights, anogenital distance, external, visceral and skeletal malformations and developmental variations).

 

In one study (on CAS 64742 -10 -5):

Maternal: 100 mg/kg/day (1350 ppm, actual intake of 113 mg/kg/day)

Developmental: 300 mg/kg/day (4100 ppm, actual intake of 355 mg/kg/day)

Maternal findings:

No mortality occurred during the treatment period.

At 1000 mg/kg/day, body weight loss was noted at the start of treatment with the test item. Mean body weight (gain) remained decreased (not always statistically significant) throughout the treatment period. Mean body weight gain corrected for gravid uterus weight was lower compared to control. Together with erected fur and hunched posture that were noted for some females, these findings were considered adverse.

At 300 mg/kg/day, erected fur was noted for some individual females, mean body weight (gain) and mean body weight gain corrected for gravid uterus weight were slightly lower compared to control. However, as the reduction in body weight gain was not entirely correlated with reduced food consumption, and comparison of body weight gain with controls between gestation days 6 and 21 shows that the treated group had not reached parity with control), the NOAEL for maternal toxicity is conservatively set at the mid-dose group (113 mg/kg/day).

Developmental findings

At 1000 mg/kg/day, lower fetal weights were observed compared to control. Fetal body weights have a small variation in general and given the magnitude of the effect (6-7%), and as mean values at 1000 mg/kg/day were below the lower limit of the historical control range, these findings were considered test item-related. It cannot be ruled out that this decrease was secondary to the observed maternal toxicity at 1000 mg/kg/day. However, as this reduction was statistically significant, the NOAEL is conservatively set at the mid-dose level (300 mg/kg/day targeted; 355 mg/kg/day actual dose).

No toxicologically relevant changes were noted in any of the remaining developmental parameters investigated in this study

 

Two key PNDT (OECD 414) studies were conducted by oral dietary administration in the rabbit.

In one study (on CAS 91995 -70 -9):

Maternal NOAEL: 900 ppm (corresponding to an actual test item intake of 27 mg/kg/day).

Developmental NOAEL: 2700 ppm (corresponding with an actual mean test item intake of 65 mg/kg/day).

Maternal NOAEL: 900 ppm (corresponding to an actual test item intake of 27 mg/kg/day), based on the mortality observed at 8000 ppm (corresponding with an actual mean test item intake of 176 mg/kg/day) and effects on body weight, food consumption and macroscopic findings on the liver at 2700 (corresponding with an actual mean test item intake of 65 mg/kg/day) and 8000 ppm.

Developmental NOAEL: 2700 ppm (corresponding with an actual mean test item intake of 65 mg/kg/day); the mean fetal weight at the lower dose was within the historical control range and not statistically significant by comparison with the control group. (A difference of 3% is usually considered within normal variation and of no toxicological relevance). There were no statistically significant differences from control for fetal body weight at 65 mg/kg/day and the difference from control was only 7% although outside of the historical control range. It is determined that there are sufficient data to conclude that the effects on the offspring (premature delivery and slightly reduced fetal body weight) are secondary to maternal toxicity.

The developmental data from the 8000 ppm group was not used directly for any conclusions as with 10 evaluable litters the minimum required number of 16 litters was not reached. However, there was sufficient information from the remaining dose groups to identify the NOAEL. Additionally, the litter data are still relevant to the understanding of the toxicity at the highest dose i.e., as to whether there was a direct effect of the test item on the offspring or if the effects were secondary to maternal toxicity.

 

In one study (on CAS 64742 -10 -5):

Maternal NOAEL: 1250 ppm (corresponding to an actual test item intake of 36 mg/kg/day).

Developmental NOAEL: 4000 ppm (corresponding with an actual mean test item intake of 105 mg/kg/day).

The maternal NOAEL was 1250 ppm (corresponding to an actual test item intake of 36 mg/kg/day), based on the observed abortions and early deliveries, effects on body weight, food consumption, macroscopic findings of the liver and increased liver weights observed at 4000 and 8000 ppm (corresponding to an actual mean test item intake of 105 and 171 mg/kg/day, respectively).

Developmental NOAEL: 4000 ppm (corresponding with an actual mean test item intake of 105 mg/kg/day); the mean fetal weights were lower than controls without reaching statistical significance. There was no dose relationship at the low and mid-dose groups. At the high dose group, reduction in fetal body weights is considered attributable to the effect on maternal body weight. There are no findings from the external, visceral or skeletal examination of the fetuses to indicate any effect of the test item on fetal development.

 

Supporting dermal developmental study

In a developmental toxicity study via dermal application, groups of 15 pregnant Sprague-Dawley rats were clipped free of hair and collared on gestation day 0 prior to treatment with Mobilsol 40 (applied once daily to the clipped and intact dorsal surface of the dams using a spatula at doses of 0, 500 or 2000 mg /kg-day until gestation day 19).

 

Pregnant rats treated with Mobilsol 40 exhibited slight skin irritation at the site of application at 500 and 2000 mg/kg-day dose levels. The study authors reported a significant lack in weight gain in animals dosed with 2000 mg/kg-day. However, they concluded that lack in weight gain was not treatment related since a similar lack in weight gain was also noted in a separate postpartum group treated with the same dose of Mobilsol 40. No evidence of developmental effects were observed during external, skeletal and visceral evaluation of rat fetuses from pregnant rats exposed to the test material. Mean fetal body weights were similar for the two dosed groups and the control group. Maternal serum chemistry of pregnant dams were marginally affected in the 2000 mg/kg-day dose. However, the study authors reported that since other indications of maternal toxicity were not present, the biological significance of serum chemistry findings were uncertain.

 

Based on these results, a NOAEL of 2000 mg/kg-day was identified for developmental toxicity by the dermal route.

Justification for classification or non-classification

There are no guideline data available for effects on reproductive performance.

 

Four key developmental toxicity studies were identified. Based on the study results, RAEs are not classified as a developmental toxicant according to the EU CLP Regulation (EC No.1272/2008).

Additional information